PubAnnotation

Id	Subject	Object	Predicate	Lexical cue
T1	0-115	Sentence	denotes	Autophagy Augmentation to Alleviate Immune Response Dysfunction, and Resolve Respiratory and COVID-19 Exacerbations
T2	117-125	Sentence	denotes	Abstract
T3	126-317	Sentence	denotes	The preservation of cellular homeostasis requires the synthesis of new proteins (proteostasis) and organelles, and the effective removal of misfolded or impaired proteins and cellular debris.
T4	318-453	Sentence	denotes	This cellular homeostasis involves two key proteostasis mechanisms, the ubiquitin proteasome system and the autophagy–lysosome pathway.
T5	454-808	Sentence	denotes	These catabolic pathways have been known to be involved in respiratory exacerbations and the pathogenesis of various lung diseases, such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and coronavirus disease-2019 (COVID-19).
T6	809-1165	Sentence	denotes	Briefly, proteostasis and autophagy processes are known to decline over time with age, cigarette or biomass smoke exposure, and/or influenced by underlying genetic factors, resulting in the accumulation of misfolded proteins and cellular debris, elevating apoptosis and cellular senescence, and initiating the pathogenesis of acute or chronic lung disease.
T7	1166-1448	Sentence	denotes	Moreover, autophagic dysfunction results in an impaired microbial clearance, post-bacterial and/or viral infection(s) which contribute to the initiation of acute and recurrent respiratory exacerbations as well as the progression of chronic obstructive and restrictive lung diseases.
T8	1449-1621	Sentence	denotes	In addition, the autophagic dysfunction-mediated cystic fibrosis transmembrane conductance regulator (CFTR) immune response impairment further exacerbates the lung disease.
T9	1622-1884	Sentence	denotes	Recent studies demonstrate the therapeutic potential of novel autophagy augmentation strategies, in alleviating the pathogenesis of chronic obstructive or restrictive lung diseases and exacerbations such as those commonly seen in COPD, CF, ALI/ARDS and COVID-19.
T10	1886-1888	Sentence	denotes	1.
T11	1889-1901	Sentence	denotes	Introduction
T12	1902-2201	Sentence	denotes	Chronic obstructive and restrictive lung diseases are among the leading causes of mortality worldwide, where acute or recurrent episodes of respiratory exacerbations are not only responsible for significant health care costs and a poor quality of life, but also an increased risk of death [1,2,3,4].
T13	2202-2399	Sentence	denotes	The airway mucosa is a primary route of entry for pathogenic microorganisms (bacteria, virus and/or fungi) and represents an important barrier in preventing the entry of these infectious organisms.
T14	2400-2839	Sentence	denotes	In the event that the pathogen evades this mucociliary defense mechanism, the airway epithelial cells utilize complex pathogen clearance mechanisms to restrict the life-threatening exacerbations, where these cells work in collaboration with our immune system, involving both innate and adaptive responses, to launch a robust immune response against the invading pathogens, which if successful, results in pathogen elimination or clearance.
T15	2840-3152	Sentence	denotes	Thus, providing proof-of-concept evidence in support of autophagy augmentation strategies for alleviating respiratory exacerbations in chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and coronavirus disease-2019 (COVID-19).
T16	3153-3406	Sentence	denotes	A plethora of studies have identified the “autophagy-lysosome pathway”, a major cellular degradation system, as one of the important mechanisms involved in regulating the immune-mediated pathogen clearance mechanisms in several infection models [5,6,7].
T17	3407-3566	Sentence	denotes	Evidence suggests that a specific form of autophagy, called “xenophagy”, is responsible for the elimination of bacterial, viral or fungal pathogens [7,8,9,10].
T18	3567-3881	Sentence	denotes	In general, autophagy (mainly macroautophagy) is one of the two components of the cellular homeostatic machinery called the “proteostasis network (PN)” [11,12,13,14], which could be termed as the “master regulator of cellular well-being”, as it regulates all the processes involved in protein turnover in the cell.
T19	3882-4217	Sentence	denotes	The other component of the PN is the ubiquitin-proteasome system (UPS), which deals primarily with the degradation of cellular proteins [15,16,17,18,19] which allows protein turnover and a replacement of misfolded proteins, as well as the regulation of vital regulatory proteins involved in a variety of cellular homeostatic processes.
T20	4218-4448	Sentence	denotes	In contrast, the autophagy-lysosome pathway can handle the degradation of much broader and larger cargo, such as protein aggregates, lipids, damaged organelles, or infectious agents such as bacteria and viruses [9,20,21,22,23,24].
T21	4449-4701	Sentence	denotes	These two components of the PN play a vital role in maintaining cellular homeostasis by facilitating the removal of these dysfunctional cellular components while maintaining or replenishing the levels of proteins, lipids, etc., via synthetic machinery.
T22	4702-4889	Sentence	denotes	Other proteostatic mechanisms include the unfolded protein response (UPR), small ubiquitin-like modifier (SUMO), and the endoplasmic reticulum (ER)-associated degradation (ERAD) pathways.
T23	4890-5099	Sentence	denotes	Both SUMO and ERAD have a role in the trafficking of the misfolded cystic fibrosis transmembrane conductance regulator (CFTR), which is the dysfunctional protein responsible for the pathogenesis of CF [25,26].
T24	5100-5273	Sentence	denotes	Furthermore, the dysregulation of UPR has been shown to lead to an exaggerated inflammatory response that plays a role in CF pathogenesis progression and exacerbations [27].
T25	5274-5540	Sentence	denotes	Therefore, it is evident that any dysregulation of the PN components leads to severe life-threatening diseases that includes proteinopathies, neurodegenerative diseases, age-related disorders, and chronic respiratory diseases such as CF and COPD [11,13,15,28,29,30].
T26	5541-5745	Sentence	denotes	Respiratory infections serve as a trigger for disease exacerbation, while exposure to tobacco, biomass smoke, and aging, are the leading causes for COPD-emphysema development and progression [4,31,32,33].
T27	5746-6073	Sentence	denotes	We and others have demonstrated that autophagy impairment is the key central mechanism for tobacco, biomass smoke or e-cigarette vapor (eCV) exposure and the age-related induction of inflammatory-oxidative stress, alveolar apoptosis and senescence, leading to COPD-emphysema pathogenesis and progression [33,34,35,36,37,38,39].
T28	6074-6278	Sentence	denotes	Additionally, the above-described causative mechanisms also hamper the pathogen clearance, and thus make the individual more prone to acute or recurrent respiratory infections or exacerbations [35,39,40].
T29	6279-6538	Sentence	denotes	Mechanistically, cigarette smoke (CS)-induced phagocytosis defects involves autophagy impairment, which blunts the clearance and promotes the survival of disease-causing pathogens, thereby facilitating chronic infections or recurrent exacerbations [34,35,36].
T30	6539-6778	Sentence	denotes	In addition, we recently demonstrated that exposure to CS and other noxious environmental agents promotes accelerated lung aging, which is another important factor contributing to increased infections in chronic lung disease subjects [33].
T31	6779-6893	Sentence	denotes	In fact, aging per se is responsible for an increased risk of pulmonary infections due to the decline of immunity.
T32	6894-7131	Sentence	denotes	Notably, the PN and autophagy are known to decrease over time with age, and therefore, serve a crucial role in determining the increased risk of lung infections in the elderly, by virtue of hampered pathogen clearance mechanisms [13,41].
T33	7132-7342	Sentence	denotes	Therefore, several studies, including our recent reports, demonstrate the therapeutic potential of novel autophagy augmentation strategies for controlling COPD-emphysema pathogenesis and progression [22,42,43].
T34	7343-7638	Sentence	denotes	Autophagy plays a crucial role in the elimination of pathogens, and the pharmacological disruption of autophagy has been shown to impair host defense against Pseudomonas aeruginosa (P. aeruginosa), while the induction of autophagy facilitates P. aeruginosa clearance from murine lungs [5,44,45].
T35	7639-7836	Sentence	denotes	Additionally, autophagy-related 7 (ATG7)-dependent autophagy is reported to have a significant role in murine host resistance to Klebsiella pneumoniae, an important respiratory track pathogen [46].
T36	7837-8078	Sentence	denotes	Similarly, during a pulmonary infection with Chlamydia pneumoniae in mice, autophagy restricts inflammasome activation, while mice deficient in autophagy demonstrate an increased mortality, highlighting the protective role of autophagy [47].
T37	8079-8159	Sentence	denotes	Immunity against viral infections in the airways is also regulated by autophagy.
T38	8160-8308	Sentence	denotes	For example, autophagy deficiency promotes interleukin (IL)-17-mediated lung pathology in mice infected with respiratory syncytial virus (RSV) [48].
T39	8309-8455	Sentence	denotes	Furthermore, a recent study demonstrates that IL-22 inhibits RSV production by blocking the virus-mediated suppression of cellular autophagy [49].
T40	8456-8754	Sentence	denotes	Moreover, recent studies on Middle East respiratory syndrome (MERS) coronavirus [50] provide proof-of-concept evidence on the therapeutic potential of autophagy modulating drugs for combating the SARS-COV2 infection, cytokine storm, and pathogenesis of severe ARDS-like COVID-19 fatal lung disease.
T41	8755-8913	Sentence	denotes	Another elaborately studied example where autophagy regulates inflammatory-oxidative stress, inflammation, and infection-mediated disease exacerbations is CF.
T42	8914-9298	Sentence	denotes	CF is a genetic disorder, wherein the ΔF508-CFTR is the most common mutation leading to lack of membrane-resident functional CFTR, where the absence of the functional CFTR on the plasma membrane (PM) deteriorates the pathogen clearance ability in CF subjects, leading to persistent infections and chronic inflammation, culminating into a catastrophic lung function decline [51,52,53].
T43	9299-9570	Sentence	denotes	Studies in CF cell lines and knockout mice suggest that the absence of CFTR by itself is sufficient to promote a pro-inflammatory milieu, at least in part, by the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) signaling [54,55,56,57].
T44	9571-9745	Sentence	denotes	Moreover, a transient transfection of wild type (WT)-CFTR reduced tumor necrosis factor α (TNFα)-mediated NFκB activation, confirming the anti-inflammatory role of CFTR [55].
T45	9746-9911	Sentence	denotes	Furthermore, a P. aeruginosa infection in CF mice leads to a more pronounced NFκB-mediated inflammatory response and pathogenesis of CF-related lung disease [51,58].
T46	9912-10092	Sentence	denotes	Thus, membrane-resident functional CFTR is demonstrated to be a critical regulator of innate and adaptive immune responses, in addition to its classical role as an ion transporter.
T47	10093-10344	Sentence	denotes	A recent comprehensive article summarizes the role of dysfunctional CFTR in the controlling cellular signaling pathways used by innate immune cells for combating infections such as airway epithelial cells, neutrophils, monocytes, and macrophages [59].
T48	10345-10560	Sentence	denotes	Additionally, we and others have shown a clear role of membrane-CFTR in regulating the function of adaptive immune cells, such as CD3+ T cells, CD4+ T cells, CD4+FoxP3+ regulatory T cells (T regs), and B cells [59].
T49	10561-10849	Sentence	denotes	A recent intriguing study found that CFTR dysfunction in platelets leads to aberrant transient receptor potential cation channel subfamily C member 6 (TRPC6)-dependent platelet activation, which was proposed as a major driver of CF-lung inflammation and impaired bacterial clearance [60].
T50	10850-11016	Sentence	denotes	Thus, autophagy plays a vital role in limiting lung infections, and it is evident that a complete or partial absence of functional CFTR leads to autophagy impairment.
T51	11017-11239	Sentence	denotes	Mechanistically, CFTR loss or dysfunction results in the reactive oxygen species (ROS)-mediated activation of transglutaminase-2 (TGM-2), and inactivation of the Beclin-1 complex, thereby causing autophagy impairment [61].
T52	11240-11477	Sentence	denotes	Apart from the genetic loss or dysfunction of CFTR, exposure to CS also leads to decreased CFTR activity and expression in vitro, in animal models and in smokers with or without COPD, primarily via ROS-dependent mechanisms [22,42,62,63].
T53	11478-11672	Sentence	denotes	This acquired CFTR dysfunction results in increased inflammatory-oxidative stress, apoptosis, cellular senescence, defective autophagy, and impaired mucociliary clearance, all hallmarks of COPD.
T54	11673-11988	Sentence	denotes	To summarize, we and others have demonstrated that autophagy augmentation has the potential to not only control CFTR dysfunction-mediated pathologies in CF and COPD, but also allows the clearance of opportunistic infections while balancing immune regulation to avoid recurrent exacerbations and disease progression.
T55	11989-12128	Sentence	denotes	This provides a potential to tailor autophagy augmentation for acute and respiratory exacerbations in CF, COPD, ALI/ARDS and COVID-19, etc.
T56	12129-12378	Sentence	denotes	Hence, we focus here on the role of autophagy in pulmonary infections and immune dysfunction, where the therapeutic potential of novel autophagy augmenting strategies to alleviate lung disease pathogenesis and respiratory exacerbations is discussed.
T57	12380-12382	Sentence	denotes	2.
T58	12383-12428	Sentence	denotes	Autophagy, Respiratory Infection and Immunity
T59	12429-12602	Sentence	denotes	Autophagy is the proteostatic process that helps maintain healthy cellular homeostasis by degrading dysfunctional cellular components, lipids, misfolded proteins, etc. [64].
T60	12603-12749	Sentence	denotes	In addition to processing dysfunctional cellular components, autophagy also plays a critical role in immunity and the clearance of pathogens [64].
T61	12750-12994	Sentence	denotes	When working at optimal levels, the autophagy pathway can clear cells of infections via xenophagy, participate in innate and adaptive immune responses, activate macrophages, and remove damaged mitochondria via mitophagy [8,9,20,61,64,65,66,67].
T62	12995-13213	Sentence	denotes	In the respiratory tract specifically, autophagy has even been shown to dictate the length of cilia in the mucociliary escalator that is responsible for the mechanical clearing of pathogens from the airways [68,69,70].
T63	13214-13317	Sentence	denotes	However, the dysfunction and inhibition of autophagy can lead to the pathogenesis of various illnesses.
T64	13318-13423	Sentence	denotes	When it comes to respiratory bacterial infections, autophagy is necessary for a complete immune response.
T65	13424-13523	Sentence	denotes	Mycobacterium tuberculosis (M. tuberculosis) is an intercellular pathogen that causes tuberculosis.
T66	13524-13694	Sentence	denotes	M. tuberculosis evades the body’s immune response by forming granulomas and blocks phagolysosome trafficking to inhibit the intracellular killing of pathogens [71,72,73].
T67	13695-13982	Sentence	denotes	Recently, studies have demonstrated the importance of functional autophagy in targeting and killing M. tuberculosis in respiratory cells by showing that the induction of autophagy pathways overcomes the inhibition of phagolysosome formation to effectively kill M. tuberculosis [6,74,75].
T68	13983-14236	Sentence	denotes	In the case of Streptococcus pneumoniae (S. pneumoniae), which is the most common pathogen causing community acquired pneumonia [76], studies have demonstrated that infection activates the autophagy pathway as part of the body’s immune response [77,78].
T69	14237-14507	Sentence	denotes	Recently, it has been shown that this induction of autophagy makes the clearance of S. pneumoniae infection more effective by enhancing the rate of phagocytosis by neutrophils [78], demonstrating that autophagy is necessary for an effective immune response in pneumonia.
T70	14508-14734	Sentence	denotes	Studies have also exhibited the activation of autophagy in alveolar macrophages by Pseudomonas aeruginosa (P. aeruginosa) [5,79] and Klebsiella pneumoniae [46,79] to induce the degradation of these pathogens in phagolysosomes.
T71	14735-14901	Sentence	denotes	Moreover, there has been evidence that autophagy is activated by lipopolysaccharide (LPS), which is a bacterial toxin on the outer membrane of Gram-negative bacteria.
T72	14902-15074	Sentence	denotes	Typically, LPS can cause inflammation that leads to lung injury [80,81]; however, the activation of autophagy in response to LPS was shown to attenuate lung injury [82,83].
T73	15075-15300	Sentence	denotes	Autophagy is not only integral to the immune response to bacterial infections within the respiratory system, but it has been demonstrated to play an important role in the response to viral pathogens as well [8,9,20,65,84,85].
T74	15301-15457	Sentence	denotes	In the case of the influenza virus, studies have demonstrated autophagy is similarly induced to attenuate the virus and limit its replication [84,85,86,87].
T75	15458-15671	Sentence	denotes	Autophagy has also been shown to be essential in the activation of dendritic cells to produce cytokines and mount an immune response to respiratory synovial virus (RSV) [88,89], MERS [50] and SARS-CoV2 [90,91,92].
T76	15672-15818	Sentence	denotes	Therefore, autophagy is an essential part of the immune response against bacterial and viral pathogens attempting to invade the respiratory tract.
T77	15820-15822	Sentence	denotes	3.
T78	15823-15858	Sentence	denotes	Mechanisms of Autophagy Dysfunction
T79	15859-16006	Sentence	denotes	Despite the importance of autophagy, there are many conditions where this process can become dysfunctional, leading to various pathological states.
T80	16007-16147	Sentence	denotes	In the lungs, the major sources of autophagy dysfunction includes first- and second-hand cigarette smoke (CS) exposure and aging [35,62,93].
T81	16148-16291	Sentence	denotes	Studies have demonstrated that CS exposure can decrease the expression of transcription factor-EB (TFEB), a master autophagy regulator [34,35].
T82	16292-16456	Sentence	denotes	This occurs by the dysfunctional processing of TFEB in response to CS, causing the perinuclear localization of TFEB which prevents the activation of autophagy [62].
T83	16457-16554	Sentence	denotes	This CS-induced autophagy impairment of TFEB leads to impaired bacterial clearance [22,33,34,35].
T84	16555-16756	Sentence	denotes	Furthermore, there is evidence that CS exposure increases the accumulation of ubiquitinated proteins and p62 (a marker of autophagy impairment) in aggresome bodies, further impairing autophagy [22,34].
T85	16757-16957	Sentence	denotes	These deleterious effects of CS exposure on autophagy have also been demonstrated to be present in eCV exposure, which similarly impairs autophagy through the accumulation of aggresome bodies [39,94].
T86	16958-17201	Sentence	denotes	Furthermore, increasing the severity of pulmonary dysfunction and autophagy impairment has been observed to statistically correlate directly with increased levels of aggresome bodies [36], demonstrating its potential as a prognostic biomarker.
T87	17202-17305	Sentence	denotes	Hence, CS exposure demonstrates a common, but preventable way autophagy can be impaired in individuals.
T88	17306-17432	Sentence	denotes	Notably, CS exposure accelerates lung aging, known to be initiated by autophagy decline, which can exacerbate infections [33].
T89	17433-17504	Sentence	denotes	In addition to smoking, autophagy can be impaired by infectious agents.
T90	17505-17648	Sentence	denotes	Due to the conserved nature of autophagy, many organisms have adapted and evolved mechanisms to impair autophagy in order to infect their host.
T91	17649-17858	Sentence	denotes	For example, studies have demonstrated that the influenza virus promotes its own survival by preventing autophagolysosome formation; thus, leading to autophagy impairment via aggresome accumulation [41,85,95].
T92	17859-17998	Sentence	denotes	Influenza has also been found to prevent the autophagy-dependent presentation of viral antigens necessary to mount an immune response [10].
T93	17999-18263	Sentence	denotes	Similarly, investigations have found that severe acute respiratory syndrome coronavirus (SARS-CoV) can inhibit autophagolysosome formation with trans membrane papain-like protease 2 (PLP2-TM) to provoke phagolysosome accumulation causing autophagy impairment [96].
T94	18264-18453	Sentence	denotes	Additionally, the nonstructural protein 6 (NSP6) of coronaviruses has also been observed to restrict autophagosome development to prevent cells from inhibiting coronavirus replication [97].
T95	18454-18540	Sentence	denotes	However, autophagy inhibition by pathogens is not something that is unique to viruses.
T96	18541-18764	Sentence	denotes	Legionella pneumophilia (L. pneumophilia) has been found to delay the progression of infected autophagosomes to lysosomes to allow the bacteria to develop an acid-tolerant state prior to autophagolysosome formation [98,99].
T97	18765-18904	Sentence	denotes	This delay allows L. pneumophilia to replicate in the acidic environment of the autophagolysosome [99] and cause infection within the host.
T98	18905-19087	Sentence	denotes	This mechanism of autophagy impairment is not unique to L. pneumophilia and has been observed as a common mechanism of bacteria to promote their invasion and replication [7,100,101].
T99	19088-19361	Sentence	denotes	M. tuberculosis has also been observed to impair phagolysosome formation; meanwhile, other studies have further demonstrated that M. tuberculosis has the ability to activate cellular pathways that inhibit autophagy within macrophages to promote intracellular survival [61].
T100	19362-19475	Sentence	denotes	Hence, there are various organisms that can infect humans and cause autophagy dysfunction for their own survival.
T101	19476-19556	Sentence	denotes	The expression of CFTR has been shown to influence autophagy as discussed above.
T102	19557-19725	Sentence	denotes	One mechanism of decreased CFTR expression is due to the genetic defects found in CF, where the most common mutation seen in these patients is ΔF508-CFTR [102,103,104].
T103	19726-19874	Sentence	denotes	Studies have demonstrated that ΔF508-CFTR causes protein misfolding that forms aggregates potentially impairing cellular proteostasis [20,42,53,61].
T104	19875-20017	Sentence	denotes	This dysfunction caused by ΔF508-CFTR includes autophagy dysfunction and decreases pathogen clearance in the airways of patients with CF [53].
T105	20018-20098	Sentence	denotes	Similar findings were observed in macrophages with dysfunctional CFTR [105,106].
T106	20099-20316	Sentence	denotes	Along with the genetic mechanism of CFTR dysfunction present in CF that can impair autophagy, CFTR function has been shown to be diminished by CS exposure [40,107,108,109], which is known as acquired CFTR dysfunction.
T107	20317-20512	Sentence	denotes	One mechanism of CS-induced CFTR dysfunction leading to impaired autophagy is through increased ceramide accumulation as a result of altered sphingolipid homeostasis in COPD patients [22,93,110].
T108	20513-20628	Sentence	denotes	CS exposure can also increase ROS which causes CFTR to accumulate in aggresome bodies and impair autophagy [42,62].
T109	20629-20791	Sentence	denotes	Thus, both genetic mechanisms and CS exposure or environmental factors play a critical role in CFTR dysfunction and the resulting autophagy impairment (Figure 1).
T110	20793-20795	Sentence	denotes	4.
T111	20796-20841	Sentence	denotes	Autophagy Dysfunction in Respiratory Diseases
