PMC:7565665 / 58686-65877 JSONTXT

{"project":"LitCovid-PD-FMA-UBERON","denotations":[{"id":"T395","span":{"begin":105,"end":109},"obj":"Body_part"},{"id":"T396","span":{"begin":239,"end":243},"obj":"Body_part"},{"id":"T397","span":{"begin":559,"end":563},"obj":"Body_part"},{"id":"T398","span":{"begin":744,"end":748},"obj":"Body_part"},{"id":"T399","span":{"begin":830,"end":834},"obj":"Body_part"},{"id":"T400","span":{"begin":835,"end":841},"obj":"Body_part"},{"id":"T401","span":{"begin":1061,"end":1063},"obj":"Body_part"},{"id":"T402","span":{"begin":1115,"end":1117},"obj":"Body_part"},{"id":"T403","span":{"begin":1386,"end":1399},"obj":"Body_part"},{"id":"T404","span":{"begin":1457,"end":1459},"obj":"Body_part"},{"id":"T405","span":{"begin":1562,"end":1566},"obj":"Body_part"},{"id":"T406","span":{"begin":1783,"end":1785},"obj":"Body_part"},{"id":"T407","span":{"begin":2120,"end":2127},"obj":"Body_part"},{"id":"T408","span":{"begin":2608,"end":2612},"obj":"Body_part"},{"id":"T409","span":{"begin":2750,"end":2752},"obj":"Body_part"},{"id":"T410","span":{"begin":3037,"end":3039},"obj":"Body_part"},{"id":"T411","span":{"begin":3137,"end":3139},"obj":"Body_part"},{"id":"T412","span":{"begin":3144,"end":3146},"obj":"Body_part"},{"id":"T413","span":{"begin":3184,"end":3193},"obj":"Body_part"},{"id":"T414","span":{"begin":3329,"end":3337},"obj":"Body_part"},{"id":"T415","span":{"begin":3565,"end":3567},"obj":"Body_part"},{"id":"T416","span":{"begin":3750,"end":3758},"obj":"Body_part"},{"id":"T417","span":{"begin":3798,"end":3800},"obj":"Body_part"},{"id":"T418","span":{"begin":3886,"end":3888},"obj":"Body_part"},{"id":"T419","span":{"begin":4146,"end":4157},"obj":"Body_part"},{"id":"T420","span":{"begin":4338,"end":4340},"obj":"Body_part"},{"id":"T421","span":{"begin":4655,"end":4659},"obj":"Body_part"},{"id":"T422","span":{"begin":4810,"end":4814},"obj":"Body_part"},{"id":"T423","span":{"begin":4940,"end":4944},"obj":"Body_part"},{"id":"T424","span":{"begin":5020,"end":5028},"obj":"Body_part"},{"id":"T425","span":{"begin":5151,"end":5153},"obj":"Body_part"},{"id":"T426","span":{"begin":6059,"end":6061},"obj":"Body_part"},{"id":"T427","span":{"begin":6141,"end":6146},"obj":"Body_part"},{"id":"T428","span":{"begin":6678,"end":6688},"obj":"Body_part"},{"id":"T429","span":{"begin":6717,"end":6742},"obj":"Body_part"},{"id":"T430","span":{"begin":6737,"end":6742},"obj":"Body_part"},{"id":"T431","span":{"begin":6801,"end":6803},"obj":"Body_part"},{"id":"T432","span":{"begin":6858,"end":6866},"obj":"Body_part"},{"id":"T433","span":{"begin":6888,"end":6893},"obj":"Body_part"},{"id":"T434","span":{"begin":7051,"end":7055},"obj":"Body_part"}],"attributes":[{"id":"A395","pred":"fma_id","subj":"T395","obj":"http://purl.org/sig/ont/fma/fma7195"},{"id":"A396","pred":"fma_id","subj":"T396","obj":"http://purl.org/sig/ont/fma/fma7195"},{"id":"A397","pred":"fma_id","subj":"T397","obj":"http://purl.org/sig/ont/fma/fma7195"},{"id":"A398","pred":"fma_id","subj":"T398","obj":"http://purl.org/sig/ont/fma/fma7195"},{"id":"A399","pred":"fma_id","subj":"T399","obj":"http://purl.org/sig/ont/fma/fma7195"},{"id":"A400","pred":"fma_id","subj":"T400","obj":"http://purl.org/sig/ont/fma/fma9637"},{"id":"A401","pred":"fma_id","subj":"T401","obj":"http://purl.org/sig/ont/fma/fma284995"},{"id":"A402","pred":"fma_id","subj":"T402","obj":"http://purl.org/sig/ont/fma/fma284995"},{"id":"A403","pred":"fma_id","subj":"T403","obj":"http://purl.org/sig/ont/fma/fma0326100"},{"id":"A404","pred":"fma_id","subj":"T404","obj":"http://purl.org/sig/ont/fma/fma284995"},{"id":"A405","pred":"fma_id","subj":"T405","obj":"http://purl.org/sig/ont/fma/fma7195"},{"id":"A406","pred":"fma_id","subj":"T406","obj":"http://purl.org/sig/ont/fma/fma284995"},{"id":"A407","pred":"fma_id","subj":"T407","obj":"http://purl.org/sig/ont/fma/fma9637"},{"id":"A408","pred":"fma_id","subj":"T408","obj":"http://purl.org/sig/ont/fma/fma7195"},{"id":"A409","pred":"fma_id","subj":"T409","obj":"http://purl.org/sig/ont/fma/fma284995"},{"id":"A410","pred":"fma_id","subj":"T410","obj":"http://purl.org/sig/ont/fma/fma63841"},{"id":"A411","pred":"fma_id","subj":"T411","obj":"http://purl.org/sig/ont/fma/fma284995"},{"id":"A412","pred":"fma_id","subj":"T412","obj":"http://purl.org/sig/ont/fma/fma284995