T112	20842-21165	Sentence	denotes	A number of recent studies have identified autophagy dysfunction as the central mechanism of elevated inflammatory-oxidative stress, alveolar apoptosis, cellular senescence, and recurrent infections, all of which contribute to the pathogenesis and progression of acute and chronic respiratory diseases [22,35,61,62,70,111].
T113	21166-21410	Sentence	denotes	The inherent ROS in the CS, and the resulting increase in cellular endogenous ROS post-CS exposure, symbiotically contribute to extremely high intracellular ROS levels, which creates an imbalance in the oxidant–antioxidant ratio [22,34,61,112].
T114	21411-21678	Sentence	denotes	This serves as the basic mechanism for lung cellular injury, tissue damage, and the pathogenesis of chronic obstructive or restrictive lung diseases, such as COPD-emphysema (obstructive) and idiopathic pulmonary fibrosis (IPF, restrictive) [37,38,61,113,114,115,116].
T115	21679-21936	Sentence	denotes	Several groups including ours have demonstrated that elevated ROS levels are the key upstream driver of autophagy dysfunction, as treatments with antioxidant drugs rescues the age-related, or smoke, or eCV exposure-induced autophagy defect [15,22,42,61,62].
T116	21938-21942	Sentence	denotes	4.1.
T117	21943-21987	Sentence	denotes	Autophagy Defects in Acute Lung Injury (ALI)
T118	21988-22359	Sentence	denotes	Extensive studies utilizing both in vitro and in vivo models of acute lung injury have demonstrated the protective role of autophagy via regulating inflammatory-oxidative stress, apoptosis, and pathogen clearance mechanisms, even though there were some initial opposing studies [117,118,119], the subsequent detailed evaluation validates the protective role as discussed.
T119	22360-22507	Sentence	denotes	In general, autophagy is induced upon exposure to common triggers of ALI, such as LPS, bacterial infections, hyperoxia, sepsis, etc. [120,121,122].
T120	22508-22646	Sentence	denotes	There seems to be a consensus that autophagy indeed plays a protective role in LPS-induced acute lung injury and inflammation [82,83,123].
T121	22647-22975	Sentence	denotes	In support of this, LPS-mediated severe lung injury in mice, as quantified by lung edema, elevated leukocyte infiltrations, hemorrhages, and increased inflammatory cytokines (IL-1β and TNFα) in the bronchoalveolar lavage fluid (BALF), was further exacerbated by autophagy inhibition, thereby suggesting its protective role [82].
T122	22976-23210	Sentence	denotes	Mechanistically, the activation of the mammalian target of rapamycin (mTOR) and the resulting autophagy dysfunction has been implicated in promoting LPS-induced lung injury, possibly through the activation of NFκB signaling [124,125].
T123	23211-23453	Sentence	denotes	Further evidence comes from studies demonstrating the utility of autophagy inducers and/or antioxidant drugs in ameliorating LPS-induced acute lung injuries, while treatment with autophagy inhibitors reversed the beneficial effects [125,126].
T124	23454-23744	Sentence	denotes	Autophagy is also protective in sepsis-induced lung injury, as a deficiency of proteins interacting with C-kinase 1 (PICK1) in mice leads to defective autophagy, and more severe acute lung injury in the cecal ligation and puncture (CLP) model of sepsis, as compared to WT animals [120,127].
T125	23745-24016	Sentence	denotes	Additionally, in murine models of hyperoxia-induced ALI, which resembles features of bronchopulmonary dysplasia (BPD), autophagy is proposed as a protective mechanism, and markers of defective autophagy are found in the lungs of human neonates with established BPD [128].
T126	24017-24425	Sentence	denotes	Another recent study describes the suppression of autophagy as a critical mechanism of chronic parenteral nutrition-mediated lung injury, and treatment with the autophagy inducer, rapamycin (an mTOR inhibitor that initiates nucleation, autophagosome elongation, autophagosome maturation, and autophagosome termination), reversed the lung injury features in the animal model of parenteral nutrition [129,130].
T127	24426-24620	Sentence	denotes	Finally, mice deficient in crucial autophagy proteins such as Atg7, Atg5 and Atg4a demonstrate more severe ALI features [83,121,130,131], thus confirming the protective role of autophagy in ALI.
T128	24622-24626	Sentence	denotes	4.2.
T129	24627-24690	Sentence	denotes	Autophagy Defects in Acute Respiratory Distress Syndrome (ARDS)
T130	24691-24777	Sentence	denotes	More severe forms of ALI may progress to acute respiratory distress syndrome, or ARDS.
T131	24778-24867	Sentence	denotes	Autophagy has been shown to play a critical role in regulating the outcome of ARDS [120].
T132	24868-24974	Sentence	denotes	The clinical manifestations of ARDS are very severe and may lead to rapid lung function decline and death.
T133	24975-25337	Sentence	denotes	Using one of most widely used murine models of ALI, the CLP, a recent study demonstrated that autophagy induction by rapamycin was able to improve the survival rate, histological scores, lung wet/dry ratios, PaO2/FiO2, and inflammatory cytokine and myeloperoxidase (MPO) levels in BALF, suggesting a protective role of autophagy in sepsis-induced ALI/ARDS [120].
T134	25338-25481	Sentence	denotes	In another study, the potential of BML-111, a lipoxin A4 receptor antagonist, was evaluated in controlling LPS-induced septic ALI/ARDS in rats.
T135	25482-25698	Sentence	denotes	The authors showed that BML-111 inhibited apoptosis and induced autophagy in alveolar macrophages, in response to the LPS challenge, via the suppression of MAPK1 and MAPK8 signaling and was independent of mTOR [132].
T136	25699-25884	Sentence	denotes	Moreover, BML-111 controlled the LPS-induced production of pro-inflammatory cytokines, and reduced apoptosis in the rat lungs, and thus warrants further investigation in ALI/ARDS [132].
T137	25885-26043	Sentence	denotes	Mechanical ventilation (MV)-induced lung injury is another severe form of ARDS, wherein the activation of inflammasome has been shown to mediate ALI symptoms.
T138	26044-26267	Sentence	denotes	In a recent article, starvation-induced autophagy augmentation was shown to protect against LPS- and MV-induced ARDS features by reducing IL-1β levels, decreasing lung permeability, and improving arterial oxygenation [133].
T139	26268-26526	Sentence	denotes	Thus, autophagy had a protective role in controlling the inflammasome activation and resolution of the MV-induced production of IL-1β, which plays a pathogenic role through inducing hypoxemia and increasing lung permeability in LPS/MV-induced ALI/ARDS [133].
T140	26527-26783	Sentence	denotes	Although some contrasting reports regarding the role of autophagy in ALI/ARDS were initially reported [134], there has been a consensus on the therapeutic advantage of autophagy augmentation in ALI/ARDS based on significant validation studies [64,120,122].
T141	26784-26877	Sentence	denotes	Thus, proper autophagy function is essential in attenuating the severity of ARDS in patients.
T142	26879-26883	Sentence	denotes	4.3.
T143	26884-26936	Sentence	denotes	Critical Role of Autophagy in COVID-19 Exacerbations
T144	26937-27073	Sentence	denotes	The ongoing SARS-CoV-2 pandemic has severely impacted quality of life with a significant health care and socio-economic burden globally.
T145	27074-27272	Sentence	denotes	In general, the cellular endocytic and autophagy pathways contribute to viral entry and replication, and thus are obvious attractive targets against SARS-CoV-2 and other viral infections [90,91,92].
T146	27273-27511	Sentence	denotes	The SARS-CoV-2 virus, which causes COVID-19, is highly infectious and can cause cytokine-storm leading to pneumonia and severe lung damage in susceptible subjects by triggering an ARDS-like lung disease, with high-risk of mortality [135].
T147	27512-27709	Sentence	denotes	Recent evidence suggests that SARS-CoV-2 may inhibit autophagy, which we anticipate as a potential mechanism for severe COVID-19 lung disease due to impaired viral clearance and immune dysfunction.
T148	27710-27875	Sentence	denotes	In a recent study of the SARS-CoV-2 genome, researchers found that the NSP6 protein of the virus binds with greater affinity to the endoplasmic reticulum (ER) [136].
T149	27876-28048	Sentence	denotes	This genetic change may allow the virus to inhibit autophagy via impaired autophagosome processing, which prevents the degradation of viral particles by the lysosome [136].
T150	28049-28288	Sentence	denotes	There is also evidence that PLP2 is over-expressed in SARS-CoV and MERS-CoV cell lines that also allows the virus to inhibit autophagolysosomal formation and autophagy flux and is likely a method of autophagy inhibition in SARS-CoV-2 [96].
T151	28289-28540	Sentence	denotes	These studies suggest potential mechanism by which SARS-CoV-2 inhibits autophagy to infect or circumvent host cells pathogenic clearance pathways and limit an adequate immune response similar to other coronaviruses that warrants further investigation.
T152	28541-28685	Sentence	denotes	The elimination of viruses by autophagy (sometimes termed as virophagy) has been well described for a variety of viral infections [8,84,85,137].
T153	28686-28859	Sentence	denotes	Although, the virus has multiple ways of entry into the cell, autophagy augmentation provides strategic advantage in reducing viral load by promoting its clearance [90,137].
T154	28860-29048	Sentence	denotes	As a proof of concept, recent study demonstrated the utility of three different autophagy-inducing drugs, spermidine, MK02206, and niclosamide, in restricting SARS-CoV-2 propagation [138].
T155	29049-29238	Sentence	denotes	Autophagy induction and related upregulation of overall immunity helps combat exacerbations and is suggested as an immunity boosting strategy as a preventive measure against COVID-19 [139].
T156	29239-29491	Sentence	denotes	In addition to boosting immunity, dampening viral load, and allowing SARS-COV2 clearance, autophagy induction may provide strategic advantage in the treatment of COVID-19 and prevention of negative outcomes, which makes it a subject of ongoing studies.
T157	29492-29759	Sentence	denotes	In support of this, autophagy inhibiting drugs, such as hydroxychloroquine (HCQ) that help dampen the immune response in rheumatoid arthritis, malaria, and other illnesses but weakens cellular ability for viral clearance by the critical homeostatic process autophagy.
T158	29760-29982	Sentence	denotes	Despite early claims that HCQ may provide benefit in treating COVID-19 [90,91,92], it has since been deemed unsafe for use in COVID-19 treatment by the FDA based on randomized double blind placebo control trials [140,141].
T159	29983-30273	Sentence	denotes	In addition, earlier studies on Middle East respiratory syndrome (MERS) coronavirus [50] provide proof-of-concept data on therapeutic potential of autophagy modulating drugs to combat SARS-COV2 infection, cytokine storm, and the pathogenesis of severe ARDS-like COVID-19 fatal lung disease.
T160	30274-30604	Sentence	denotes	Prior studies showing a protective role of autophagy induction in other models of ARDS demonstrate the scope of autophagy augmenting strategies in combating SARS-CoV-2 infections (Figure 1) and thus is part of ongoing validation and rapid clinical development studies that may help limit the burden and spread of this novel virus.
T161	30605-30873	Sentence	denotes	As discussed above for other lung diseases, targeting autophagy to prevent the replication of SARS-CoV-2 is not the only potential benefit of autophagy augmentation for the treatment of COVID-19, but it may also allow the fine-tuning of optimal inflammatory responses.
T162	30874-31093	Sentence	denotes	As now known, the pathogenesis of SARS-CoV-2-mediated severe COVID-19 involves the activation of numerous pro-inflammatory cytokines as part of the aforementioned cytokine storm causing a hyper-inflammatory state [142].
T163	31094-31355	Sentence	denotes	In addition to the destruction of the lungs and ARDS associated with COVID-19, this inflammatory response can cause damage to the cardiovascular, nervous, renal, hepatic, and gastrointestinal systems with wide ranging immediate and long-term consequences [142].
T164	31356-31499	Sentence	denotes	In support of this, studies have demonstrated the role of autophagy in the inflammatory response within the lungs and other organ systems [61].
T165	31500-31620	Sentence	denotes	As mentioned above, autophagy induction has been demonstrated to attenuate lung inflammation when exposed to a pathogen.
T166	31621-31839	Sentence	denotes	Thus, autophagy induction to limit the inflammatory response, in addition to infection, has an immense therapeutic potential as an effective treatment for COVID-19 and decreasing the associated mortality and morbidity.
T167	31841-31845	Sentence	denotes	4.4.
T168	31846-31871	Sentence	denotes	Autophagy Defects in COPD
T169	31872-32099	Sentence	denotes	We and others have described autophagy dysfunction as a prime causative factor utilizing in vitro and animal models of smoke- (cigarette and waterpipe) or eCV (nicotine)-induced lung injury and COPD-emphysema [33,34,39,94,109].
T170	32100-32389	Sentence	denotes	Moreover, these were validated in human subjects where defective autophagy was verified using human lung tissues from COPD-emphysema subjects, where classical autophagy impairment features, such as aggresome bodies, were associated with the severity and progression of the disease [22,36].
T171	32390-32694	Sentence	denotes	These aggresome bodies are perinuclear accumulations of misfolded or aggregated proteins, which are poly-ubiquitinated and co-localize with p62 and the autophagy protein microtubule-associated protein 1 light-chain-3B(+) (LC3B+) bodies, and are the key indicators of defective autophagy flux [33,36,143].
T172	32695-32993	Sentence	denotes	Additionally, we and others have also noted the increase in aggresome body formation in aged mice lungs that correlated with alveolar airspace enlargement (emphysema phenotype), indicating that age-related decline in autophagy contributes to COPD-emphysema development, similar to CS exposure [33].
T173	32994-33242	Sentence	denotes	Moreover, an increase in emphysema severity (GOLD 0-IV) in smokers with a minimal age difference [33] also correlated with an increase in alveolar senescence, indicating the presence of accelerated lung aging in severe COPD-emphysema subject lungs.
T174	33243-33369	Sentence	denotes	We further validate smoke-induced accelerated lung aging using aging markers and in vitro and murine models of COPD-emphysema.
T175	33370-33713	Sentence	denotes	In further studies, a clear mechanistic and protective role of TFEB, the master autophagy regulator, was observed in CS-induced lung disease models where other pathogenic features of COPD-emphysema, such as inflammatory-oxidative stress, senescence, apoptosis, and aggresome formation, were used for the validation of pathogenic roles [34,35].
T176	33714-33934	Sentence	denotes	In fact, the CS-induced sequestration of TFEB protein into aggresome bodies leads to its decreased availability, which prevents its function as a transcription factor to positively regulate the autophagy process [34,35].
T177	33935-34245	Sentence	denotes	Moreover, TFEB-mediated autophagy was shown to be protective against oxidative stress and hepatotoxicity induced by ethyl carbamate (a toxicant in CS) [144], suggesting that TFEB-autophagy is a protective mechanism against CS exposure-induced toxicity, not only in the lungs, but in other vital organs as well.
T178	34246-34461	Sentence	denotes	Additionally, TFEB-mediated autophagy has also been shown to control CS-induced cellular senescence, and bacterial phagocytic clearance, thus highlighting its protective role in CS-induced COPD-emphysema [22,34,35].
T179	34462-34685	Sentence	denotes	In addition to TFEB, other mechanistic mediators of autophagy have been shown to participate in the sequential dysfunction or impairment of autophagy processes, contributing as a key mediator of COPD-emphysema pathogenesis.
T180	34686-34906	Sentence	denotes	For example, increased levels of bicaudal D1 (BICD1), an adaptor for the dynein–dynactin motor complex, were found in the peripheral lung tissues of COPD patients, which was associated with increased p62 oligomers [145].
T181	34907-35218	Sentence	denotes	Additionally, the exposure of bronchial epithelial cells or mice to CS led to increased BICD1 levels, along with defective autophagosome maturation, and an accumulation of BICD1 with p62 and ubiquitin-associated p62-oligomers, thus confirming the mechanistic role of BICD1 in CS-induced autophagy defects [145].
T182	35219-35318	Sentence	denotes	Dysfunctional autophagy has also been associated with defects in specific cell types of the airway.
T183	35319-35445	Sentence	denotes	The secretory cells of the airway, such as the club and goblet cells, play an important role in host defense during infection.
T184	35446-35568	Sentence	denotes	Autophagy has been recently shown to be required to maintain the function of club cells, independent of CS exposure [146].
T185	35569-35820	Sentence	denotes	Mice deficient in autophagy protein Atg5, demonstrate a diminished expression of the host defense protein secretoglobulin family 1A member 1 (SCGB1A1) and surfactant proteins A1 and D (Sftpa1 and Sftpd), as well as abnormal club cell morphology [146].
T186	35821-35969	Sentence	denotes	Moreover, a diminished SCGB1A1 expression in club cells correlates with evidence of reduced autophagy in lung tissue from COPD former smokers [146].
T187	35970-36178	Sentence	denotes	CS exposure has also been demonstrated to cause the accumulation of damaged mitochondrial via impaired mitophagy, which has been demonstrated to play a role in COPD pathogenesis disease progression [147,148].
T188	36179-36388	Sentence	denotes	Thus, it can be postulated that CS-induced autophagy dysfunction would further deteriorate the structure and function of club cells, resulting in altered or diminished host defense mechanisms in COPD subjects.
T189	36390-36394	Sentence	denotes	4.5.
T190	36395-36431	Sentence	denotes	Autophagy Defects in Cystic Fibrosis
T191	36432-36637	Sentence	denotes	Cystic fibrosis is a chronic obstructive lung disease which is marked by recurrent infections, chronic inflammatory-oxidative stress, and mucus overproduction that contributes to severe airway obstruction.
T192	36638-36826	Sentence	denotes	Initial seminal studies by Luciani A et al. established the link between defective CFTR and the presence of aggresome bodies, lung inflammation, and ROS-mediated autophagy inhibition [53].
T193	36827-37200	Sentence	denotes	We and others have not only validated that defective CFTR-mediated ROS-TG2 pathway drives the crosslinking of Beclin-1, which results in the accumulation of misfolded ΔF508-CFTR into p62+HDAC6+ aggresome bodies leading to autophagy dysfunction, but we have also demonstrated the key central role of autophagy in regulating CF pathogenesis and exacerbations [42,58,149,150].
T194	37201-37342	Sentence	denotes	These studies describe the specific role of defective autophagy in CF-related chronic infections and resulting inflammatory-oxidative stress.
T195	37343-37568	Sentence	denotes	In addition, CF macrophages demonstrate impaired phagocytic activity and thus CF patients are more prone to bacterial infections, such as P. aeruginosa and Burkholderia cenocepacia (B. cenocepacia) [45,51,58,106,151,152,153].
T196	37569-37665	Sentence	denotes	A recent study investigated the precise mechanism of weak autophagic activity in CF macrophages.
T197	37666-38018	Sentence	denotes	Using the technique of reduced representation bisulfite sequencing (RRBS) to determine the DNA methylation profile, the authors found that the promoter regions of Atg12 in CF macrophages are significantly more methylated as compared to the control WT cells, thereby elucidating a novel mechanism for reduced autophagy activity in CF immune cells [154].
T198	38019-38229	Sentence	denotes	In a separate study, an increased expression of the microRNA (Mir)c1/Mir17-92 cluster was identified as a potential negative regulator of autophagy in CF macrophages when compared to normal control cells [105].
T199	38230-38387	Sentence	denotes	Furthermore, the in vivo downregulation of Mir17 and Mir20a, partially restored autophagy gene expression and improved the clearance of B. cenocepacia [105].
T200	38388-38536	Sentence	denotes	These studies highlight the importance of autophagy as a key protective mechanism in CF exacerbation, and lung disease pathogenesis and progression.
T201	38538-38542	Sentence	denotes	4.6.
T202	38543-38567	Sentence	denotes	Autophagy Defects in IPF
T203	38568-38678	Sentence	denotes	IPF is a chronic, progressive, and frequently fatal disease associated with aging and dysfunctional autophagy.
T204	38679-38981	Sentence	denotes	It is accepted that accelerated epithelial cell senescence plays a vital role in IPF pathogenesis by virtue of atypical epithelial–mesenchymal interactions, and insufficient autophagy is attributed as a mechanism of accelerated epithelial cell senescence and myofibroblast differentiation in IPF [155].
T205	38982-39048	Sentence	denotes	Bleomycin is widely used as a model of drug-induced lung fibrosis.
T206	39049-39187	Sentence	denotes	The first study to describe the protective role of autophagy in bleomycin-induced lung fibrosis used the Atg4b-deficient mice model [156].
T207	39188-39371	Sentence	denotes	After 7 days of bleomycin treatment, these mice demonstrated a significantly higher neutrophilic infiltration and inflammatory cytokine production as compared to untreated mice [156].
T208	39372-39584	Sentence	denotes	Additionally, after 28 days of bleomycin treatment, mice developed extensive lung fibrosis, which was accompanied by an elevated collagen deposition and deregulated expression of extracellular matrix genes [156].
T209	39585-39853	Sentence	denotes	Similarly, in mice deficient in LC3B (LC3B−/−), bleomycin-mediated lung injury and fibrotic changes were more pronounced, suggesting the protective role of autophagy in bleomycin-induced lung injury and the resulting development of fibrotic lung disease in mice [157].
T210	39854-39975	Sentence	denotes	Another recent study describes the protective role of the anti-inflammatory cytokine IL-37 in the IPF murine model [158].
T211	39976-40176	Sentence	denotes	A further mechanistic delve into the mechanism of IL-37-mediated protection showed that it induces Beclin-1-dependent autophagy while downregulating TGFβ1-mediated lung fibroblast proliferation [158].
T212	40177-40390	Sentence	denotes	Moreover, IL-37 also decreased inflammation and collagen deposition in bleomycin-treated murine lungs while the protective effect was reversed by treatment with 3-methyladinine (3MA), an autophagy inhibitor [158].
T213	40391-40501	Sentence	denotes	Thus, it is plausible that a decrease in IL-37-mediated autophagy might be involved in the progression of IPF.
T214	40502-40621	Sentence	denotes	Moreover, the protective effects of autophagy are apparent from this and the other mechanistic studies mentioned above.
T215	40622-40917	Sentence	denotes	Additional mechanistic evidence comes from a study that showed bleomycin directly binds to annexin A2 (ANXA2) in lung epithelial cells, thereby preventing the nuclear translocation of TFEB; thus, there is an inhibition of the autophagy flux resulting in fibrotic lung disease pathogenesis [159].
T216	40918-41043	Sentence	denotes	Moreover, torin1-mediated TFEB activation restores autophagy flux and ameliorates bleomycin-induced pulmonary fibrosis [159].
T217	41044-41349	Sentence	denotes	Autophagy dysfunction is also reported in human lung fibroblasts from IPF patients, and it is believed that defective autophagy is required to maintain a cell death-resistant phenotype in IPF fibroblasts, suggesting that autophagy dysfunction is a profibrotic mechanism and promotes IPF pathogenesis [64].
T218	41350-41551	Sentence	denotes	Hence, in age-related IPF pathogenesis, autophagy declines with age and the resulting imbalance of inflammatory-oxidative responses is anticipated to mediate the initiation of fibrotic pathophysiology.
T219	41552-41679	Sentence	denotes	However, further clinical evaluation is needed to evaluate the therapeutic potential of autophagy augmentation in IPF patients.
T220	41681-41683	Sentence	denotes	5.
T221	41684-41739	Sentence	denotes	Autophagy-Mediated CFTR and Immune Response Dysfunction
T222	41740-41884	Sentence	denotes	The genetic loss of CFTR or a decrease in its expression and/or activity due to environmental insults such as CS leads to autophagy dysfunction.
T223	41885-42160	Sentence	denotes	An investigation of CFTR-deficient mice or cells isolated from CF subjects revealed an intrinsic defect in autophagy in the absence of CFTR, and the mechanism of defective CFTR-mediated autophagy impairment via the ROS-TG2-Beclin-1 pathway is well established [22,42,53,150].
T224	42161-42426	Sentence	denotes	Supporting studies demonstrate that autophagy augmentation restores CS-induced CFTR dysfunction, inflammatory-oxidative stress, ceramide accumulation, and COPD-emphysema pathogenesis by rescuing aggresome-bound mutant ΔF508-CFTR to the plasma membrane (PM) [22,35].
T225	42427-42611	Sentence	denotes	Conversely, restoring CFTR levels by S-nitrosoglutathione (GSNO) augmentation corrects CS-induced autophagy dysfunction, inflammatory-oxidative stress and COPD-emphysema features [62].
T226	42612-42812	Sentence	denotes	These findings not only highlight the intricate relationship between CFTR and autophagy but also provide a unique therapeutic opportunity to control exacerbations and chronic lung disease progression.
T227	42813-43013	Sentence	denotes	Several reports have suggested that the inherently elevated inflammatory-oxidative stress in CF cells, primarily due to activated NFκB signaling, could be dampened by autophagy augmentation [124,160].
T228	43014-43241	Sentence	denotes	Moreover, it’s conceivable that CFTR dysfunction leads to impaired pathogen clearance, as the autophagy-mediated degradation of both intracellular and extracellular pathogens (xenophagy) is well demonstrated [35,45,58,151,161].
T229	43242-43457	Sentence	denotes	An alternate mechanism called LC3-associated phagocytosis (LAP) is also described, which is similar to the normal macroautophagy pathway but does not involve the formation of a double membrane autophagosome [7,162].
T230	43458-43684	Sentence	denotes	Nonetheless, LAP assists in the processing of both intracellular and extracellular pathogens, through the recruitment of LC3 to the phagosomal membrane and subsequent delivery to lysosomes for terminal degradation [7,151,162].
T231	43685-43836	Sentence	denotes	Autophagy per se plays a very crucial role in regulating innate and adaptive immunity both in normal conditions and in response to pathogen challenges.
T232	43837-44050	Sentence	denotes	Autophagy directly governs key aspects of the innate immune activation, including the secretion of inflammatory mediators, such as cytokines, which are essential to combat different microbial pathogens [7,8,9,84].
T233	44051-44255	Sentence	denotes	The “inflammasome” is a cytoplasmic multiprotein complex that detects pathogenic microorganisms or other cellular stresses and activates potent pro-inflammatory cytokines such as IL-1β and IL-18 [87,133].
T234	44256-44427	Sentence	denotes	Although inflammasome activation is an early innate response to protect the host, its prolonged activation can lead to severe hyperinflammation and tissue injury [47,130].
T235	44428-44644	Sentence	denotes	Recent studies suggest that autophagy is a negative regulator of inflammasome activation as a deficiency of autophagy components such as LC3B or Beclin-1 promotes NLRP3-dependent inflammasome activation [47,130,133].
T236	44645-44948	Sentence	denotes	Apart from its regulation of inflammasome, autophagy also suppresses the overactivation of other inflammation-inducing factors such as NFκB, suggesting a general protective role of autophagy in keeping a check of uncontrolled innate immune activation that may contribute to lung injury [11,37,38,54,55].
T237	44949-45178	Sentence	denotes	In the adaptive immune system, functional autophagy is required for the survival, development, maturation, and function of immune cells such as CD4+ T cells, CD8+ T cells, B cells, neutrophils, and monocytes [7,9,84,163,164,165].
T238	45179-45347	Sentence	denotes	Moreover, in dendritic cells (DC’s), antigen processing and presentation to MHC-II is dependent on the autophagic generation of suitable peptides [9,20,88,163,164,165].
T239	45348-45569	Sentence	denotes	Additionally, antigen presentation to CD8+ T cells on MHC-I is also dependent on autophagy, thus implicating its indispensable role in generating an adequate immune response to bacterial and viral pathogens [163,164,165].
T240	45570-45808	Sentence	denotes	Hence, autophagy promotes adequate antigen presentation to T cells in numerous infection models, thereby facilitating a robust adaptive immune response and further demonstrating the necessary functional role autophagy plays in infections.
T241	45809-45955	Sentence	denotes	The lack of functional CFTR in macrophages results in an increased production of inflammatory cytokines, and impaired pathogen clearance capacity.
T242	45956-46161	Sentence	denotes	The diminished expression of HLA-DQ and HLA-DR (MHC-II molecules) on monocytes derived from ΔF508-CFTR homozygous CF subjects [166], might explain the impaired pathogen clearance ability of CF macrophages.
T243	46162-46303	Sentence	denotes	In addition, CFTR deficiency has been implicated in diminished Treg effector function and a more pronounced Th2-biased immune response [167].
T244	46304-46462	Sentence	denotes	The CF defect has also been shown to affect the activation of neutrophils [168], which are the cells responsible for the first line of defense in the airways.
T245	46463-46857	Sentence	denotes	Although, airway epithelial cells and lung-resident macrophages sense the invading pathogens and secrete a plethora of factors to induce the recruitment and activation of neutrophils, neutrophils from CF subjects have diminished phagocytic potentials by virtue of the reduced cell surface expression of toll-like receptors (TLRs) and disrupted chloride transport to the phagolysosome [169,170].
T246	46858-46931	Sentence	denotes	Thus the CFTR mutation in CF results in impaired bacterial killing [171].
T247	46932-47079	Sentence	denotes	Moreover, CF neutrophils also demonstrate an increased capacity to release their primary granule contents such as MPO and neutrophil elastase (NE).
T248	47080-47179	Sentence	denotes	The uncontrolled release of these enzymes causes lung tissue damage and severe airway inflammation.
T249	47180-47509	Sentence	denotes	We have shown that P. aeruginosa LPS-induced MPO levels can be reduced by treatment with the histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA), plausibly by restoring the trafficking of ΔF508-CFTR, suggesting that a functional CFTR is required to keep a tab on uncontrolled neutrophil activation [172].
T250	47510-47715	Sentence	denotes	Mechanistically, an absence or dysfunction of CFTR in neutrophils results in the deactivation of the guanosine triphosphate (GTP)-binding protein Rab27a, which causes impaired granule exocytosis [168,172].
T251	47716-47945	Sentence	denotes	Several studies now agree that the pharmacological inhibition of CFTR or the mutant ΔF508-CFTR is sufficient to cause deregulated neutrophil activation via the activation of the NFκB pathway, resulting in hyperinflammation [172].
T252	47946-48069	Sentence	denotes	Therefore, autophagy and CFTR share an intimate relationship in terms of regulating the immune response against infections.
T253	48070-48225	Sentence	denotes	Moreover, the rescue of mutant CFTR to the PM corrects the autophagy-mediated immune dysfunction, controlling chronic lung disease pathogenesis (Figure 1).
T254	48227-48229	Sentence	denotes	6.
T255	48230-48296	Sentence	denotes	Autophagy-CFTR Dysfunction Induces Acute and Chronic Exacerbations
T256	48297-48422	Sentence	denotes	As discussed above, many patients with chronic respiratory diseases such as COPD and CF face acute and chronic exacerbations.
T257	48423-48568	Sentence	denotes	These pulmonary exacerbations are characterized by a worsening lung function, significantly below what is normal for their conditions [4,31,173].
T258	48569-48841	Sentence	denotes	These exacerbations are caused by environmental exposures or bacterial and viral infections that result in further deterioration of the patient’s condition [4,31,173,174,175], leading to hospitalization for individuals causing increased morbidity and mortality [4,31,173].
T259	48842-48958	Sentence	denotes	Exacerbations also pose a significant financial burden for patients with chronic respiratory diseases [1,2,176,177].
T260	48959-49168	Sentence	denotes	Since pulmonary exacerbations are commonly triggered by infections, the autophagy dysfunction seen in these chronic conditions plays a role in the pathogenesis of this state via the mechanisms discussed above.
T261	49169-49329	Sentence	denotes	A common pathogen that colonizes the lungs of individuals with chronic respiratory diseases and can lead to exacerbations is P. aeruginosa [4,31,44,58,173,178].
T262	49330-49496	Sentence	denotes	Studies have demonstrated that defects in CFTR impair the ability of cells to clear P. aeruginosa infections via autophagy, especially in patients with CF [22,40,53].
T263	49497-49669	Sentence	denotes	Furthermore, it has been shown that the induction of autophagy is able to ameliorate autophagy dysfunction and promote the clearance of P. aeruginosa infections [35,45,58].
T264	49670-50003	Sentence	denotes	As previously mentioned, CS exposure can also cause CFTR dysfunction, where a recent investigation demonstrated that CS exposure decreased CFTR expression while a treatment of CS-exposed macrophages with the autophagy inducer fisetin, which works by modulating autophagosome degradation, significantly recovered CFTR expression [35].
T265	50004-50120	Sentence	denotes	This same investigation showed that the CS-induced inhibition of CFTR decreased the clearance of P. aeruginosa [35].
T266	50121-50269	Sentence	denotes	This impaired clearance was then alleviated by autophagy induction with fisetin, supporting the findings of other previously mentioned studies [35].
T267	50270-50386	Sentence	denotes	Hence, CFTR-autophagy dysfunction in chronic lung diseases such as CF and COPD leads to P. aeruginosa exacerbations.
T268	50387-50527	Sentence	denotes	Similarly, Burkholderia cepacia (B. cepacia), an opportunistic infection that afflicts 3–5% of CF patients, can provoke exacerbations [151].
T269	50528-50718	Sentence	denotes	It has been found that macrophages can kill B. cepacia within autophagolysosomes; however, macrophages with ΔF508-CFTR lacked the bacteria in autophagolysosomes indicating dysfunction [151].
T270	50719-50908	Sentence	denotes	When these macrophages were treated with the autophagy inducer rapamycin, ΔF508-CFTR macrophages were able to fight the B. cepacia infection and reduce the resulting inflammation [153,179].
T271	50909-51124	Sentence	denotes	This demonstrates the importance of CFTR-dependent autophagy in not only clearing bacteria that can provoke pulmonary exacerbations, but also decreasing inflammation that can lead to worsened lung functions as well.
T272	51125-51214	Sentence	denotes	In regard to viral infections, CFTR-autophagy dysfunction limits viral clearance as well.
T273	51215-51368	Sentence	denotes	In a recent study, it was determined that CFTR-deficient mice infected with RSV had an impaired ability to clear the virus compare to control mice [180].
T274	51369-51552	Sentence	denotes	Similarly, despite similar cytokine responses, respiratory epithelial cells with ΔF508-CFTR had a higher viral load when infected with rhinovirus in comparison to control cells [181].
T275	51553-51805	Sentence	denotes	From what we know about CFTR-autophagy’s role in pathogen clearance, it is likely that the observed findings in this study are a result of decreased autophagy in the ΔF508-CFTR cells that leads to decreased rhinovirus clearance and a higher viral load.
T276	51806-51936	Sentence	denotes	Thus, proper CFTR-dependent autophagy function is necessary for the clearance of both bacterial and viral pathogens in the airway.
T277	51937-52081	Sentence	denotes	Besides infection, CFTR-autophagy dysfunction can lead to an impaired clearance of cellular debris and products that would normally be degraded.
T278	52082-52233	Sentence	denotes	One such product is ceramide, which in response to CFTR-autophagy dysfunction can accumulate in aggresome bodies within cells [22,110,182,183,184,185].
T279	52234-52409	Sentence	denotes	Ceramide accumulation has been observed in both CF patients with CFTR mutations [182,183,186] and COPD patients who have acquired CFTR dysfunction due to CS exposure [22,110].
T280	52410-52534	Sentence	denotes	In the presence of CS, ceramide has been found to accumulate in p62+ aggresome bodies, indicating autophagy impairment [22].
T281	52535-52797	Sentence	denotes	As CFTR-autophagy becomes impaired in both CF and COPD, cells have chronically elevated intracellular levels of ROS altering cellular homeostasis, causing exacerbations and accelerating the pathogenesis and progression of these respiratory diseases [22,110,182].
T282	52798-52976	Sentence	denotes	Moreover, the deleterious effect of ceramide accumulation on CFTR-autophagy has been demonstrated to directly impair defenses against bacteria [52,184,186,187] and viruses [188].
T283	52977-53183	Sentence	denotes	As such, ceramide accumulation as a result of either inherent or acquired CFTR dysfunction leads to autophagy impairment causing a diminished immune response and bacterial colonization or viral replication.
T284	53184-53408	Sentence	denotes	Hence, dysfunctional CFTR and autophagy dysfunction go hand in hand with an increased susceptibility of individuals to pathogens that significantly decrease lung function and cause acute and chronic exacerbations (Figure 1).
T285	53410-53412	Sentence	denotes	7.
T286	53413-53494	Sentence	denotes	CFTR- Autophagy Dysfunction and Pathogenesis of Chronic Obstructive Lung Diseases
T287	53495-53890	Sentence	denotes	The homeostatic autophagy process in the airways is prone to dysregulation by a variety of factors such as exposure to first- or second-hand CS [40], eCV [39], biomass smoke [14,43], waterpipe smoke (WPS) [94], wildfire smoke [189], environmental pollution [61], genetic polymorphisms [53,61,149], aging [190], obesity [191,192], and changes in the expression and/or activity of CFTR [22,35,53].
T288	53891-54166	Sentence	denotes	Elevated levels of ROS/RNS ensuing from exposure to the above-described risk factors is the primary driver of autophagy impairment (Figure 1), which is considered a central mechanism for the advent of inflammatory-oxidative stress, cellular senescence, and apoptosis [62,94].
T289	54167-54342	Sentence	denotes	These potentially deleterious changes result in the initiation and progression of COPD-emphysema, as they correlate with the severity of emphysema in COPD subjects [22,33,62].
T290	54343-54533	Sentence	denotes	We and others have demonstrated the important role of transcription factor-EB (TFEB), the master autophagy regulator, in controlling inflammatory-oxidative and immune signaling [34,143,193].
T291	54534-54831	Sentence	denotes	In a relatively recent study, we showed that CS-induced accumulation or trapping of TFEB proteins into perinuclear aggresome bodies prevents it from entering the nucleus and performing its function as an autophagy regulating transcription factor, thereby culminating in autophagy dysfunction [34].
T292	54832-55037	Sentence	denotes	These findings were confirmed in human lung tissue sections from smoker and nonsmoker COPD subjects, where the perinuclear accumulation of TFEB into aggresome bodies increases with emphysema severity [34].
T293	55038-55264	Sentence	denotes	Moreover, smokers showed a more prominent increase in TFEB-aggresome localization as compared to nonsmokers, emphasizing that CS exposure leads to defective autophagy via functional trapping of TFEB into aggresome bodies [34].
T294	55265-55542	Sentence	denotes	It is evident from innumerable studies that a complete loss or decrease in the levels of functional WT-CFTR from the PM due to genetic mutations leads to several deleterious changes in the airways that ultimately results in obstructive lung disease pathogenesis in CF subjects.
T295	55543-55917	Sentence	denotes	Specifically, a decrease in/loss of WT-CFTR is causally related to increased ROS-mediated inflammatory-oxidative stress, mucus hypersecretion, elevated ceramide levels, and hampered mucociliary clearance resulting in an increased incident of recurrent and chronic pulmonary infections, all of which result in chronic obstructive pathologies in CF airways [15,51,53,110,194].
T296	55918-56167	Sentence	denotes	It is now well documented that CS exposure [22,40,63,107,108], eCV [39,195], or certain infectious agents [196,197,198] also induce a decrease in the activity or expression of CFTR in the airways and was aptly described as acquired CFTR dysfunction.
T297	56168-56316	Sentence	denotes	As expected, CS-induced ROS and the resulting oxidative stress was found to be the main cause of acquired CFTR dysfunction in COPD [62,107,108,109].
T298	56317-56634	Sentence	denotes	Moreover, the mechanistic confirmation of the role of acquired CFTR dysfunction in COPD pathogenesis comes from studies which showed that the pharmacological rescue of mutant CFTR to the PM was able to correct CS-induced inflammatory-oxidative stress, autophagy impairment, and COPD-emphysema pathogenesis [14,42,62].
T299	56635-56928	Sentence	denotes	Another important mechanism which plays a crucial pathogenic role in both CF and COPD-emphysema is ceramide accumulation (Figure 1), and numerous studies have highlighted that a loss or decrease in CFTR and/or CS exposure leads to an increase in ceramide levels [22,52,93,110,182,183,186,188].
T300	56929-57174	Sentence	denotes	Our earlier studies described a direct correlation between a lack of lipid-raft CFTR expression and CS-induced apoptosis along with defective autophagy and the progression of COPD-emphysema via ceramide or lactosylceramide accumulation [93,110].
T301	57175-57520	Sentence	denotes	Lately, we also demonstrated that autophagy augmentation alleviates CS-induced CFTR dysfunction, ceramide accumulation (lipophagy impairment), and resulting COPD-emphysema pathogenesis [22], thus demonstrating that autophagy and CFTR share an interconnected biology crucial for the initiation and progression of chronic lung diseases (Figure 1).
T302	57521-57690	Sentence	denotes	We further went on to demonstrate that CS-induced autophagy dysfunction and the dysfunction of its component lipophagy lead to intracellular ceramide accumulation [110].
T303	57691-57797	Sentence	denotes	Meanwhile, acquired CFTR dysfunctions caused ASM activation-dependent membrane ceramide accumulation [22].
T304	57798-58050	Sentence	denotes	The pathogenic role of ceramide has also been implicated in CF lung disease, wherein it mediates the inflammation, apoptosis, and increased susceptibility to P. aeruginosa infection [183,186,199], and is elevated in the airways of CF mice and patients.
T305	58051-58206	Sentence	denotes	Mechanistically, it was proven that the ROS-dependent activation of acid sphingomyelinase (ASM) resulted in increased membrane ceramide accumulation [200].
T306	58207-58382	Sentence	denotes	Thus, several ASM inhibitors have been tested and were shown to reduce ceramide accumulation along with resulting infection and inflammation in the lungs of CF mice [186,200].
T307	58383-58684	Sentence	denotes	Therefore, there is strong evidence that CFTR-autophagy dysfunction is a prime factor that promotes multiple host destructive phenomena, including inflammatory-oxidative stress and recurrent infection-related exacerbations, which eventually contribute to chronic obstructive lung disease pathogenesis.
T308	58686-58688	Sentence	denotes	8.
T309	58689-58804	Sentence	denotes	Autophagy Augmentation Strategies to Mitigate the Pathogenesis and Progression of Chronic Obstructive Lung Diseases
T310	58805-59059	Sentence	denotes	As discussed above, autophagy-CFTR dysfunction plays a vital role in regulating the pathogenesis of chronic obstructive lung diseases, including facilitating recurrent infections leading to severe disease exacerbations and an increased risk of mortality.
T311	59060-59272	Sentence	denotes	Therefore, it is apparent that pharmacological interventions targeted to correct the autophagy-CFTR dysfunction provides a lucrative therapeutic strategy to control chronic obstructive lung diseases pathogenesis.
T312	59273-59602	Sentence	denotes	Indeed, using in vitro and pre-clinical murine models, we and others have shown that autophagy augmentation mitigates several pathogenic features of chronic lung diseases, such as inflammatory-oxidative stress, apoptosis, cellular senescence, lung tissue damage, and bacterial or viral infections [22,35,42,45,58,62,149,151,153].
T313	59603-59868	Sentence	denotes	The utility of pharmacological or natural compounds that can alleviate autophagy-CFTR dysfunction has been comprehensively investigated in both CS-induced in vitro and pre-clinical murine models of CS exposure, with or without P. aeruginosa co-infection [34,35,42].
T314	59869-60291	Sentence	denotes	We have extensively tested the pre-clinical therapeutic efficacy of cysteamine, a naturally occurring FDA-approved aminothiol compound, which is a known proteostasis and autophagy regulator that induces autophagosome formation, in controlling various pathogenic features of CS- and aging-induced inflammatory-oxidative stress, apoptosis, cellular senescence, pathogen clearance, lung injury, and COPD-emphysema [22,33,94].
T315	60292-60606	Sentence	denotes	Even though cysteamine offers several beneficial attributes such as its antioxidant, bactericidal, mucolytic, and, the most promising, CFTR-rescuing potential that corrects the CS-induced acquired CFTR dysfunction, there are some limitations such as the optimization of beneficial dose and airway delivery methods.
T316	60607-60764	Sentence	denotes	We and others have devised strategies such as nano/dendrimer-based formulations which can be efficiently delivered through intranasal inhalation [42,45,149].
T317	60765-61015	Sentence	denotes	The more specific targeting of pulmonary tissues using nano/dendrimer-based drugs improves the therapeutic potential while mitigating some system-wide side effects that may be associated with systemic and nontargeted delivery methods [42,45,149,201].
T318	61016-61307	Sentence	denotes	We believe that cysteamine or its nano/dendrimer formulations have a significant potential of controlling COPD-emphysema pathogenic features, including recurrent exacerbations, based on its known pre-clinical efficacy and ongoing clinical evaluations in controlling obstructive lung disease.
T319	61308-61534	Sentence	denotes	Our relatively recent study using GSNO, an endogenously occurring nitric oxide donor, highlights the biological significance of CS-induced CFTR dysfunction-related autophagy impairment in mediating COPD-emphysema pathogenesis.
T320	61535-61731	Sentence	denotes	We showed that an augmentation of GSNO decreases cigarette smoke extract (CSE)-induced ROS activation and autophagy-flux impairment by rescuing the aggresome-bound perinuclear CFTR to the PM [62].
T321	61732-62116	Sentence	denotes	Furthermore, using a preclinical COPD-emphysema murine model, we demonstrated that chronic CS (Ch-CS) induced an increase in inflammatory cytokines in BALF, aggresome formation, CFTR-aggresome localization, oxidative/nitrosative stress, and apoptosis, and the emphysematous changes (alveolar airspace enlargement) were significantly improved by augmenting the airway GSNO levels [62].
T322	62117-62285	Sentence	denotes	Thus, this study provides proof-of-concept evidence that GSNO augmentation could be further tested as a potential strategy to correct CS-induced CFTR-autophagy defects.
T323	62286-62549	Sentence	denotes	Apart from cysteamine and GSNO, we also tested the potential of other FDA-approved autophagy-inducing drugs, such as gemfibrozil (GEM), which induces lysosome formation, and fisetin, in controlling CS-induced autophagy dysfunction and hampered pathogen clearance.
T324	62550-62742	Sentence	denotes	Our study showed that CS/CSE-induced TFEB/autophagy impairment, inflammatory-oxidative stress, apoptosis, and senescence can be mitigated by treatment with GEM/fisetin via TFEB induction [34].
T325	62743-62956	Sentence	denotes	In a subsequent investigation, we demonstrated that CSE-induced autophagy dysfunction in macrophages is a critical mechanism of phagocytosis defects and the resulting diminished clearance of P. aeruginosa [33,35].
T326	62957-63224	Sentence	denotes	The autophagy-inducing antioxidant fisetin was able to restore the CS-induced phagocytosis defect and facilitate P. aeruginosa clearance [35], suggesting the potential of autophagy-inducing strategies in controlling exacerbations prevalent in COPD-emphysema subjects.
T327	63225-63411	Sentence	denotes	The therapeutic potential of autophagy augmenting drugs has been extensively investigated in controlling chronic CF lung disease and associated pulmonary infection-related exacerbations.
T328	63412-63661	Sentence	denotes	There have been extensive studies on the use of rapamycin in controlling CF-related lung infections, but its clinical use is hampered due to its potent immunosuppressive property and certain reports of significant lung toxicity [5,6,44,151,153,202].
T329	63662-63846	Sentence	denotes	Lately, the efficacy of the thymic peptide, Thymosin α-1 (Tα1), was demonstrated in correcting the basic defect in CF, which is the restoration of misfolded ΔF508-CFTR to the PM [203].
T330	63847-63995	Sentence	denotes	Tα1 possesses anti-inflammatory properties and is also known to induce autophagy [204], which could be its mechanism of action to rescue ΔF508-CFTR.
T331	63996-64165	Sentence	denotes	Nonetheless, future pre-clinical and clinical studies will be essential before it could be any therapeutic benefit in CF-related autophagy dysfunction and exacerbations.
T332	64166-64395	Sentence	denotes	The utility of cysteamine, a potent antioxidant drug with autophagy-inducing potential, has been widely tested in CF in vitro, in vivo models, and is currently being investigated in phase 2 human clinical trials [58,205,206,207].
T333	64396-64566	Sentence	denotes	However, a previously completed study of 10 patients with the ΔF508-CFTR mutation demonstrated a significant improvement in CFTR function with cysteamine treatment [208].
T334	64567-64838	Sentence	denotes	Similarly, our recent studies validated cysteamine’s extensive repertoire of protective mechanisms in CF, and demonstrated for the first time that cysteamine was able to control CS-induced lipophagy impairment and the resulting ceramide accumulation in murine lungs [22].
T335	64839-65036	Sentence	denotes	This finding might have implications in controlling both COPD and CF-related infections and exacerbations, knowing the deleterious role of ceramide in promoting pulmonary infections in COPD and CF.
T336	65037-65264	Sentence	denotes	In addition, autophagy dysfunction has been now widely accepted as a pathogenic mechanism in IPF, and thus strategies to augment autophagy are justified as relevant potential interventions in controlling IPF pathogenesis [209].
T337	65265-65435	Sentence	denotes	Indeed, some recent studies have shown that autophagy mitigates IPF pathogenesis by regulating the fibroblast apoptosis and senescence of alveolar epithelial cells [209].
T338	65436-65629	Sentence	denotes	Moreover, a recent report describes the utility of IL-37 in reducing the bleomycin-induced inflammation and collagen deposition in murine lungs by increasing Beclin-1-dependent autophagy [158].
T339	65630-65877	Sentence	denotes	Therefore, autophagy augmentation strategies likely have a strong potential to control chronic obstructive lung disease pathogenesis, including suppressing the severe pulmonary exacerbations which frequently result in patient mortality (Figure 2).
T340	65879-65881	Sentence	denotes	9.
T341	65882-65893	Sentence	denotes	Perspective
T342	65894-65977	Sentence	denotes	The burden of exacerbations on the health care system is substantial [1,3,177,210].
T343	65978-66194	Sentence	denotes	For patients with COPD in the United States, the average annual health care costs associated with their condition was estimated to be USD 9981; meanwhile, the average cost to society was USD 30,826 per patient [211].
T344	66195-66368	Sentence	denotes	Similarly, CF exacerbations were demonstrated to cost Medicaid on average between USD 44,589 and USD 116,169 annually with the costs increasing with the age of patients [2].
T345	66369-66468	Sentence	denotes	Another study found that the average cost per episode of all CF exacerbations was USD 12,784 [176].
T346	66469-66681	Sentence	denotes	As such, investigating new methods to prevent recurrent exacerbations is necessary to lower the burden on the health care system while improving the quality of life for patients with chronic pulmonary conditions.
T347	66682-66853	Sentence	denotes	The potential of autophagy augmenting therapeutics to correct CFTR-autophagy dysfunction and resulting exacerbations provides a possible solution to this issue (Figure 2).
T348	66854-67022	Sentence	denotes	As a proof of concept, numerous recent studies have demonstrated the potential of targeting CFTR-autophagy dysfunction as a method for reducing recurrent exacerbations.
T349	67023-67180	Sentence	denotes	One drug that has shown promise in alleviating autophagy impairment to provide possible therapeutic benefits in the treatment of exacerbations is cysteamine.
T350	67181-67382	Sentence	denotes	Cysteamine is an FDA approved drug for the treatment of cystinosis; however, it also possesses antioxidant, anti-inflammatory, autophagy-inducing, mucolytic, and anti-bacterial properties [58,205,207].
T351	67383-67577	Sentence	denotes	Recently, Ferrari et al. demonstrated that cysteamine could re-establish P. aeruginosa clearance in macrophages with the ΔF508-CFTR deletion by salvaging ΔF508-CFTR function in macrophages [58].
T352	67578-67760	Sentence	denotes	This restoration of function allowed macrophages to both increase the internalization and clearance of P. aeruginosa via a Beclin-1-mediated initiation of the autophagy pathway [58].
T353	67761-67896	Sentence	denotes	This reveals a possible therapy to restore both CFTR and autophagy function in CF patients that could limit P. aeruginosa colonization.
T354	67897-68142	Sentence	denotes	An improved clearance of P. aeruginosa in CF patients is especially important due to the prevalence of P. aeruginosa infections in exacerbations, and a drug that improves the immune response in this way offers a method to decrease exacerbations.
T355	68143-68213	Sentence	denotes	Studies exploring cysteamine-dendrimers have revealed similar results.
T356	68214-68421	Sentence	denotes	Two of our recent studies demonstrated that cysteamine-based dendrimers were able to not only decrease ΔF508-CFTR aggregation, but also rescue the protein to increase the plasma membrane expression [45,149].
T357	68422-68598	Sentence	denotes	Moreover, these investigations showed that this recue of CFTR by the cysteamine-dendrimers alleviated the autophagy impairment associated with the ΔF508-CFTR mutation [45,149].
T358	68599-68743	Sentence	denotes	This alleviation of CFTR-autophagy impairment was further shown to increase the clearance and killing of P. aeruginosa in both studies [45,149].
T359	68744-68871	Sentence	denotes	Hence, cysteamine-based dendrimers provide a therapeutic option in the treatment of both acute and chronic exacerbations in CF.
T360	68872-69074	Sentence	denotes	Cysteamine’s dendrimer-based formulation also proved beneficial for clearing P. aeruginosa, and thus has potential for treating other infections in CF and non-CF patients who are prone to exacerbations.
T361	69075-69313	Sentence	denotes	The added advantage of this intervention strategy is that exacerbations in respiratory diseases including those with CFTR dysfunction may be treated and prevented without antibiotics, where multidrug-resistant (MDR) infections are common.
T362	69314-69477	Sentence	denotes	Further studies into the therapeutic potential of other autophagy inducers for exacerbations in chronic respiratory diseases have shown promise as well (Figure 2).
T363	69478-69653	Sentence	denotes	These studies have demonstrated that rapamycin can induce autophagy and aid in the killing of different types of bacteria that are known to cause exacerbations [6,44,153,202].
T364	69654-69843	Sentence	denotes	Similarly, fisetin, which is an over the counter antioxidant used for brain health, induces autophagy [34,43] to improve bacterial clearance by ameliorating CFTR-autophagy dysfunction [35].
T365	69844-69965	Sentence	denotes	Thus, the use of various autophagy inducers shows promise in restoring the CFTR-autophagy pathway to treat exacerbations.
T366	69966-70182	Sentence	denotes	However, future studies and clinical trials need to be conducted to evaluate and standardize the safety and efficacy of these treatments to provide benefit in human subjects as a part of ongoing clinical development.
T367	70183-70392	Sentence	denotes	Another reason to explore treatments that restore the CFTR-autophagy function to treat exacerbations is that the current first-line treatment for exacerbations usually includes antibiotics [4,173,210,212,213].
T368	70393-70546	Sentence	denotes	In situations where patients experience severe exacerbations, they are often hospitalized and given powerful intravenous (IV) antibiotics [4,31,173,176].
T369	70547-70640	Sentence	denotes	This is part of what plays into the exorbitant costs associated with recurrent exacerbations.
T370	70641-70789	Sentence	denotes	When looking specifically at exacerbations requiring hospitalization and IV-antibiotics, the cost is USD 36,319 per exacerbation for patients [176].
T371	70790-71041	Sentence	denotes	This frequent use of antibiotics in both the out-patient and in-patient treatment of exacerbations causes bacteria to develop MDR, which poses a significant issue for patients as the treatment of future infections becomes more difficult [151,214,215].
T372	71042-71129	Sentence	denotes	In fact, many pathogens that cause exacerbations have been found to have MDR [214,215].
T373	71130-71288	Sentence	denotes	As more bacteria demonstrate MDR, more powerful antibiotics are needed to fight off infections, but these powerful antibiotics can have negative side effects.
T374	71289-71436	Sentence	denotes	As such, researchers have begun investigating the potential of targeting the autophagy pathway to fight off the MDR bacteria causing exacerbations.
T375	71437-71590	Sentence	denotes	One recent study explored the potential of cysteamine to improve the clearance and killing of different MDR bacteria by macrophages in CF patients [206].
T376	71591-71778	Sentence	denotes	The researchers demonstrated that there was a significantly increased clearance of B. cenocepacia, B. multivorans, and P. aeruginosa by alveolar macrophages treated with cysteamine [206].
T377	71779-71985	Sentence	denotes	Further exploration revealed a decrease in the markers of autophagy impairment in these cysteamine-treated macrophages, along with an increase in expression of CFTR on the membrane of the macrophages [206].
T378	71986-72164	Sentence	denotes	Thus, it can be concluded that cysteamine has the ability to promote host clearance of MDR pathogens in pulmonary exacerbations via the alleviation of CFTR-autophagy dysfunction.
T379	72165-72300	Sentence	denotes	A similar finding was found in a study that explored a novel autophagy inducer that works by initiating autophagosome formation, AR-13.
T380	72301-72529	Sentence	denotes	The investigators in this study demonstrated that AR-13 on its own was able to significantly reduce the infectious burden of methicillin-resistant Staphylococcus aureus and P. aeruginosa in both CF and non-CF immune cells [152].
T381	72530-72700	Sentence	denotes	Meanwhile, in the case of B. cenocepacia, AR-13 in combination with antibiotics was able to significantly improve the bacterial clearance from infected macrophages [152].
T382	72701-72805	Sentence	denotes	This improved bacterial clearance was attributed to the alleviation of CFTR-autophagy dysfunction [152].
T383	72806-72942	Sentence	denotes	Hence, therapeutics that aim to restore CFTR-autophagy function demonstrate promise in fighting MDR infections that cause exacerbations.
T384	72943-73190	Sentence	denotes	If clinical trials of these drugs were to show promise, they may decrease the length of hospitalization and recurrence of exacerbations to decrease both the costs and decreased quality of life faced by individuals with chronic respiratory disease.
T385	73191-73317	Sentence	denotes	Moreover, the fact that these drugs have been demonstrated to work by inducing autophagy is critical in fighting MDR bacteria.
T386	73318-73499	Sentence	denotes	Since the mechanism involves the host immune response and there would be less of a need for antibiotics, there is the possibility of decreased incidence of MDR bacteria development.
T387	73500-73575	Sentence	denotes	However, bacteria are not the only pathogens responsible for exacerbations.
T388	73576-73682	Sentence	denotes	Viruses are also a common cause of exacerbations in patients with chronic respiratory diseases [4,31,173].
T389	73683-73775	Sentence	denotes	However, the treatment of viruses is significantly different than the treatment of bacteria.
T390	73776-73864	Sentence	denotes	For most bacteria, there is an antibiotic that can be prescribed to fight the infection.
T391	73865-74002	Sentence	denotes	On the other hand, most viruses tend to be treated with supportive care due to the lack of antiviral therapies for many types of viruses.
T392	74003-74246	Sentence	denotes	As such, being able to clear viruses via autophagy/Tvirophagy may provide a unique therapeutic benefit in both reducing the severity of viral infections and decreasing the duration of viral infections, resulting in a decrease in exacerbations.
T393	74247-74376	Sentence	denotes	The focus on targeting autophagy to treat exacerbations in lieu of antiviral medications is limited but is gaining more interest.
T394	74377-74498	Sentence	denotes	One recent study has demonstrated the promise of budesonide, a corticosteroid, in the treatment of rhinovirus infections.
T395	74499-74629	Sentence	denotes	Rhinovirus causes the common cold and is a common viral cause of exacerbations in CF [32,175], asthma [32,216], and COPD [32,217].
T396	74630-74754	Sentence	denotes	In this study, researchers found that intranasal budesonide decreased the viral load of rhinovirus in patients’ lungs [218].
T397	74755-74978	Sentence	denotes	The investigators determined the antiviral effect of budesonide was due to autophagy induction as autophagy inhibition with chloroquine and bafilomycin A1 both significantly reduced the antiviral effect of budesonide [218].
T398	74979-75155	Sentence	denotes	Similarly, a study performed with dexamethasone, another corticosteroid, demonstrated that it is an effective treatment of rhinovirus through autophagy induction as well [219].
T399	75156-75272	Sentence	denotes	Thus, there is promise in treating and preventing exacerbations caused by rhinovirus using autophagy-inducing drugs.
T400	75273-75562	Sentence	denotes	In theory, targeting the induction of autophagy should provide a therapeutic mechanism for the treatment of other viruses that cause exacerbations in patients with chronic respiratory disease due to the role of autophagy in the immune response in many viruses, yet more research is needed.
T401	75563-75734	Sentence	denotes	In addition to showing promise in targeting viruses that cause exacerbations, the induction of autophagy may also aid in fighting novel viruses that can lead to pandemics.
T402	75735-75877	Sentence	denotes	For example, the novel coronavirus SARS-CoV2-mediated human respiratory infection, leading to COVID-19, was first reported in late 2019 [137].
T403	75878-75972	Sentence	denotes	By March 2020, the World Health Organization had declared a pandemic in response to the virus.
T404	75973-76232	Sentence	denotes	SARS-CoV-2 has caused numerous deaths, due to lack of a potent effective treatment, where antivirals such as remdesevir, favipiravir, etc., although minimally effective in reducing the hospitalization time of severe lung disease subjects, are in short supply.
T405	76233-76552	Sentence	denotes	Moreover due to the novel nature of the virus, susceptible population groups and aerosol-based rapid transmission, we see variations in the control of transmission and mortality between different countries, where mitigation measures are dependent on socio-economic, health care disparities and political will [137,220].
T406	76553-76812	Sentence	denotes	As such, there is a need to rapidly deliver on potent treatments in addition to vaccines, and autophagy augmentation with drugs that are FDA-approved for other conditions (Figure 2), provide significant potential for clinical validation and rapid translation.
T407	76813-77142	Sentence	denotes	In fact, a recent pre-print study that we mentioned above has investigated the use of spermidine (an autophagy inducer), MK-2206 (an AKT inhibitor), and niclosamide (a Beclin-1 stabilizer) in the treatment of COVID-19, and has been found to demonstrate some therapeutic benefits as an antiviral treatment against the virus [138].
T408	77143-77217	Sentence	denotes	Thus, autophagy induction may provide a beneficial treatment of the virus.
T409	77218-77305	Sentence	denotes	However, further investigation into these drugs and other autophagy inducers is needed.
T410	77306-77460	Sentence	denotes	Still, the mechanism of autophagy induction may prove crucial as a treatment of COVID-19 over classical antivirals and provide a tool to end the pandemic.
T411	77461-77659	Sentence	denotes	This mechanism may also prevent a future epidemic or pandemic by offering possible treatments to novel viruses without vaccines and antivirals that take significant development time for each strain.
T412	77660-77763	Sentence	denotes	Therefore, targeting and inducing the autophagy pathway is an area of tremendous clinical significance.
T413	77764-78026	Sentence	denotes	Autophagy-inducing drugs may be necessary for overcoming the CFTR-autophagy impairment found in many chronic respiratory diseases to prevent exacerbations and improve the morbidity and mortality for patients while cutting health care costs for these individuals.
T414	78027-78179	Sentence	denotes	Moreover, autophagy-inducing drugs offer the ability to fight pathogens without causing MDR bacteria and the need to develop strain specific antivirals.
T415	78180-78472	Sentence	denotes	As a result, an autophagy induction intervention strategy to handle MDR bacterial infections or novel viral infections provides significant benefits in terms of controlling exacerbations, whereas autophagy induction with drugs currently approved for other conditions allows rapid translation.
T416	78473-78651	Sentence	denotes	Moreover, the proposed autophagy augmenting therapeutic strategy also provides a possible treatment in situations where it is not possible to develop an antiviral for a pathogen.
T417	78652-78759	Sentence	denotes	Furthermore, autophagy induction also can offer an effective way to treat current recurring MDR infections.
T418	78760-79039	Sentence	denotes	Hence, future clinical studies need to expand their scope beyond the horizon of antibiotics and antivirals for the treatment of many respiratory diseases and begin investigating the therapeutic benefits that autophagy augmenting drugs may have in a myriad of clinical situations.
T419	79040-79263	Sentence	denotes	In doing so, we can achieve a significant reduction in the overwhelming health care costs and resources needed for respiratory exacerbations while improving the quality of life with a reduction in the mortality of patients.
T420	79265-79280	Sentence	denotes	Acknowledgments
T421	79281-79490	Sentence	denotes	NV was supported by the NIH (CTSA RRO25005 and RHL096931), Flight Attendant Medical Research Institute’s (FAMRI), Young Clinical Scientist Award (YCSA_082131) and CFF (CFF, R025-CR07 and VIJ07IO) grants to NV.
T422	79491-79642	Sentence	denotes	We thank Manish Bodas former postdoc in Vij’s lab for support with sections related to our laboratories prior work, related literature, and schematics.
T423	79644-79651	Sentence	denotes	Funding
T424	79652-79830	Sentence	denotes	The funders or institution had no role in design, decision to publish or preparation of the manuscript as its authors independent perspective based on prior and ongoing research.
T425	79832-79853	Sentence	denotes	Conflicts of Interest
T426	79854-79986	Sentence	denotes	NV is the lead inventor on patent targeting proteostasis mechanisms for rescuing CFTR protein-processing defect and CF lung disease.
T427	79987-80110	Sentence	denotes	NV is also the lead inventor of nano-based selective drug delivery and therapeutic targeting for obstructive lung diseases.
T428	80111-80304	Sentence	denotes	NV is a founder of PRECISION THERANOSTICS INC and VIJ BIOTECH that focuses on the bench-side translation of novel respiratory therapeutics and declares that he has no other competing interests.
T429	80306-80419	Sentence	denotes	Figure 1 Schematic representation showing mechanisms of respiratory exacerbations and lung disease pathogenesis.
T430	80420-80628	Sentence	denotes	The inflammatory/pathogenic receptors and cystic fibrosis transmembrane conductance regulator (CFTR) localized in lipid-raft membranes modulate immune response on viral or bacterial infection of airway cells.
T431	80629-80957	Sentence	denotes	In subjects with decreased expression of CFTR (chronic obstructive pulmonary disease (COPD)), misfolded-CFTR (ΔF508 CFTR, cystic fibrosis (CF)), or elderly subjects, increase in reactive oxygen species (ROS) activity within the cells inhibits the progression of endocytosed viruses and phagocytosed bacteria into phagolysosomes.
T432	80958-81163	Sentence	denotes	Furthermore, the ROS resulting from misfolded/ΔF508 CFTR or age-related changes causes ceramide accumulation within the plasma membrane, and increases TG2 expression, which causes crosslinking of Beclin-1.
T433	81164-81348	Sentence	denotes	This Beclin-1 crosslinking results in perinuclear aggresome body formation that further impairs autophagolysosomes formation to degrade autophagic cargo and clear infectious pathogens.
T434	81349-81474	Sentence	denotes	As a result of this impaired degradation or clearance, the immune response is further impaired leading to more ROS formation.
T435	81475-81570	Sentence	denotes	This ultimately develops into chronic lung disease with recurrent exacerbations and infections.
T436	81571-81731	Sentence	denotes	In case of viral infections such as SARS-CoV-2, the virus binds to the ACE2 receptor TMPRSS2 complex, to fuse with the host cell and gain entry for replication.
T437	81732-81957	Sentence	denotes	Autophagosome-lysosomal processing is a standard mechanism for clearance of viruses and other pathogen via xenophagy, which when impaired results in exacerbation, chronic inflammation, and pathogenesis of severe lung disease.
T438	81958-82136	Sentence	denotes	Figure 2 Autophagy-inducing compounds and their potential in treating inflammatory-oxidative stress responses, respiratory exacerbations and coronavirus disease-2019 (COVID-19).
T439	82137-82278	Sentence	denotes	The autophagy induction and other properties of various therapeutic compounds for treating pulmonary pathologies and exacerbations are shown.
T440	82279-82542	Sentence	denotes	The ability of these compounds to induce autophagy to rescue dysfunctional CFTR or clearance of misfolded proteins from aggresome bodies is a critical therapeutic property to consider when evaluating possible treatments for age-related and respiratory conditions.
T441	82543-82946	Sentence	denotes	In addition, anti-inflammatory, antioxidant, anti-biofilm, bactericidal, immune boosting, and mucolytic properties are further aspects of these compounds that have significant therapeutic potential in controlling chronic immune responses and exacerbations that trigger fatal lung conditions such as COPD, CF, acute respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis (IPF), and COVID-19.

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Autophagy Augmentation to Alleviate Immune Response Dysfunction, and Resolve Respiratory and COVID-19 Exacerbations

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Abstract

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The preservation of cellular homeostasis requires the synthesis of new proteins (proteostasis) and organelles, and the effective removal of misfolded or impaired proteins and cellular debris.

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This cellular homeostasis involves two key proteostasis mechanisms, the ubiquitin proteasome system and the autophagy–lysosome pathway.

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These catabolic pathways have been known to be involved in respiratory exacerbations and the pathogenesis of various lung diseases, such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and coronavirus disease-2019 (COVID-19).

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Sentence

denotes

Briefly, proteostasis and autophagy processes are known to decline over time with age, cigarette or biomass smoke exposure, and/or influenced by underlying genetic factors, resulting in the accumulation of misfolded proteins and cellular debris, elevating apoptosis and cellular senescence, and initiating the pathogenesis of acute or chronic lung disease.

T7

1166-1448

Sentence

denotes

Moreover, autophagic dysfunction results in an impaired microbial clearance, post-bacterial and/or viral infection(s) which contribute to the initiation of acute and recurrent respiratory exacerbations as well as the progression of chronic obstructive and restrictive lung diseases.

T8

1449-1621

Sentence

denotes

In addition, the autophagic dysfunction-mediated cystic fibrosis transmembrane conductance regulator (CFTR) immune response impairment further exacerbates the lung disease.

T9

1622-1884

Sentence

denotes

Recent studies demonstrate the therapeutic potential of novel autophagy augmentation strategies, in alleviating the pathogenesis of chronic obstructive or restrictive lung diseases and exacerbations such as those commonly seen in COPD, CF, ALI/ARDS and COVID-19.

T10

1886-1888

Sentence

denotes

1.

T11

1889-1901

Sentence

denotes

Introduction

T12

1902-2201

Sentence

denotes

Chronic obstructive and restrictive lung diseases are among the leading causes of mortality worldwide, where acute or recurrent episodes of respiratory exacerbations are not only responsible for significant health care costs and a poor quality of life, but also an increased risk of death [1,2,3,4].

T13

2202-2399

Sentence

denotes

The airway mucosa is a primary route of entry for pathogenic microorganisms (bacteria, virus and/or fungi) and represents an important barrier in preventing the entry of these infectious organisms.

T14

2400-2839

Sentence

denotes

In the event that the pathogen evades this mucociliary defense mechanism, the airway epithelial cells utilize complex pathogen clearance mechanisms to restrict the life-threatening exacerbations, where these cells work in collaboration with our immune system, involving both innate and adaptive responses, to launch a robust immune response against the invading pathogens, which if successful, results in pathogen elimination or clearance.

T15

2840-3152

Sentence

denotes

Thus, providing proof-of-concept evidence in support of autophagy augmentation strategies for alleviating respiratory exacerbations in chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and coronavirus disease-2019 (COVID-19).

T16

3153-3406

Sentence

denotes

A plethora of studies have identified the “autophagy-lysosome pathway”, a major cellular degradation system, as one of the important mechanisms involved in regulating the immune-mediated pathogen clearance mechanisms in several infection models [5,6,7].

T17

3407-3566

Sentence

denotes

Evidence suggests that a specific form of autophagy, called “xenophagy”, is responsible for the elimination of bacterial, viral or fungal pathogens [7,8,9,10].

T18

3567-3881

Sentence

denotes

In general, autophagy (mainly macroautophagy) is one of the two components of the cellular homeostatic machinery called the “proteostasis network (PN)” [11,12,13,14], which could be termed as the “master regulator of cellular well-being”, as it regulates all the processes involved in protein turnover in the cell.

T19

3882-4217

Sentence

denotes

The other component of the PN is the ubiquitin-proteasome system (UPS), which deals primarily with the degradation of cellular proteins [15,16,17,18,19] which allows protein turnover and a replacement of misfolded proteins, as well as the regulation of vital regulatory proteins involved in a variety of cellular homeostatic processes.

T20

4218-4448

Sentence

denotes

In contrast, the autophagy-lysosome pathway can handle the degradation of much broader and larger cargo, such as protein aggregates, lipids, damaged organelles, or infectious agents such as bacteria and viruses [9,20,21,22,23,24].

T21

4449-4701

Sentence

denotes

These two components of the PN play a vital role in maintaining cellular homeostasis by facilitating the removal of these dysfunctional cellular components while maintaining or replenishing the levels of proteins, lipids, etc., via synthetic machinery.

T22

4702-4889

Sentence

denotes

Other proteostatic mechanisms include the unfolded protein response (UPR), small ubiquitin-like modifier (SUMO), and the endoplasmic reticulum (ER)-associated degradation (ERAD) pathways.

T23

4890-5099

Sentence

denotes

Both SUMO and ERAD have a role in the trafficking of the misfolded cystic fibrosis transmembrane conductance regulator (CFTR), which is the dysfunctional protein responsible for the pathogenesis of CF [25,26].

T24

5100-5273

Sentence

denotes

Furthermore, the dysregulation of UPR has been shown to lead to an exaggerated inflammatory response that plays a role in CF pathogenesis progression and exacerbations [27].

T25

5274-5540

Sentence

denotes

Therefore, it is evident that any dysregulation of the PN components leads to severe life-threatening diseases that includes proteinopathies, neurodegenerative diseases, age-related disorders, and chronic respiratory diseases such as CF and COPD [11,13,15,28,29,30].

T26

5541-5745

Sentence

denotes

Respiratory infections serve as a trigger for disease exacerbation, while exposure to tobacco, biomass smoke, and aging, are the leading causes for COPD-emphysema development and progression [4,31,32,33].

T27

5746-6073

Sentence

denotes

We and others have demonstrated that autophagy impairment is the key central mechanism for tobacco, biomass smoke or e-cigarette vapor (eCV) exposure and the age-related induction of inflammatory-oxidative stress, alveolar apoptosis and senescence, leading to COPD-emphysema pathogenesis and progression [33,34,35,36,37,38,39].

T28

6074-6278

Sentence

denotes

Additionally, the above-described causative mechanisms also hamper the pathogen clearance, and thus make the individual more prone to acute or recurrent respiratory infections or exacerbations [35,39,40].

T29

6279-6538

Sentence

denotes

Mechanistically, cigarette smoke (CS)-induced phagocytosis defects involves autophagy impairment, which blunts the clearance and promotes the survival of disease-causing pathogens, thereby facilitating chronic infections or recurrent exacerbations [34,35,36].

T30

6539-6778

Sentence

denotes

In addition, we recently demonstrated that exposure to CS and other noxious environmental agents promotes accelerated lung aging, which is another important factor contributing to increased infections in chronic lung disease subjects [33].

T31

6779-6893

Sentence

denotes

In fact, aging per se is responsible for an increased risk of pulmonary infections due to the decline of immunity.

T32

6894-7131

Sentence

denotes

Notably, the PN and autophagy are known to decrease over time with age, and therefore, serve a crucial role in determining the increased risk of lung infections in the elderly, by virtue of hampered pathogen clearance mechanisms [13,41].

T33

7132-7342

Sentence

denotes

Therefore, several studies, including our recent reports, demonstrate the therapeutic potential of novel autophagy augmentation strategies for controlling COPD-emphysema pathogenesis and progression [22,42,43].

T34

7343-7638

Sentence

denotes

Autophagy plays a crucial role in the elimination of pathogens, and the pharmacological disruption of autophagy has been shown to impair host defense against Pseudomonas aeruginosa (P. aeruginosa), while the induction of autophagy facilitates P. aeruginosa clearance from murine lungs [5,44,45].

T35

7639-7836

Sentence

denotes

Additionally, autophagy-related 7 (ATG7)-dependent autophagy is reported to have a significant role in murine host resistance to Klebsiella pneumoniae, an important respiratory track pathogen [46].

T36

7837-8078

Sentence

denotes

Similarly, during a pulmonary infection with Chlamydia pneumoniae in mice, autophagy restricts inflammasome activation, while mice deficient in autophagy demonstrate an increased mortality, highlighting the protective role of autophagy [47].

T37

8079-8159

Sentence

denotes

Immunity against viral infections in the airways is also regulated by autophagy.

T38

8160-8308

Sentence

denotes

For example, autophagy deficiency promotes interleukin (IL)-17-mediated lung pathology in mice infected with respiratory syncytial virus (RSV) [48].

T39

8309-8455

Sentence

denotes

Furthermore, a recent study demonstrates that IL-22 inhibits RSV production by blocking the virus-mediated suppression of cellular autophagy [49].

T40

8456-8754

Sentence

denotes

Moreover, recent studies on Middle East respiratory syndrome (MERS) coronavirus [50] provide proof-of-concept evidence on the therapeutic potential of autophagy modulating drugs for combating the SARS-COV2 infection, cytokine storm, and pathogenesis of severe ARDS-like COVID-19 fatal lung disease.

T41

8755-8913

Sentence

denotes

Another elaborately studied example where autophagy regulates inflammatory-oxidative stress, inflammation, and infection-mediated disease exacerbations is CF.

T42

8914-9298

Sentence

denotes

CF is a genetic disorder, wherein the ΔF508-CFTR is the most common mutation leading to lack of membrane-resident functional CFTR, where the absence of the functional CFTR on the plasma membrane (PM) deteriorates the pathogen clearance ability in CF subjects, leading to persistent infections and chronic inflammation, culminating into a catastrophic lung function decline [51,52,53].

T43

9299-9570

Sentence

denotes

Studies in CF cell lines and knockout mice suggest that the absence of CFTR by itself is sufficient to promote a pro-inflammatory milieu, at least in part, by the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) signaling [54,55,56,57].

T44

9571-9745

Sentence

denotes

Moreover, a transient transfection of wild type (WT)-CFTR reduced tumor necrosis factor α (TNFα)-mediated NFκB activation, confirming the anti-inflammatory role of CFTR [55].

T45

9746-9911

Sentence

denotes

Furthermore, a P. aeruginosa infection in CF mice leads to a more pronounced NFκB-mediated inflammatory response and pathogenesis of CF-related lung disease [51,58].

T46

9912-10092

Sentence

denotes

Thus, membrane-resident functional CFTR is demonstrated to be a critical regulator of innate and adaptive immune responses, in addition to its classical role as an ion transporter.

T47

10093-10344

Sentence

denotes

A recent comprehensive article summarizes the role of dysfunctional CFTR in the controlling cellular signaling pathways used by innate immune cells for combating infections such as airway epithelial cells, neutrophils, monocytes, and macrophages [59].

T48

10345-10560

Sentence

denotes

Additionally, we and others have shown a clear role of membrane-CFTR in regulating the function of adaptive immune cells, such as CD3+ T cells, CD4+ T cells, CD4+FoxP3+ regulatory T cells (T regs), and B cells [59].

T49

10561-10849

Sentence

denotes

A recent intriguing study found that CFTR dysfunction in platelets leads to aberrant transient receptor potential cation channel subfamily C member 6 (TRPC6)-dependent platelet activation, which was proposed as a major driver of CF-lung inflammation and impaired bacterial clearance [60].

T50

10850-11016

Sentence

denotes

Thus, autophagy plays a vital role in limiting lung infections, and it is evident that a complete or partial absence of functional CFTR leads to autophagy impairment.

T51

11017-11239

Sentence

denotes

Mechanistically, CFTR loss or dysfunction results in the reactive oxygen species (ROS)-mediated activation of transglutaminase-2 (TGM-2), and inactivation of the Beclin-1 complex, thereby causing autophagy impairment [61].

T52

11240-11477

Sentence

denotes

Apart from the genetic loss or dysfunction of CFTR, exposure to CS also leads to decreased CFTR activity and expression in vitro, in animal models and in smokers with or without COPD, primarily via ROS-dependent mechanisms [22,42,62,63].

T53

11478-11672

Sentence

denotes

This acquired CFTR dysfunction results in increased inflammatory-oxidative stress, apoptosis, cellular senescence, defective autophagy, and impaired mucociliary clearance, all hallmarks of COPD.

T54

11673-11988

Sentence

denotes

To summarize, we and others have demonstrated that autophagy augmentation has the potential to not only control CFTR dysfunction-mediated pathologies in CF and COPD, but also allows the clearance of opportunistic infections while balancing immune regulation to avoid recurrent exacerbations and disease progression.

T55

11989-12128

Sentence

denotes

This provides a potential to tailor autophagy augmentation for acute and respiratory exacerbations in CF, COPD, ALI/ARDS and COVID-19, etc.

T56

12129-12378

Sentence

denotes

Hence, we focus here on the role of autophagy in pulmonary infections and immune dysfunction, where the therapeutic potential of novel autophagy augmenting strategies to alleviate lung disease pathogenesis and respiratory exacerbations is discussed.

T57

12380-12382

Sentence

denotes

2.

T58

12383-12428

Sentence

denotes

Autophagy, Respiratory Infection and Immunity

T59

12429-12602

Sentence

denotes

Autophagy is the proteostatic process that helps maintain healthy cellular homeostasis by degrading dysfunctional cellular components, lipids, misfolded proteins, etc. [64].

T60

12603-12749

Sentence

denotes

In addition to processing dysfunctional cellular components, autophagy also plays a critical role in immunity and the clearance of pathogens [64].

T61

12750-12994

Sentence

denotes

When working at optimal levels, the autophagy pathway can clear cells of infections via xenophagy, participate in innate and adaptive immune responses, activate macrophages, and remove damaged mitochondria via mitophagy [8,9,20,61,64,65,66,67].

T62

12995-13213

Sentence

denotes

In the respiratory tract specifically, autophagy has even been shown to dictate the length of cilia in the mucociliary escalator that is responsible for the mechanical clearing of pathogens from the airways [68,69,70].

T63

13214-13317

Sentence

denotes

However, the dysfunction and inhibition of autophagy can lead to the pathogenesis of various illnesses.

T64

13318-13423

Sentence

denotes

When it comes to respiratory bacterial infections, autophagy is necessary for a complete immune response.

T65

13424-13523

Sentence

denotes

Mycobacterium tuberculosis (M. tuberculosis) is an intercellular pathogen that causes tuberculosis.

T66

13524-13694

Sentence

denotes

M. tuberculosis evades the body’s immune response by forming granulomas and blocks phagolysosome trafficking to inhibit the intracellular killing of pathogens [71,72,73].

T67

13695-13982

Sentence

denotes

Recently, studies have demonstrated the importance of functional autophagy in targeting and killing M. tuberculosis in respiratory cells by showing that the induction of autophagy pathways overcomes the inhibition of phagolysosome formation to effectively kill M. tuberculosis [6,74,75].

T68

13983-14236

Sentence

denotes

In the case of Streptococcus pneumoniae (S. pneumoniae), which is the most common pathogen causing community acquired pneumonia [76], studies have demonstrated that infection activates the autophagy pathway as part of the body’s immune response [77,78].

T69

14237-14507

Sentence

denotes

Recently, it has been shown that this induction of autophagy makes the clearance of S. pneumoniae infection more effective by enhancing the rate of phagocytosis by neutrophils [78], demonstrating that autophagy is necessary for an effective immune response in pneumonia.

T70

14508-14734

Sentence

denotes

Studies have also exhibited the activation of autophagy in alveolar macrophages by Pseudomonas aeruginosa (P. aeruginosa) [5,79] and Klebsiella pneumoniae [46,79] to induce the degradation of these pathogens in phagolysosomes.

T71

14735-14901

Sentence

denotes

Moreover, there has been evidence that autophagy is activated by lipopolysaccharide (LPS), which is a bacterial toxin on the outer membrane of Gram-negative bacteria.

T72

14902-15074

Sentence

denotes

Typically, LPS can cause inflammation that leads to lung injury [80,81]; however, the activation of autophagy in response to LPS was shown to attenuate lung injury [82,83].

T73

15075-15300

Sentence

denotes

Autophagy is not only integral to the immune response to bacterial infections within the respiratory system, but it has been demonstrated to play an important role in the response to viral pathogens as well [8,9,20,65,84,85].

T74

15301-15457

Sentence

denotes

In the case of the influenza virus, studies have demonstrated autophagy is similarly induced to attenuate the virus and limit its replication [84,85,86,87].

T75

15458-15671

Sentence

denotes

Autophagy has also been shown to be essential in the activation of dendritic cells to produce cytokines and mount an immune response to respiratory synovial virus (RSV) [88,89], MERS [50] and SARS-CoV2 [90,91,92].

T76

15672-15818

Sentence

denotes

Therefore, autophagy is an essential part of the immune response against bacterial and viral pathogens attempting to invade the respiratory tract.

T77

15820-15822

Sentence

denotes

3.

T78

15823-15858

Sentence

denotes

Mechanisms of Autophagy Dysfunction

T79

15859-16006

Sentence

denotes

Despite the importance of autophagy, there are many conditions where this process can become dysfunctional, leading to various pathological states.

T80

16007-16147

Sentence

denotes

In the lungs, the major sources of autophagy dysfunction includes first- and second-hand cigarette smoke (CS) exposure and aging [35,62,93].

T81

16148-16291

Sentence

denotes

Studies have demonstrated that CS exposure can decrease the expression of transcription factor-EB (TFEB), a master autophagy regulator [34,35].

T82

16292-16456

Sentence

denotes

This occurs by the dysfunctional processing of TFEB in response to CS, causing the perinuclear localization of TFEB which prevents the activation of autophagy [62].

T83

16457-16554

Sentence

denotes

This CS-induced autophagy impairment of TFEB leads to impaired bacterial clearance [22,33,34,35].

T84

16555-16756

Sentence

denotes

Furthermore, there is evidence that CS exposure increases the accumulation of ubiquitinated proteins and p62 (a marker of autophagy impairment) in aggresome bodies, further impairing autophagy [22,34].

T85

16757-16957

Sentence

denotes

These deleterious effects of CS exposure on autophagy have also been demonstrated to be present in eCV exposure, which similarly impairs autophagy through the accumulation of aggresome bodies [39,94].

T86

16958-17201

Sentence

denotes

Furthermore, increasing the severity of pulmonary dysfunction and autophagy impairment has been observed to statistically correlate directly with increased levels of aggresome bodies [36], demonstrating its potential as a prognostic biomarker.

T87

17202-17305

Sentence

denotes

Hence, CS exposure demonstrates a common, but preventable way autophagy can be impaired in individuals.

T88

17306-17432

Sentence

denotes

Notably, CS exposure accelerates lung aging, known to be initiated by autophagy decline, which can exacerbate infections [33].

T89

17433-17504

Sentence

denotes

In addition to smoking, autophagy can be impaired by infectious agents.

T90

17505-17648

Sentence

denotes

Due to the conserved nature of autophagy, many organisms have adapted and evolved mechanisms to impair autophagy in order to infect their host.

T91

17649-17858

Sentence

denotes

For example, studies have demonstrated that the influenza virus promotes its own survival by preventing autophagolysosome formation; thus, leading to autophagy impairment via aggresome accumulation [41,85,95].

T92

17859-17998

Sentence

denotes

Influenza has also been found to prevent the autophagy-dependent presentation of viral antigens necessary to mount an immune response [10].

T93

17999-18263

Sentence

denotes

Similarly, investigations have found that severe acute respiratory syndrome coronavirus (SARS-CoV) can inhibit autophagolysosome formation with trans membrane papain-like protease 2 (PLP2-TM) to provoke phagolysosome accumulation causing autophagy impairment [96].

T94

18264-18453

Sentence

denotes

Additionally, the nonstructural protein 6 (NSP6) of coronaviruses has also been observed to restrict autophagosome development to prevent cells from inhibiting coronavirus replication [97].

T95

18454-18540

Sentence

denotes

However, autophagy inhibition by pathogens is not something that is unique to viruses.

T96

18541-18764

Sentence

denotes

Legionella pneumophilia (L. pneumophilia) has been found to delay the progression of infected autophagosomes to lysosomes to allow the bacteria to develop an acid-tolerant state prior to autophagolysosome formation [98,99].

T97

18765-18904

Sentence

denotes

This delay allows L. pneumophilia to replicate in the acidic environment of the autophagolysosome [99] and cause infection within the host.

T98

18905-19087

Sentence

denotes

This mechanism of autophagy impairment is not unique to L. pneumophilia and has been observed as a common mechanism of bacteria to promote their invasion and replication [7,100,101].

T99

19088-19361

Sentence

denotes

M. tuberculosis has also been observed to impair phagolysosome formation; meanwhile, other studies have further demonstrated that M. tuberculosis has the ability to activate cellular pathways that inhibit autophagy within macrophages to promote intracellular survival [61].

T100

19362-19475

Sentence

denotes

Hence, there are various organisms that can infect humans and cause autophagy dysfunction for their own survival.

T101

19476-19556

Sentence

denotes

The expression of CFTR has been shown to influence autophagy as discussed above.

T102

19557-19725

Sentence

denotes

One mechanism of decreased CFTR expression is due to the genetic defects found in CF, where the most common mutation seen in these patients is ΔF508-CFTR [102,103,104].

T103

19726-19874

Sentence

denotes

Studies have demonstrated that ΔF508-CFTR causes protein misfolding that forms aggregates potentially impairing cellular proteostasis [20,42,53,61].

T104

19875-20017

Sentence

denotes

This dysfunction caused by ΔF508-CFTR includes autophagy dysfunction and decreases pathogen clearance in the airways of patients with CF [53].

T105

20018-20098

Sentence

denotes

Similar findings were observed in macrophages with dysfunctional CFTR [105,106].

T106

20099-20316

Sentence

denotes

Along with the genetic mechanism of CFTR dysfunction present in CF that can impair autophagy, CFTR function has been shown to be diminished by CS exposure [40,107,108,109], which is known as acquired CFTR dysfunction.

T107

20317-20512

Sentence

denotes

One mechanism of CS-induced CFTR dysfunction leading to impaired autophagy is through increased ceramide accumulation as a result of altered sphingolipid homeostasis in COPD patients [22,93,110].

T108

20513-20628

Sentence

denotes

CS exposure can also increase ROS which causes CFTR to accumulate in aggresome bodies and impair autophagy [42,62].

T109

20629-20791

Sentence

denotes

Thus, both genetic mechanisms and CS exposure or environmental factors play a critical role in CFTR dysfunction and the resulting autophagy impairment (Figure 1).

T110

20793-20795

Sentence

denotes

4.

T111

20796-20841

Sentence

denotes

Autophagy Dysfunction in Respiratory Diseases

T112

20842-21165

Sentence

denotes

A number of recent studies have identified autophagy dysfunction as the central mechanism of elevated inflammatory-oxidative stress, alveolar apoptosis, cellular senescence, and recurrent infections, all of which contribute to the pathogenesis and progression of acute and chronic respiratory diseases [22,35,61,62,70,111].

T113

21166-21410

Sentence

denotes

The inherent ROS in the CS, and the resulting increase in cellular endogenous ROS post-CS exposure, symbiotically contribute to extremely high intracellular ROS levels, which creates an imbalance in the oxidant–antioxidant ratio [22,34,61,112].

T114

21411-21678

Sentence

denotes

This serves as the basic mechanism for lung cellular injury, tissue damage, and the pathogenesis of chronic obstructive or restrictive lung diseases, such as COPD-emphysema (obstructive) and idiopathic pulmonary fibrosis (IPF, restrictive) [37,38,61,113,114,115,116].

T115

21679-21936

Sentence

denotes

Several groups including ours have demonstrated that elevated ROS levels are the key upstream driver of autophagy dysfunction, as treatments with antioxidant drugs rescues the age-related, or smoke, or eCV exposure-induced autophagy defect [15,22,42,61,62].

T116

21938-21942

Sentence

denotes

4.1.

T117

21943-21987

Sentence

denotes

Autophagy Defects in Acute Lung Injury (ALI)

T118

21988-22359

Sentence

denotes

Extensive studies utilizing both in vitro and in vivo models of acute lung injury have demonstrated the protective role of autophagy via regulating inflammatory-oxidative stress, apoptosis, and pathogen clearance mechanisms, even though there were some initial opposing studies [117,118,119], the subsequent detailed evaluation validates the protective role as discussed.

T119

22360-22507

Sentence

denotes

In general, autophagy is induced upon exposure to common triggers of ALI, such as LPS, bacterial infections, hyperoxia, sepsis, etc. [120,121,122].

T120

22508-22646

Sentence

denotes

There seems to be a consensus that autophagy indeed plays a protective role in LPS-induced acute lung injury and inflammation [82,83,123].

T121

22647-22975

Sentence

denotes

In support of this, LPS-mediated severe lung injury in mice, as quantified by lung edema, elevated leukocyte infiltrations, hemorrhages, and increased inflammatory cytokines (IL-1β and TNFα) in the bronchoalveolar lavage fluid (BALF), was further exacerbated by autophagy inhibition, thereby suggesting its protective role [82].

T122

22976-23210

Sentence

denotes

Mechanistically, the activation of the mammalian target of rapamycin (mTOR) and the resulting autophagy dysfunction has been implicated in promoting LPS-induced lung injury, possibly through the activation of NFκB signaling [124,125].

T123

23211-23453

Sentence

denotes

Further evidence comes from studies demonstrating the utility of autophagy inducers and/or antioxidant drugs in ameliorating LPS-induced acute lung injuries, while treatment with autophagy inhibitors reversed the beneficial effects [125,126].

T124

23454-23744

Sentence

denotes

Autophagy is also protective in sepsis-induced lung injury, as a deficiency of proteins interacting with C-kinase 1 (PICK1) in mice leads to defective autophagy, and more severe acute lung injury in the cecal ligation and puncture (CLP) model of sepsis, as compared to WT animals [120,127].

T125

23745-24016

Sentence

denotes

Additionally, in murine models of hyperoxia-induced ALI, which resembles features of bronchopulmonary dysplasia (BPD), autophagy is proposed as a protective mechanism, and markers of defective autophagy are found in the lungs of human neonates with established BPD [128].

T126

24017-24425

Sentence

denotes

Another recent study describes the suppression of autophagy as a critical mechanism of chronic parenteral nutrition-mediated lung injury, and treatment with the autophagy inducer, rapamycin (an mTOR inhibitor that initiates nucleation, autophagosome elongation, autophagosome maturation, and autophagosome termination), reversed the lung injury features in the animal model of parenteral nutrition [129,130].

T127

24426-24620

Sentence

denotes

Finally, mice deficient in crucial autophagy proteins such as Atg7, Atg5 and Atg4a demonstrate more severe ALI features [83,121,130,131], thus confirming the protective role of autophagy in ALI.

T128

24622-24626

Sentence

denotes

4.2.

T129

24627-24690

Sentence

denotes

Autophagy Defects in Acute Respiratory Distress Syndrome (ARDS)

T130

24691-24777

Sentence

denotes

More severe forms of ALI may progress to acute respiratory distress syndrome, or ARDS.

T131

24778-24867

Sentence

denotes

Autophagy has been shown to play a critical role in regulating the outcome of ARDS [120].

T132

24868-24974

Sentence

denotes

The clinical manifestations of ARDS are very severe and may lead to rapid lung function decline and death.

T133

24975-25337

Sentence

denotes

Using one of most widely used murine models of ALI, the CLP, a recent study demonstrated that autophagy induction by rapamycin was able to improve the survival rate, histological scores, lung wet/dry ratios, PaO2/FiO2, and inflammatory cytokine and myeloperoxidase (MPO) levels in BALF, suggesting a protective role of autophagy in sepsis-induced ALI/ARDS [120].

T134

25338-25481

Sentence

denotes

In another study, the potential of BML-111, a lipoxin A4 receptor antagonist, was evaluated in controlling LPS-induced septic ALI/ARDS in rats.

T135

25482-25698

Sentence

denotes

The authors showed that BML-111 inhibited apoptosis and induced autophagy in alveolar macrophages, in response to the LPS challenge, via the suppression of MAPK1 and MAPK8 signaling and was independent of mTOR [132].

T136

25699-25884

Sentence

denotes

Moreover, BML-111 controlled the LPS-induced production of pro-inflammatory cytokines, and reduced apoptosis in the rat lungs, and thus warrants further investigation in ALI/ARDS [132].

T137

25885-26043

Sentence

denotes

Mechanical ventilation (MV)-induced lung injury is another severe form of ARDS, wherein the activation of inflammasome has been shown to mediate ALI symptoms.

T138

26044-26267

Sentence

denotes

In a recent article, starvation-induced autophagy augmentation was shown to protect against LPS- and MV-induced ARDS features by reducing IL-1β levels, decreasing lung permeability, and improving arterial oxygenation [133].

T139

26268-26526

Sentence

denotes

Thus, autophagy had a protective role in controlling the inflammasome activation and resolution of the MV-induced production of IL-1β, which plays a pathogenic role through inducing hypoxemia and increasing lung permeability in LPS/MV-induced ALI/ARDS [133].

T140

26527-26783

Sentence

denotes

Although some contrasting reports regarding the role of autophagy in ALI/ARDS were initially reported [134], there has been a consensus on the therapeutic advantage of autophagy augmentation in ALI/ARDS based on significant validation studies [64,120,122].

T141

26784-26877

Sentence

denotes

Thus, proper autophagy function is essential in attenuating the severity of ARDS in patients.

T142

26879-26883

Sentence

denotes

4.3.

T143

26884-26936

Sentence

denotes

Critical Role of Autophagy in COVID-19 Exacerbations

T144

26937-27073

Sentence

denotes

The ongoing SARS-CoV-2 pandemic has severely impacted quality of life with a significant health care and socio-economic burden globally.

T145

27074-27272

Sentence

denotes

In general, the cellular endocytic and autophagy pathways contribute to viral entry and replication, and thus are obvious attractive targets against SARS-CoV-2 and other viral infections [90,91,92].

T146

27273-27511

Sentence

denotes

The SARS-CoV-2 virus, which causes COVID-19, is highly infectious and can cause cytokine-storm leading to pneumonia and severe lung damage in susceptible subjects by triggering an ARDS-like lung disease, with high-risk of mortality [135].

T147

27512-27709

Sentence

denotes

Recent evidence suggests that SARS-CoV-2 may inhibit autophagy, which we anticipate as a potential mechanism for severe COVID-19 lung disease due to impaired viral clearance and immune dysfunction.

T148

27710-27875

Sentence

denotes

In a recent study of the SARS-CoV-2 genome, researchers found that the NSP6 protein of the virus binds with greater affinity to the endoplasmic reticulum (ER) [136].

T149

27876-28048

Sentence

denotes

This genetic change may allow the virus to inhibit autophagy via impaired autophagosome processing, which prevents the degradation of viral particles by the lysosome [136].

T150

28049-28288

Sentence

denotes

There is also evidence that PLP2 is over-expressed in SARS-CoV and MERS-CoV cell lines that also allows the virus to inhibit autophagolysosomal formation and autophagy flux and is likely a method of autophagy inhibition in SARS-CoV-2 [96].

T151

28289-28540

Sentence

denotes

These studies suggest potential mechanism by which SARS-CoV-2 inhibits autophagy to infect or circumvent host cells pathogenic clearance pathways and limit an adequate immune response similar to other coronaviruses that warrants further investigation.

T152

28541-28685

Sentence

denotes

The elimination of viruses by autophagy (sometimes termed as virophagy) has been well described for a variety of viral infections [8,84,85,137].

T153

28686-28859

Sentence

denotes

Although, the virus has multiple ways of entry into the cell, autophagy augmentation provides strategic advantage in reducing viral load by promoting its clearance [90,137].

T154

28860-29048

Sentence

denotes

As a proof of concept, recent study demonstrated the utility of three different autophagy-inducing drugs, spermidine, MK02206, and niclosamide, in restricting SARS-CoV-2 propagation [138].

T155

29049-29238

Sentence

denotes

Autophagy induction and related upregulation of overall immunity helps combat exacerbations and is suggested as an immunity boosting strategy as a preventive measure against COVID-19 [139].

T156

29239-29491

Sentence

denotes

In addition to boosting immunity, dampening viral load, and allowing SARS-COV2 clearance, autophagy induction may provide strategic advantage in the treatment of COVID-19 and prevention of negative outcomes, which makes it a subject of ongoing studies.

T157

29492-29759

Sentence

denotes

In support of this, autophagy inhibiting drugs, such as hydroxychloroquine (HCQ) that help dampen the immune response in rheumatoid arthritis, malaria, and other illnesses but weakens cellular ability for viral clearance by the critical homeostatic process autophagy.

T158

29760-29982

Sentence

denotes

Despite early claims that HCQ may provide benefit in treating COVID-19 [90,91,92], it has since been deemed unsafe for use in COVID-19 treatment by the FDA based on randomized double blind placebo control trials [140,141].

T159

29983-30273

Sentence

denotes

In addition, earlier studies on Middle East respiratory syndrome (MERS) coronavirus [50] provide proof-of-concept data on therapeutic potential of autophagy modulating drugs to combat SARS-COV2 infection, cytokine storm, and the pathogenesis of severe ARDS-like COVID-19 fatal lung disease.

T160

30274-30604

Sentence

denotes

Prior studies showing a protective role of autophagy induction in other models of ARDS demonstrate the scope of autophagy augmenting strategies in combating SARS-CoV-2 infections (Figure 1) and thus is part of ongoing validation and rapid clinical development studies that may help limit the burden and spread of this novel virus.

T161

30605-30873

Sentence

denotes

As discussed above for other lung diseases, targeting autophagy to prevent the replication of SARS-CoV-2 is not the only potential benefit of autophagy augmentation for the treatment of COVID-19, but it may also allow the fine-tuning of optimal inflammatory responses.

T162

30874-31093

Sentence

denotes

As now known, the pathogenesis of SARS-CoV-2-mediated severe COVID-19 involves the activation of numerous pro-inflammatory cytokines as part of the aforementioned cytokine storm causing a hyper-inflammatory state [142].

T163

31094-31355

Sentence

denotes

In addition to the destruction of the lungs and ARDS associated with COVID-19, this inflammatory response can cause damage to the cardiovascular, nervous, renal, hepatic, and gastrointestinal systems with wide ranging immediate and long-term consequences [142].

T164

31356-31499

Sentence

denotes

In support of this, studies have demonstrated the role of autophagy in the inflammatory response within the lungs and other organ systems [61].

T165

31500-31620

Sentence

denotes

As mentioned above, autophagy induction has been demonstrated to attenuate lung inflammation when exposed to a pathogen.

T166

31621-31839

Sentence

denotes

Thus, autophagy induction to limit the inflammatory response, in addition to infection, has an immense therapeutic potential as an effective treatment for COVID-19 and decreasing the associated mortality and morbidity.

T167

31841-31845

Sentence

denotes

4.4.

T168

31846-31871

Sentence

denotes

Autophagy Defects in COPD

T169

31872-32099

Sentence

denotes

We and others have described autophagy dysfunction as a prime causative factor utilizing in vitro and animal models of smoke- (cigarette and waterpipe) or eCV (nicotine)-induced lung injury and COPD-emphysema [33,34,39,94,109].

T170

32100-32389

Sentence

denotes

Moreover, these were validated in human subjects where defective autophagy was verified using human lung tissues from COPD-emphysema subjects, where classical autophagy impairment features, such as aggresome bodies, were associated with the severity and progression of the disease [22,36].

T171

32390-32694

Sentence

denotes

These aggresome bodies are perinuclear accumulations of misfolded or aggregated proteins, which are poly-ubiquitinated and co-localize with p62 and the autophagy protein microtubule-associated protein 1 light-chain-3B(+) (LC3B+) bodies, and are the key indicators of defective autophagy flux [33,36,143].

T172

32695-32993

Sentence

denotes

Additionally, we and others have also noted the increase in aggresome body formation in aged mice lungs that correlated with alveolar airspace enlargement (emphysema phenotype), indicating that age-related decline in autophagy contributes to COPD-emphysema development, similar to CS exposure [33].

T173

32994-33242

Sentence

denotes

Moreover, an increase in emphysema severity (GOLD 0-IV) in smokers with a minimal age difference [33] also correlated with an increase in alveolar senescence, indicating the presence of accelerated lung aging in severe COPD-emphysema subject lungs.

T174

33243-33369

Sentence

denotes

We further validate smoke-induced accelerated lung aging using aging markers and in vitro and murine models of COPD-emphysema.

T175

33370-33713

Sentence

denotes

In further studies, a clear mechanistic and protective role of TFEB, the master autophagy regulator, was observed in CS-induced lung disease models where other pathogenic features of COPD-emphysema, such as inflammatory-oxidative stress, senescence, apoptosis, and aggresome formation, were used for the validation of pathogenic roles [34,35].

T176

33714-33934

Sentence

denotes

In fact, the CS-induced sequestration of TFEB protein into aggresome bodies leads to its decreased availability, which prevents its function as a transcription factor to positively regulate the autophagy process [34,35].

T177

33935-34245

Sentence

denotes

Moreover, TFEB-mediated autophagy was shown to be protective against oxidative stress and hepatotoxicity induced by ethyl carbamate (a toxicant in CS) [144], suggesting that TFEB-autophagy is a protective mechanism against CS exposure-induced toxicity, not only in the lungs, but in other vital organs as well.

T178

34246-34461

Sentence

denotes

Additionally, TFEB-mediated autophagy has also been shown to control CS-induced cellular senescence, and bacterial phagocytic clearance, thus highlighting its protective role in CS-induced COPD-emphysema [22,34,35].

T179

34462-34685

Sentence

denotes

In addition to TFEB, other mechanistic mediators of autophagy have been shown to participate in the sequential dysfunction or impairment of autophagy processes, contributing as a key mediator of COPD-emphysema pathogenesis.

T180

34686-34906

Sentence

denotes

For example, increased levels of bicaudal D1 (BICD1), an adaptor for the dynein–dynactin motor complex, were found in the peripheral lung tissues of COPD patients, which was associated with increased p62 oligomers [145].

T181

34907-35218

Sentence

denotes

Additionally, the exposure of bronchial epithelial cells or mice to CS led to increased BICD1 levels, along with defective autophagosome maturation, and an accumulation of BICD1 with p62 and ubiquitin-associated p62-oligomers, thus confirming the mechanistic role of BICD1 in CS-induced autophagy defects [145].

T182

35219-35318

Sentence

denotes

Dysfunctional autophagy has also been associated with defects in specific cell types of the airway.

T183

35319-35445

Sentence

denotes

The secretory cells of the airway, such as the club and goblet cells, play an important role in host defense during infection.

T184

35446-35568

Sentence

denotes

Autophagy has been recently shown to be required to maintain the function of club cells, independent of CS exposure [146].

T185

35569-35820

Sentence

denotes

Mice deficient in autophagy protein Atg5, demonstrate a diminished expression of the host defense protein secretoglobulin family 1A member 1 (SCGB1A1) and surfactant proteins A1 and D (Sftpa1 and Sftpd), as well as abnormal club cell morphology [146].

T186

35821-35969

Sentence

denotes

Moreover, a diminished SCGB1A1 expression in club cells correlates with evidence of reduced autophagy in lung tissue from COPD former smokers [146].

T187

35970-36178

Sentence

denotes

CS exposure has also been demonstrated to cause the accumulation of damaged mitochondrial via impaired mitophagy, which has been demonstrated to play a role in COPD pathogenesis disease progression [147,148].

T188

36179-36388

Sentence

denotes

Thus, it can be postulated that CS-induced autophagy dysfunction would further deteriorate the structure and function of club cells, resulting in altered or diminished host defense mechanisms in COPD subjects.

T189

36390-36394

Sentence

denotes

4.5.

T190

36395-36431

Sentence

denotes

Autophagy Defects in Cystic Fibrosis

T191

36432-36637

Sentence

denotes

Cystic fibrosis is a chronic obstructive lung disease which is marked by recurrent infections, chronic inflammatory-oxidative stress, and mucus overproduction that contributes to severe airway obstruction.

T192

36638-36826

Sentence

denotes

Initial seminal studies by Luciani A et al. established the link between defective CFTR and the presence of aggresome bodies, lung inflammation, and ROS-mediated autophagy inhibition [53].

T193

36827-37200

Sentence

denotes

We and others have not only validated that defective CFTR-mediated ROS-TG2 pathway drives the crosslinking of Beclin-1, which results in the accumulation of misfolded ΔF508-CFTR into p62+HDAC6+ aggresome bodies leading to autophagy dysfunction, but we have also demonstrated the key central role of autophagy in regulating CF pathogenesis and exacerbations [42,58,149,150].

T194

37201-37342

Sentence

denotes

These studies describe the specific role of defective autophagy in CF-related chronic infections and resulting inflammatory-oxidative stress.

T195

37343-37568

Sentence

denotes

In addition, CF macrophages demonstrate impaired phagocytic activity and thus CF patients are more prone to bacterial infections, such as P. aeruginosa and Burkholderia cenocepacia (B. cenocepacia) [45,51,58,106,151,152,153].

T196

37569-37665

Sentence

denotes

A recent study investigated the precise mechanism of weak autophagic activity in CF macrophages.

T197

37666-38018

Sentence

denotes

Using the technique of reduced representation bisulfite sequencing (RRBS) to determine the DNA methylation profile, the authors found that the promoter regions of Atg12 in CF macrophages are significantly more methylated as compared to the control WT cells, thereby elucidating a novel mechanism for reduced autophagy activity in CF immune cells [154].

T198

38019-38229

Sentence

denotes

In a separate study, an increased expression of the microRNA (Mir)c1/Mir17-92 cluster was identified as a potential negative regulator of autophagy in CF macrophages when compared to normal control cells [105].

T199

38230-38387

Sentence

denotes

Furthermore, the in vivo downregulation of Mir17 and Mir20a, partially restored autophagy gene expression and improved the clearance of B. cenocepacia [105].

T200

38388-38536

Sentence

denotes

These studies highlight the importance of autophagy as a key protective mechanism in CF exacerbation, and lung disease pathogenesis and progression.

T201

38538-38542

Sentence

denotes

4.6.

T202

38543-38567

Sentence

denotes

Autophagy Defects in IPF

T203

38568-38678

Sentence

denotes

IPF is a chronic, progressive, and frequently fatal disease associated with aging and dysfunctional autophagy.

T204

38679-38981

Sentence

denotes

It is accepted that accelerated epithelial cell senescence plays a vital role in IPF pathogenesis by virtue of atypical epithelial–mesenchymal interactions, and insufficient autophagy is attributed as a mechanism of accelerated epithelial cell senescence and myofibroblast differentiation in IPF [155].

T205

38982-39048

Sentence

denotes

Bleomycin is widely used as a model of drug-induced lung fibrosis.

T206

39049-39187

Sentence

denotes

The first study to describe the protective role of autophagy in bleomycin-induced lung fibrosis used the Atg4b-deficient mice model [156].

T207

39188-39371

Sentence

denotes

After 7 days of bleomycin treatment, these mice demonstrated a significantly higher neutrophilic infiltration and inflammatory cytokine production as compared to untreated mice [156].

T208

39372-39584

Sentence

denotes

Additionally, after 28 days of bleomycin treatment, mice developed extensive lung fibrosis, which was accompanied by an elevated collagen deposition and deregulated expression of extracellular matrix genes [156].

T209

39585-39853

Sentence

denotes

Similarly, in mice deficient in LC3B (LC3B−/−), bleomycin-mediated lung injury and fibrotic changes were more pronounced, suggesting the protective role of autophagy in bleomycin-induced lung injury and the resulting development of fibrotic lung disease in mice [157].

T210

39854-39975

Sentence

denotes

Another recent study describes the protective role of the anti-inflammatory cytokine IL-37 in the IPF murine model [158].

T211

39976-40176

Sentence

denotes

A further mechanistic delve into the mechanism of IL-37-mediated protection showed that it induces Beclin-1-dependent autophagy while downregulating TGFβ1-mediated lung fibroblast proliferation [158].

T212

40177-40390

Sentence

denotes

Moreover, IL-37 also decreased inflammation and collagen deposition in bleomycin-treated murine lungs while the protective effect was reversed by treatment with 3-methyladinine (3MA), an autophagy inhibitor [158].

T213

40391-40501

Sentence

denotes

Thus, it is plausible that a decrease in IL-37-mediated autophagy might be involved in the progression of IPF.

T214

40502-40621

Sentence

denotes

Moreover, the protective effects of autophagy are apparent from this and the other mechanistic studies mentioned above.

T215

40622-40917

Sentence

denotes

Additional mechanistic evidence comes from a study that showed bleomycin directly binds to annexin A2 (ANXA2) in lung epithelial cells, thereby preventing the nuclear translocation of TFEB; thus, there is an inhibition of the autophagy flux resulting in fibrotic lung disease pathogenesis [159].

T216

40918-41043

Sentence

denotes

Moreover, torin1-mediated TFEB activation restores autophagy flux and ameliorates bleomycin-induced pulmonary fibrosis [159].

T217

41044-41349

Sentence

denotes

Autophagy dysfunction is also reported in human lung fibroblasts from IPF patients, and it is believed that defective autophagy is required to maintain a cell death-resistant phenotype in IPF fibroblasts, suggesting that autophagy dysfunction is a profibrotic mechanism and promotes IPF pathogenesis [64].

T218

41350-41551

Sentence

denotes

Hence, in age-related IPF pathogenesis, autophagy declines with age and the resulting imbalance of inflammatory-oxidative responses is anticipated to mediate the initiation of fibrotic pathophysiology.

T219

41552-41679

Sentence

denotes

However, further clinical evaluation is needed to evaluate the therapeutic potential of autophagy augmentation in IPF patients.

T220

41681-41683

Sentence

denotes

5.

T221

41684-41739

Sentence

denotes

Autophagy-Mediated CFTR and Immune Response Dysfunction

T222

41740-41884

Sentence

denotes

The genetic loss of CFTR or a decrease in its expression and/or activity due to environmental insults such as CS leads to autophagy dysfunction.

T223

41885-42160

Sentence

denotes

An investigation of CFTR-deficient mice or cells isolated from CF subjects revealed an intrinsic defect in autophagy in the absence of CFTR, and the mechanism of defective CFTR-mediated autophagy impairment via the ROS-TG2-Beclin-1 pathway is well established [22,42,53,150].

T224

42161-42426

Sentence

denotes

Supporting studies demonstrate that autophagy augmentation restores CS-induced CFTR dysfunction, inflammatory-oxidative stress, ceramide accumulation, and COPD-emphysema pathogenesis by rescuing aggresome-bound mutant ΔF508-CFTR to the plasma membrane (PM) [22,35].

T225

42427-42611

Sentence

denotes

Conversely, restoring CFTR levels by S-nitrosoglutathione (GSNO) augmentation corrects CS-induced autophagy dysfunction, inflammatory-oxidative stress and COPD-emphysema features [62].

T226

42612-42812

Sentence

denotes

These findings not only highlight the intricate relationship between CFTR and autophagy but also provide a unique therapeutic opportunity to control exacerbations and chronic lung disease progression.

T227

42813-43013

Sentence

denotes

Several reports have suggested that the inherently elevated inflammatory-oxidative stress in CF cells, primarily due to activated NFκB signaling, could be dampened by autophagy augmentation [124,160].

T228

43014-43241

Sentence

denotes

Moreover, it’s conceivable that CFTR dysfunction leads to impaired pathogen clearance, as the autophagy-mediated degradation of both intracellular and extracellular pathogens (xenophagy) is well demonstrated [35,45,58,151,161].

T229

43242-43457

Sentence

denotes

An alternate mechanism called LC3-associated phagocytosis (LAP) is also described, which is similar to the normal macroautophagy pathway but does not involve the formation of a double membrane autophagosome [7,162].

T230

43458-43684

Sentence

denotes

Nonetheless, LAP assists in the processing of both intracellular and extracellular pathogens, through the recruitment of LC3 to the phagosomal membrane and subsequent delivery to lysosomes for terminal degradation [7,151,162].

T231

43685-43836

Sentence

denotes

Autophagy per se plays a very crucial role in regulating innate and adaptive immunity both in normal conditions and in response to pathogen challenges.

T232

43837-44050

Sentence

denotes

Autophagy directly governs key aspects of the innate immune activation, including the secretion of inflammatory mediators, such as cytokines, which are essential to combat different microbial pathogens [7,8,9,84].

T233

44051-44255

Sentence

denotes

The “inflammasome” is a cytoplasmic multiprotein complex that detects pathogenic microorganisms or other cellular stresses and activates potent pro-inflammatory cytokines such as IL-1β and IL-18 [87,133].

T234

44256-44427

Sentence

denotes

Although inflammasome activation is an early innate response to protect the host, its prolonged activation can lead to severe hyperinflammation and tissue injury [47,130].

T235

44428-44644

Sentence

denotes

Recent studies suggest that autophagy is a negative regulator of inflammasome activation as a deficiency of autophagy components such as LC3B or Beclin-1 promotes NLRP3-dependent inflammasome activation [47,130,133].

T236

44645-44948

Sentence

denotes

Apart from its regulation of inflammasome, autophagy also suppresses the overactivation of other inflammation-inducing factors such as NFκB, suggesting a general protective role of autophagy in keeping a check of uncontrolled innate immune activation that may contribute to lung injury [11,37,38,54,55].

T237

44949-45178

Sentence

denotes

In the adaptive immune system, functional autophagy is required for the survival, development, maturation, and function of immune cells such as CD4+ T cells, CD8+ T cells, B cells, neutrophils, and monocytes [7,9,84,163,164,165].

T238

45179-45347

Sentence

denotes

Moreover, in dendritic cells (DC’s), antigen processing and presentation to MHC-II is dependent on the autophagic generation of suitable peptides [9,20,88,163,164,165].

T239

45348-45569

Sentence

denotes

Additionally, antigen presentation to CD8+ T cells on MHC-I is also dependent on autophagy, thus implicating its indispensable role in generating an adequate immune response to bacterial and viral pathogens [163,164,165].

T240

45570-45808

Sentence

denotes

Hence, autophagy promotes adequate antigen presentation to T cells in numerous infection models, thereby facilitating a robust adaptive immune response and further demonstrating the necessary functional role autophagy plays in infections.

T241

45809-45955

Sentence

denotes

The lack of functional CFTR in macrophages results in an increased production of inflammatory cytokines, and impaired pathogen clearance capacity.

T242

45956-46161

Sentence

denotes

The diminished expression of HLA-DQ and HLA-DR (MHC-II molecules) on monocytes derived from ΔF508-CFTR homozygous CF subjects [166], might explain the impaired pathogen clearance ability of CF macrophages.

T243

46162-46303

Sentence

denotes

In addition, CFTR deficiency has been implicated in diminished Treg effector function and a more pronounced Th2-biased immune response [167].

T244

46304-46462

Sentence

denotes

The CF defect has also been shown to affect the activation of neutrophils [168], which are the cells responsible for the first line of defense in the airways.

T245

46463-46857

Sentence

denotes

Although, airway epithelial cells and lung-resident macrophages sense the invading pathogens and secrete a plethora of factors to induce the recruitment and activation of neutrophils, neutrophils from CF subjects have diminished phagocytic potentials by virtue of the reduced cell surface expression of toll-like receptors (TLRs) and disrupted chloride transport to the phagolysosome [169,170].

T246

46858-46931

Sentence

denotes

Thus the CFTR mutation in CF results in impaired bacterial killing [171].

T247

46932-47079

Sentence

denotes

Moreover, CF neutrophils also demonstrate an increased capacity to release their primary granule contents such as MPO and neutrophil elastase (NE).

T248

47080-47179

Sentence

denotes

The uncontrolled release of these enzymes causes lung tissue damage and severe airway inflammation.

T249

47180-47509

Sentence

denotes

We have shown that P. aeruginosa LPS-induced MPO levels can be reduced by treatment with the histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA), plausibly by restoring the trafficking of ΔF508-CFTR, suggesting that a functional CFTR is required to keep a tab on uncontrolled neutrophil activation [172].

T250

47510-47715

Sentence

denotes

Mechanistically, an absence or dysfunction of CFTR in neutrophils results in the deactivation of the guanosine triphosphate (GTP)-binding protein Rab27a, which causes impaired granule exocytosis [168,172].

T251

47716-47945

Sentence

denotes

Several studies now agree that the pharmacological inhibition of CFTR or the mutant ΔF508-CFTR is sufficient to cause deregulated neutrophil activation via the activation of the NFκB pathway, resulting in hyperinflammation [172].

T252

47946-48069

Sentence

denotes

Therefore, autophagy and CFTR share an intimate relationship in terms of regulating the immune response against infections.

T253

48070-48225

Sentence

denotes

Moreover, the rescue of mutant CFTR to the PM corrects the autophagy-mediated immune dysfunction, controlling chronic lung disease pathogenesis (Figure 1).

T254

48227-48229

Sentence

denotes

6.

T255

48230-48296

Sentence

denotes

Autophagy-CFTR Dysfunction Induces Acute and Chronic Exacerbations

T256

48297-48422

Sentence

denotes

As discussed above, many patients with chronic respiratory diseases such as COPD and CF face acute and chronic exacerbations.

T257

48423-48568

Sentence

denotes

These pulmonary exacerbations are characterized by a worsening lung function, significantly below what is normal for their conditions [4,31,173].

T258

48569-48841

Sentence

denotes

These exacerbations are caused by environmental exposures or bacterial and viral infections that result in further deterioration of the patient’s condition [4,31,173,174,175], leading to hospitalization for individuals causing increased morbidity and mortality [4,31,173].

T259

48842-48958

Sentence

denotes

Exacerbations also pose a significant financial burden for patients with chronic respiratory diseases [1,2,176,177].

T260

48959-49168

Sentence

denotes

Since pulmonary exacerbations are commonly triggered by infections, the autophagy dysfunction seen in these chronic conditions plays a role in the pathogenesis of this state via the mechanisms discussed above.

T261

49169-49329

Sentence

denotes

A common pathogen that colonizes the lungs of individuals with chronic respiratory diseases and can lead to exacerbations is P. aeruginosa [4,31,44,58,173,178].

T262

49330-49496

Sentence

denotes

Studies have demonstrated that defects in CFTR impair the ability of cells to clear P. aeruginosa infections via autophagy, especially in patients with CF [22,40,53].

T263

49497-49669

Sentence

denotes

Furthermore, it has been shown that the induction of autophagy is able to ameliorate autophagy dysfunction and promote the clearance of P. aeruginosa infections [35,45,58].

T264

49670-50003

Sentence

denotes

As previously mentioned, CS exposure can also cause CFTR dysfunction, where a recent investigation demonstrated that CS exposure decreased CFTR expression while a treatment of CS-exposed macrophages with the autophagy inducer fisetin, which works by modulating autophagosome degradation, significantly recovered CFTR expression [35].

T265

50004-50120

Sentence

denotes

This same investigation showed that the CS-induced inhibition of CFTR decreased the clearance of P. aeruginosa [35].

T266

50121-50269

Sentence

denotes

This impaired clearance was then alleviated by autophagy induction with fisetin, supporting the findings of other previously mentioned studies [35].

T267

50270-50386

Sentence

denotes

Hence, CFTR-autophagy dysfunction in chronic lung diseases such as CF and COPD leads to P. aeruginosa exacerbations.

T268

50387-50527

Sentence

denotes

Similarly, Burkholderia cepacia (B. cepacia), an opportunistic infection that afflicts 3–5% of CF patients, can provoke exacerbations [151].

T269

50528-50718

Sentence

denotes

It has been found that macrophages can kill B. cepacia within autophagolysosomes; however, macrophages with ΔF508-CFTR lacked the bacteria in autophagolysosomes indicating dysfunction [151].

T270

50719-50908

Sentence

denotes

When these macrophages were treated with the autophagy inducer rapamycin, ΔF508-CFTR macrophages were able to fight the B. cepacia infection and reduce the resulting inflammation [153,179].

T271

50909-51124

Sentence

denotes

This demonstrates the importance of CFTR-dependent autophagy in not only clearing bacteria that can provoke pulmonary exacerbations, but also decreasing inflammation that can lead to worsened lung functions as well.

T272

51125-51214

Sentence

denotes

In regard to viral infections, CFTR-autophagy dysfunction limits viral clearance as well.

T273

51215-51368

Sentence

denotes

In a recent study, it was determined that CFTR-deficient mice infected with RSV had an impaired ability to clear the virus compare to control mice [180].

T274

51369-51552

Sentence

denotes

Similarly, despite similar cytokine responses, respiratory epithelial cells with ΔF508-CFTR had a higher viral load when infected with rhinovirus in comparison to control cells [181].

T275

51553-51805

Sentence

denotes

From what we know about CFTR-autophagy’s role in pathogen clearance, it is likely that the observed findings in this study are a result of decreased autophagy in the ΔF508-CFTR cells that leads to decreased rhinovirus clearance and a higher viral load.

T276

51806-51936

Sentence

denotes

Thus, proper CFTR-dependent autophagy function is necessary for the clearance of both bacterial and viral pathogens in the airway.

T277

51937-52081

Sentence

denotes

Besides infection, CFTR-autophagy dysfunction can lead to an impaired clearance of cellular debris and products that would normally be degraded.

T278

52082-52233

Sentence

denotes

One such product is ceramide, which in response to CFTR-autophagy dysfunction can accumulate in aggresome bodies within cells [22,110,182,183,184,185].

T279

52234-52409

Sentence

denotes

Ceramide accumulation has been observed in both CF patients with CFTR mutations [182,183,186] and COPD patients who have acquired CFTR dysfunction due to CS exposure [22,110].

T280

52410-52534

Sentence

denotes

In the presence of CS, ceramide has been found to accumulate in p62+ aggresome bodies, indicating autophagy impairment [22].

T281

52535-52797

Sentence

denotes

As CFTR-autophagy becomes impaired in both CF and COPD, cells have chronically elevated intracellular levels of ROS altering cellular homeostasis, causing exacerbations and accelerating the pathogenesis and progression of these respiratory diseases [22,110,182].

T282

52798-52976

Sentence

denotes

Moreover, the deleterious effect of ceramide accumulation on CFTR-autophagy has been demonstrated to directly impair defenses against bacteria [52,184,186,187] and viruses [188].

T283

52977-53183

Sentence

denotes

As such, ceramide accumulation as a result of either inherent or acquired CFTR dysfunction leads to autophagy impairment causing a diminished immune response and bacterial colonization or viral replication.

T284

53184-53408

Sentence

denotes

Hence, dysfunctional CFTR and autophagy dysfunction go hand in hand with an increased susceptibility of individuals to pathogens that significantly decrease lung function and cause acute and chronic exacerbations (Figure 1).

T285

53410-53412

Sentence

denotes

7.

T286

53413-53494

Sentence

denotes

CFTR- Autophagy Dysfunction and Pathogenesis of Chronic Obstructive Lung Diseases

T287

53495-53890

Sentence

denotes

The homeostatic autophagy process in the airways is prone to dysregulation by a variety of factors such as exposure to first- or second-hand CS [40], eCV [39], biomass smoke [14,43], waterpipe smoke (WPS) [94], wildfire smoke [189], environmental pollution [61], genetic polymorphisms [53,61,149], aging [190], obesity [191,192], and changes in the expression and/or activity of CFTR [22,35,53].

T288

53891-54166

Sentence

denotes

Elevated levels of ROS/RNS ensuing from exposure to the above-described risk factors is the primary driver of autophagy impairment (Figure 1), which is considered a central mechanism for the advent of inflammatory-oxidative stress, cellular senescence, and apoptosis [62,94].

T289

54167-54342

Sentence

denotes

These potentially deleterious changes result in the initiation and progression of COPD-emphysema, as they correlate with the severity of emphysema in COPD subjects [22,33,62].

T290

54343-54533

Sentence

denotes

We and others have demonstrated the important role of transcription factor-EB (TFEB), the master autophagy regulator, in controlling inflammatory-oxidative and immune signaling [34,143,193].

T291

54534-54831

Sentence

denotes

In a relatively recent study, we showed that CS-induced accumulation or trapping of TFEB proteins into perinuclear aggresome bodies prevents it from entering the nucleus and performing its function as an autophagy regulating transcription factor, thereby culminating in autophagy dysfunction [34].

T292

54832-55037

Sentence

denotes

These findings were confirmed in human lung tissue sections from smoker and nonsmoker COPD subjects, where the perinuclear accumulation of TFEB into aggresome bodies increases with emphysema severity [34].

T293

55038-55264

Sentence

denotes

Moreover, smokers showed a more prominent increase in TFEB-aggresome localization as compared to nonsmokers, emphasizing that CS exposure leads to defective autophagy via functional trapping of TFEB into aggresome bodies [34].

T294

55265-55542

Sentence

denotes

It is evident from innumerable studies that a complete loss or decrease in the levels of functional WT-CFTR from the PM due to genetic mutations leads to several deleterious changes in the airways that ultimately results in obstructive lung disease pathogenesis in CF subjects.

T295

55543-55917

Sentence

denotes

Specifically, a decrease in/loss of WT-CFTR is causally related to increased ROS-mediated inflammatory-oxidative stress, mucus hypersecretion, elevated ceramide levels, and hampered mucociliary clearance resulting in an increased incident of recurrent and chronic pulmonary infections, all of which result in chronic obstructive pathologies in CF airways [15,51,53,110,194].

T296

55918-56167

Sentence

denotes

It is now well documented that CS exposure [22,40,63,107,108], eCV [39,195], or certain infectious agents [196,197,198] also induce a decrease in the activity or expression of CFTR in the airways and was aptly described as acquired CFTR dysfunction.

T297

56168-56316

Sentence

denotes

As expected, CS-induced ROS and the resulting oxidative stress was found to be the main cause of acquired CFTR dysfunction in COPD [62,107,108,109].

T298

56317-56634

Sentence

denotes

Moreover, the mechanistic confirmation of the role of acquired CFTR dysfunction in COPD pathogenesis comes from studies which showed that the pharmacological rescue of mutant CFTR to the PM was able to correct CS-induced inflammatory-oxidative stress, autophagy impairment, and COPD-emphysema pathogenesis [14,42,62].

T299

56635-56928

Sentence

denotes

Another important mechanism which plays a crucial pathogenic role in both CF and COPD-emphysema is ceramide accumulation (Figure 1), and numerous studies have highlighted that a loss or decrease in CFTR and/or CS exposure leads to an increase in ceramide levels [22,52,93,110,182,183,186,188].

T300

56929-57174

Sentence

denotes

Our earlier studies described a direct correlation between a lack of lipid-raft CFTR expression and CS-induced apoptosis along with defective autophagy and the progression of COPD-emphysema via ceramide or lactosylceramide accumulation [93,110].

T301

57175-57520

Sentence

denotes

Lately, we also demonstrated that autophagy augmentation alleviates CS-induced CFTR dysfunction, ceramide accumulation (lipophagy impairment), and resulting COPD-emphysema pathogenesis [22], thus demonstrating that autophagy and CFTR share an interconnected biology crucial for the initiation and progression of chronic lung diseases (Figure 1).

T302

57521-57690

Sentence

denotes

We further went on to demonstrate that CS-induced autophagy dysfunction and the dysfunction of its component lipophagy lead to intracellular ceramide accumulation [110].

T303

57691-57797

Sentence

denotes

Meanwhile, acquired CFTR dysfunctions caused ASM activation-dependent membrane ceramide accumulation [22].

T304

57798-58050

Sentence

denotes

The pathogenic role of ceramide has also been implicated in CF lung disease, wherein it mediates the inflammation, apoptosis, and increased susceptibility to P. aeruginosa infection [183,186,199], and is elevated in the airways of CF mice and patients.

T305

58051-58206

Sentence

denotes

Mechanistically, it was proven that the ROS-dependent activation of acid sphingomyelinase (ASM) resulted in increased membrane ceramide accumulation [200].

T306

58207-58382

Sentence

denotes

Thus, several ASM inhibitors have been tested and were shown to reduce ceramide accumulation along with resulting infection and inflammation in the lungs of CF mice [186,200].

T307

58383-58684

Sentence

denotes

Therefore, there is strong evidence that CFTR-autophagy dysfunction is a prime factor that promotes multiple host destructive phenomena, including inflammatory-oxidative stress and recurrent infection-related exacerbations, which eventually contribute to chronic obstructive lung disease pathogenesis.

T308

58686-58688

Sentence

denotes

8.

T309

58689-58804

Sentence

denotes

Autophagy Augmentation Strategies to Mitigate the Pathogenesis and Progression of Chronic Obstructive Lung Diseases

T310

58805-59059

Sentence

denotes

As discussed above, autophagy-CFTR dysfunction plays a vital role in regulating the pathogenesis of chronic obstructive lung diseases, including facilitating recurrent infections leading to severe disease exacerbations and an increased risk of mortality.

T311

59060-59272

Sentence

denotes

Therefore, it is apparent that pharmacological interventions targeted to correct the autophagy-CFTR dysfunction provides a lucrative therapeutic strategy to control chronic obstructive lung diseases pathogenesis.

T312

59273-59602

Sentence

denotes

Indeed, using in vitro and pre-clinical murine models, we and others have shown that autophagy augmentation mitigates several pathogenic features of chronic lung diseases, such as inflammatory-oxidative stress, apoptosis, cellular senescence, lung tissue damage, and bacterial or viral infections [22,35,42,45,58,62,149,151,153].

T313

59603-59868

Sentence

denotes

The utility of pharmacological or natural compounds that can alleviate autophagy-CFTR dysfunction has been comprehensively investigated in both CS-induced in vitro and pre-clinical murine models of CS exposure, with or without P. aeruginosa co-infection [34,35,42].

T314

59869-60291

Sentence

denotes

We have extensively tested the pre-clinical therapeutic efficacy of cysteamine, a naturally occurring FDA-approved aminothiol compound, which is a known proteostasis and autophagy regulator that induces autophagosome formation, in controlling various pathogenic features of CS- and aging-induced inflammatory-oxidative stress, apoptosis, cellular senescence, pathogen clearance, lung injury, and COPD-emphysema [22,33,94].

T315

60292-60606

Sentence

denotes

Even though cysteamine offers several beneficial attributes such as its antioxidant, bactericidal, mucolytic, and, the most promising, CFTR-rescuing potential that corrects the CS-induced acquired CFTR dysfunction, there are some limitations such as the optimization of beneficial dose and airway delivery methods.

T316

60607-60764

Sentence

denotes

We and others have devised strategies such as nano/dendrimer-based formulations which can be efficiently delivered through intranasal inhalation [42,45,149].

T317

60765-61015

Sentence

denotes

The more specific targeting of pulmonary tissues using nano/dendrimer-based drugs improves the therapeutic potential while mitigating some system-wide side effects that may be associated with systemic and nontargeted delivery methods [42,45,149,201].

T318

61016-61307

Sentence

denotes

We believe that cysteamine or its nano/dendrimer formulations have a significant potential of controlling COPD-emphysema pathogenic features, including recurrent exacerbations, based on its known pre-clinical efficacy and ongoing clinical evaluations in controlling obstructive lung disease.

T319

61308-61534

Sentence

denotes

Our relatively recent study using GSNO, an endogenously occurring nitric oxide donor, highlights the biological significance of CS-induced CFTR dysfunction-related autophagy impairment in mediating COPD-emphysema pathogenesis.

T320

61535-61731

Sentence

denotes

We showed that an augmentation of GSNO decreases cigarette smoke extract (CSE)-induced ROS activation and autophagy-flux impairment by rescuing the aggresome-bound perinuclear CFTR to the PM [62].

T321

61732-62116

Sentence

denotes

Furthermore, using a preclinical COPD-emphysema murine model, we demonstrated that chronic CS (Ch-CS) induced an increase in inflammatory cytokines in BALF, aggresome formation, CFTR-aggresome localization, oxidative/nitrosative stress, and apoptosis, and the emphysematous changes (alveolar airspace enlargement) were significantly improved by augmenting the airway GSNO levels [62].

T322

62117-62285

Sentence

denotes

Thus, this study provides proof-of-concept evidence that GSNO augmentation could be further tested as a potential strategy to correct CS-induced CFTR-autophagy defects.

T323

62286-62549

Sentence

denotes

Apart from cysteamine and GSNO, we also tested the potential of other FDA-approved autophagy-inducing drugs, such as gemfibrozil (GEM), which induces lysosome formation, and fisetin, in controlling CS-induced autophagy dysfunction and hampered pathogen clearance.

T324

62550-62742

Sentence

denotes

Our study showed that CS/CSE-induced TFEB/autophagy impairment, inflammatory-oxidative stress, apoptosis, and senescence can be mitigated by treatment with GEM/fisetin via TFEB induction [34].

T325

62743-62956

Sentence

denotes

In a subsequent investigation, we demonstrated that CSE-induced autophagy dysfunction in macrophages is a critical mechanism of phagocytosis defects and the resulting diminished clearance of P. aeruginosa [33,35].

T326

62957-63224

Sentence

denotes

The autophagy-inducing antioxidant fisetin was able to restore the CS-induced phagocytosis defect and facilitate P. aeruginosa clearance [35], suggesting the potential of autophagy-inducing strategies in controlling exacerbations prevalent in COPD-emphysema subjects.

T327

63225-63411

Sentence

denotes

The therapeutic potential of autophagy augmenting drugs has been extensively investigated in controlling chronic CF lung disease and associated pulmonary infection-related exacerbations.

T328

63412-63661

Sentence

denotes

There have been extensive studies on the use of rapamycin in controlling CF-related lung infections, but its clinical use is hampered due to its potent immunosuppressive property and certain reports of significant lung toxicity [5,6,44,151,153,202].

T329

63662-63846

Sentence

denotes

Lately, the efficacy of the thymic peptide, Thymosin α-1 (Tα1), was demonstrated in correcting the basic defect in CF, which is the restoration of misfolded ΔF508-CFTR to the PM [203].

T330

63847-63995

Sentence

denotes

Tα1 possesses anti-inflammatory properties and is also known to induce autophagy [204], which could be its mechanism of action to rescue ΔF508-CFTR.

T331

63996-64165

Sentence

denotes

Nonetheless, future pre-clinical and clinical studies will be essential before it could be any therapeutic benefit in CF-related autophagy dysfunction and exacerbations.

T332

64166-64395

Sentence

denotes

The utility of cysteamine, a potent antioxidant drug with autophagy-inducing potential, has been widely tested in CF in vitro, in vivo models, and is currently being investigated in phase 2 human clinical trials [58,205,206,207].

T333

64396-64566

Sentence

denotes

However, a previously completed study of 10 patients with the ΔF508-CFTR mutation demonstrated a significant improvement in CFTR function with cysteamine treatment [208].

T334

64567-64838

Sentence

denotes

Similarly, our recent studies validated cysteamine’s extensive repertoire of protective mechanisms in CF, and demonstrated for the first time that cysteamine was able to control CS-induced lipophagy impairment and the resulting ceramide accumulation in murine lungs [22].

T335

64839-65036

Sentence

denotes

This finding might have implications in controlling both COPD and CF-related infections and exacerbations, knowing the deleterious role of ceramide in promoting pulmonary infections in COPD and CF.

T336

65037-65264

Sentence

denotes

In addition, autophagy dysfunction has been now widely accepted as a pathogenic mechanism in IPF, and thus strategies to augment autophagy are justified as relevant potential interventions in controlling IPF pathogenesis [209].

T337

65265-65435

Sentence

denotes

Indeed, some recent studies have shown that autophagy mitigates IPF pathogenesis by regulating the fibroblast apoptosis and senescence of alveolar epithelial cells [209].

T338

65436-65629

Sentence

denotes

Moreover, a recent report describes the utility of IL-37 in reducing the bleomycin-induced inflammation and collagen deposition in murine lungs by increasing Beclin-1-dependent autophagy [158].

T339

65630-65877

Sentence

denotes

Therefore, autophagy augmentation strategies likely have a strong potential to control chronic obstructive lung disease pathogenesis, including suppressing the severe pulmonary exacerbations which frequently result in patient mortality (Figure 2).

T340

65879-65881

Sentence

denotes

9.

T341

65882-65893

Sentence

denotes

Perspective

T342

65894-65977

Sentence

denotes

The burden of exacerbations on the health care system is substantial [1,3,177,210].

T343

65978-66194

Sentence

denotes

For patients with COPD in the United States, the average annual health care costs associated with their condition was estimated to be USD 9981; meanwhile, the average cost to society was USD 30,826 per patient [211].

T344

66195-66368

Sentence

denotes

Similarly, CF exacerbations were demonstrated to cost Medicaid on average between USD 44,589 and USD 116,169 annually with the costs increasing with the age of patients [2].

T345

66369-66468

Sentence

denotes

Another study found that the average cost per episode of all CF exacerbations was USD 12,784 [176].

T346

66469-66681

Sentence

denotes

As such, investigating new methods to prevent recurrent exacerbations is necessary to lower the burden on the health care system while improving the quality of life for patients with chronic pulmonary conditions.

T347

66682-66853

Sentence

denotes

The potential of autophagy augmenting therapeutics to correct CFTR-autophagy dysfunction and resulting exacerbations provides a possible solution to this issue (Figure 2).

T348

66854-67022

Sentence

denotes

As a proof of concept, numerous recent studies have demonstrated the potential of targeting CFTR-autophagy dysfunction as a method for reducing recurrent exacerbations.

T349

67023-67180

Sentence

denotes

One drug that has shown promise in alleviating autophagy impairment to provide possible therapeutic benefits in the treatment of exacerbations is cysteamine.

T350

67181-67382

Sentence

denotes

Cysteamine is an FDA approved drug for the treatment of cystinosis; however, it also possesses antioxidant, anti-inflammatory, autophagy-inducing, mucolytic, and anti-bacterial properties [58,205,207].

T351

67383-67577

Sentence

denotes

Recently, Ferrari et al. demonstrated that cysteamine could re-establish P. aeruginosa clearance in macrophages with the ΔF508-CFTR deletion by salvaging ΔF508-CFTR function in macrophages [58].

T352

67578-67760

Sentence

denotes

This restoration of function allowed macrophages to both increase the internalization and clearance of P. aeruginosa via a Beclin-1-mediated initiation of the autophagy pathway [58].

T353

67761-67896

Sentence

denotes

This reveals a possible therapy to restore both CFTR and autophagy function in CF patients that could limit P. aeruginosa colonization.

T354

67897-68142

Sentence

denotes

An improved clearance of P. aeruginosa in CF patients is especially important due to the prevalence of P. aeruginosa infections in exacerbations, and a drug that improves the immune response in this way offers a method to decrease exacerbations.

T355

68143-68213

Sentence

denotes

Studies exploring cysteamine-dendrimers have revealed similar results.

T356

68214-68421

Sentence

denotes

Two of our recent studies demonstrated that cysteamine-based dendrimers were able to not only decrease ΔF508-CFTR aggregation, but also rescue the protein to increase the plasma membrane expression [45,149].

T357

68422-68598

Sentence

denotes

Moreover, these investigations showed that this recue of CFTR by the cysteamine-dendrimers alleviated the autophagy impairment associated with the ΔF508-CFTR mutation [45,149].

T358

68599-68743

Sentence

denotes

This alleviation of CFTR-autophagy impairment was further shown to increase the clearance and killing of P. aeruginosa in both studies [45,149].

T359

68744-68871

Sentence

denotes

Hence, cysteamine-based dendrimers provide a therapeutic option in the treatment of both acute and chronic exacerbations in CF.

T360

68872-69074

Sentence

denotes

Cysteamine’s dendrimer-based formulation also proved beneficial for clearing P. aeruginosa, and thus has potential for treating other infections in CF and non-CF patients who are prone to exacerbations.

T361

69075-69313

Sentence

denotes

The added advantage of this intervention strategy is that exacerbations in respiratory diseases including those with CFTR dysfunction may be treated and prevented without antibiotics, where multidrug-resistant (MDR) infections are common.

T362

69314-69477

Sentence

denotes

Further studies into the therapeutic potential of other autophagy inducers for exacerbations in chronic respiratory diseases have shown promise as well (Figure 2).

T363

69478-69653

Sentence

denotes

These studies have demonstrated that rapamycin can induce autophagy and aid in the killing of different types of bacteria that are known to cause exacerbations [6,44,153,202].

T364

69654-69843

Sentence

denotes

Similarly, fisetin, which is an over the counter antioxidant used for brain health, induces autophagy [34,43] to improve bacterial clearance by ameliorating CFTR-autophagy dysfunction [35].

T365

69844-69965

Sentence

denotes

Thus, the use of various autophagy inducers shows promise in restoring the CFTR-autophagy pathway to treat exacerbations.

T366

69966-70182

Sentence

denotes

However, future studies and clinical trials need to be conducted to evaluate and standardize the safety and efficacy of these treatments to provide benefit in human subjects as a part of ongoing clinical development.

T367

70183-70392

Sentence

denotes

Another reason to explore treatments that restore the CFTR-autophagy function to treat exacerbations is that the current first-line treatment for exacerbations usually includes antibiotics [4,173,210,212,213].

T368

70393-70546

Sentence

denotes

In situations where patients experience severe exacerbations, they are often hospitalized and given powerful intravenous (IV) antibiotics [4,31,173,176].

T369

70547-70640

Sentence

denotes

This is part of what plays into the exorbitant costs associated with recurrent exacerbations.

T370

70641-70789

Sentence

denotes

When looking specifically at exacerbations requiring hospitalization and IV-antibiotics, the cost is USD 36,319 per exacerbation for patients [176].

T371

70790-71041

Sentence

denotes

This frequent use of antibiotics in both the out-patient and in-patient treatment of exacerbations causes bacteria to develop MDR, which poses a significant issue for patients as the treatment of future infections becomes more difficult [151,214,215].

T372

71042-71129

Sentence

denotes

In fact, many pathogens that cause exacerbations have been found to have MDR [214,215].

T373

71130-71288

Sentence

denotes

As more bacteria demonstrate MDR, more powerful antibiotics are needed to fight off infections, but these powerful antibiotics can have negative side effects.

T374

71289-71436

Sentence

denotes

As such, researchers have begun investigating the potential of targeting the autophagy pathway to fight off the MDR bacteria causing exacerbations.

T375

71437-71590

Sentence

denotes

One recent study explored the potential of cysteamine to improve the clearance and killing of different MDR bacteria by macrophages in CF patients [206].

T376

71591-71778

Sentence

denotes

The researchers demonstrated that there was a significantly increased clearance of B. cenocepacia, B. multivorans, and P. aeruginosa by alveolar macrophages treated with cysteamine [206].

T377

71779-71985

Sentence

denotes

Further exploration revealed a decrease in the markers of autophagy impairment in these cysteamine-treated macrophages, along with an increase in expression of CFTR on the membrane of the macrophages [206].

T378

71986-72164

Sentence

denotes

Thus, it can be concluded that cysteamine has the ability to promote host clearance of MDR pathogens in pulmonary exacerbations via the alleviation of CFTR-autophagy dysfunction.

T379

72165-72300

Sentence

denotes

A similar finding was found in a study that explored a novel autophagy inducer that works by initiating autophagosome formation, AR-13.

T380

72301-72529

Sentence

denotes

The investigators in this study demonstrated that AR-13 on its own was able to significantly reduce the infectious burden of methicillin-resistant Staphylococcus aureus and P. aeruginosa in both CF and non-CF immune cells [152].

T381

72530-72700

Sentence

denotes

Meanwhile, in the case of B. cenocepacia, AR-13 in combination with antibiotics was able to significantly improve the bacterial clearance from infected macrophages [152].

T382

72701-72805

Sentence

denotes

This improved bacterial clearance was attributed to the alleviation of CFTR-autophagy dysfunction [152].

T383

72806-72942

Sentence

denotes

Hence, therapeutics that aim to restore CFTR-autophagy function demonstrate promise in fighting MDR infections that cause exacerbations.

T384

72943-73190

Sentence

denotes

If clinical trials of these drugs were to show promise, they may decrease the length of hospitalization and recurrence of exacerbations to decrease both the costs and decreased quality of life faced by individuals with chronic respiratory disease.

T385

73191-73317

Sentence

denotes

Moreover, the fact that these drugs have been demonstrated to work by inducing autophagy is critical in fighting MDR bacteria.

T386

73318-73499

Sentence

denotes

Since the mechanism involves the host immune response and there would be less of a need for antibiotics, there is the possibility of decreased incidence of MDR bacteria development.

T387

73500-73575

Sentence

denotes

However, bacteria are not the only pathogens responsible for exacerbations.

T388

73576-73682

Sentence

denotes

Viruses are also a common cause of exacerbations in patients with chronic respiratory diseases [4,31,173].

T389

73683-73775

Sentence

denotes

However, the treatment of viruses is significantly different than the treatment of bacteria.

T390

73776-73864

Sentence

denotes

For most bacteria, there is an antibiotic that can be prescribed to fight the infection.

T391

73865-74002

Sentence

denotes

On the other hand, most viruses tend to be treated with supportive care due to the lack of antiviral therapies for many types of viruses.

T392

74003-74246

Sentence

denotes

As such, being able to clear viruses via autophagy/Tvirophagy may provide a unique therapeutic benefit in both reducing the severity of viral infections and decreasing the duration of viral infections, resulting in a decrease in exacerbations.

T393

74247-74376

Sentence

denotes

The focus on targeting autophagy to treat exacerbations in lieu of antiviral medications is limited but is gaining more interest.

T394

74377-74498

Sentence

denotes

One recent study has demonstrated the promise of budesonide, a corticosteroid, in the treatment of rhinovirus infections.

T395

74499-74629

Sentence

denotes

Rhinovirus causes the common cold and is a common viral cause of exacerbations in CF [32,175], asthma [32,216], and COPD [32,217].

T396

74630-74754

Sentence

denotes

In this study, researchers found that intranasal budesonide decreased the viral load of rhinovirus in patients’ lungs [218].

T397

74755-74978

Sentence

denotes

The investigators determined the antiviral effect of budesonide was due to autophagy induction as autophagy inhibition with chloroquine and bafilomycin A1 both significantly reduced the antiviral effect of budesonide [218].

T398

74979-75155

Sentence

denotes

Similarly, a study performed with dexamethasone, another corticosteroid, demonstrated that it is an effective treatment of rhinovirus through autophagy induction as well [219].

T399

75156-75272

Sentence

denotes

Thus, there is promise in treating and preventing exacerbations caused by rhinovirus using autophagy-inducing drugs.

T400

75273-75562

Sentence

denotes

In theory, targeting the induction of autophagy should provide a therapeutic mechanism for the treatment of other viruses that cause exacerbations in patients with chronic respiratory disease due to the role of autophagy in the immune response in many viruses, yet more research is needed.

T401

75563-75734

Sentence

denotes

In addition to showing promise in targeting viruses that cause exacerbations, the induction of autophagy may also aid in fighting novel viruses that can lead to pandemics.

T402

75735-75877

Sentence

denotes

For example, the novel coronavirus SARS-CoV2-mediated human respiratory infection, leading to COVID-19, was first reported in late 2019 [137].

T403

75878-75972

Sentence

denotes

By March 2020, the World Health Organization had declared a pandemic in response to the virus.

T404

75973-76232

Sentence

denotes

SARS-CoV-2 has caused numerous deaths, due to lack of a potent effective treatment, where antivirals such as remdesevir, favipiravir, etc., although minimally effective in reducing the hospitalization time of severe lung disease subjects, are in short supply.

T405

76233-76552

Sentence

denotes

Moreover due to the novel nature of the virus, susceptible population groups and aerosol-based rapid transmission, we see variations in the control of transmission and mortality between different countries, where mitigation measures are dependent on socio-economic, health care disparities and political will [137,220].

T406

76553-76812

Sentence

denotes

As such, there is a need to rapidly deliver on potent treatments in addition to vaccines, and autophagy augmentation with drugs that are FDA-approved for other conditions (Figure 2), provide significant potential for clinical validation and rapid translation.

T407

76813-77142

Sentence

denotes

In fact, a recent pre-print study that we mentioned above has investigated the use of spermidine (an autophagy inducer), MK-2206 (an AKT inhibitor), and niclosamide (a Beclin-1 stabilizer) in the treatment of COVID-19, and has been found to demonstrate some therapeutic benefits as an antiviral treatment against the virus [138].

T408

77143-77217

Sentence

denotes

Thus, autophagy induction may provide a beneficial treatment of the virus.

T409

77218-77305

Sentence

denotes

However, further investigation into these drugs and other autophagy inducers is needed.

T410

77306-77460

Sentence

denotes

Still, the mechanism of autophagy induction may prove crucial as a treatment of COVID-19 over classical antivirals and provide a tool to end the pandemic.

T411

77461-77659

Sentence

denotes

This mechanism may also prevent a future epidemic or pandemic by offering possible treatments to novel viruses without vaccines and antivirals that take significant development time for each strain.

T412

77660-77763

Sentence

denotes

Therefore, targeting and inducing the autophagy pathway is an area of tremendous clinical significance.

T413

77764-78026

Sentence

denotes

Autophagy-inducing drugs may be necessary for overcoming the CFTR-autophagy impairment found in many chronic respiratory diseases to prevent exacerbations and improve the morbidity and mortality for patients while cutting health care costs for these individuals.

T414

78027-78179

Sentence

denotes

Moreover, autophagy-inducing drugs offer the ability to fight pathogens without causing MDR bacteria and the need to develop strain specific antivirals.

T415

78180-78472

Sentence

denotes

As a result, an autophagy induction intervention strategy to handle MDR bacterial infections or novel viral infections provides significant benefits in terms of controlling exacerbations, whereas autophagy induction with drugs currently approved for other conditions allows rapid translation.

T416

78473-78651

Sentence

denotes

Moreover, the proposed autophagy augmenting therapeutic strategy also provides a possible treatment in situations where it is not possible to develop an antiviral for a pathogen.

T417

78652-78759

Sentence

denotes

Furthermore, autophagy induction also can offer an effective way to treat current recurring MDR infections.

T418

78760-79039

Sentence

denotes

Hence, future clinical studies need to expand their scope beyond the horizon of antibiotics and antivirals for the treatment of many respiratory diseases and begin investigating the therapeutic benefits that autophagy augmenting drugs may have in a myriad of clinical situations.

T419

79040-79263

Sentence

denotes

In doing so, we can achieve a significant reduction in the overwhelming health care costs and resources needed for respiratory exacerbations while improving the quality of life with a reduction in the mortality of patients.

T420

79265-79280

Sentence

denotes

Acknowledgments

T421

79281-79490

Sentence

denotes

NV was supported by the NIH (CTSA RRO25005 and RHL096931), Flight Attendant Medical Research Institute’s (FAMRI), Young Clinical Scientist Award (YCSA_082131) and CFF (CFF, R025-CR07 and VIJ07IO) grants to NV.

T422

79491-79642

Sentence

denotes

We thank Manish Bodas former postdoc in Vij’s lab for support with sections related to our laboratories prior work, related literature, and schematics.

T423

79644-79651

Sentence

denotes

Funding

T424

79652-79830

Sentence

denotes

The funders or institution had no role in design, decision to publish or preparation of the manuscript as its authors independent perspective based on prior and ongoing research.

T425

79832-79853

Sentence

denotes

Conflicts of Interest

T426

79854-79986

Sentence

denotes

NV is the lead inventor on patent targeting proteostasis mechanisms for rescuing CFTR protein-processing defect and CF lung disease.

T427

79987-80110

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NV is also the lead inventor of nano-based selective drug delivery and therapeutic targeting for obstructive lung diseases.

T428

80111-80304

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denotes

NV is a founder of PRECISION THERANOSTICS INC and VIJ BIOTECH that focuses on the bench-side translation of novel respiratory therapeutics and declares that he has no other competing interests.

T429

80306-80419

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denotes

Figure 1 Schematic representation showing mechanisms of respiratory exacerbations and lung disease pathogenesis.

T430

80420-80628

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The inflammatory/pathogenic receptors and cystic fibrosis transmembrane conductance regulator (CFTR) localized in lipid-raft membranes modulate immune response on viral or bacterial infection of airway cells.

T431

80629-80957

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In subjects with decreased expression of CFTR (chronic obstructive pulmonary disease (COPD)), misfolded-CFTR (ΔF508 CFTR, cystic fibrosis (CF)), or elderly subjects, increase in reactive oxygen species (ROS) activity within the cells inhibits the progression of endocytosed viruses and phagocytosed bacteria into phagolysosomes.

T432

80958-81163

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Furthermore, the ROS resulting from misfolded/ΔF508 CFTR or age-related changes causes ceramide accumulation within the plasma membrane, and increases TG2 expression, which causes crosslinking of Beclin-1.

T433

81164-81348

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This Beclin-1 crosslinking results in perinuclear aggresome body formation that further impairs autophagolysosomes formation to degrade autophagic cargo and clear infectious pathogens.

T434

81349-81474

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As a result of this impaired degradation or clearance, the immune response is further impaired leading to more ROS formation.

T435

81475-81570

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This ultimately develops into chronic lung disease with recurrent exacerbations and infections.

T436

81571-81731

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In case of viral infections such as SARS-CoV-2, the virus binds to the ACE2 receptor TMPRSS2 complex, to fuse with the host cell and gain entry for replication.

T437

81732-81957

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Autophagosome-lysosomal processing is a standard mechanism for clearance of viruses and other pathogen via xenophagy, which when impaired results in exacerbation, chronic inflammation, and pathogenesis of severe lung disease.

T438

81958-82136

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Figure 2 Autophagy-inducing compounds and their potential in treating inflammatory-oxidative stress responses, respiratory exacerbations and coronavirus disease-2019 (COVID-19).

T439

82137-82278

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The autophagy induction and other properties of various therapeutic compounds for treating pulmonary pathologies and exacerbations are shown.

T440

82279-82542

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The ability of these compounds to induce autophagy to rescue dysfunctional CFTR or clearance of misfolded proteins from aggresome bodies is a critical therapeutic property to consider when evaluating possible treatments for age-related and respiratory conditions.

T441

82543-82946

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In addition, anti-inflammatory, antioxidant, anti-biofilm, bactericidal, immune boosting, and mucolytic properties are further aspects of these compounds that have significant therapeutic potential in controlling chronic immune responses and exacerbations that trigger fatal lung conditions such as COPD, CF, acute respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis (IPF), and COVID-19.

PMC:7565665 JSON TXT 17 Projects

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PMC:7565665 JSONTXT 17 Projects

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PMC:7565665 JSON TXT 17 Projects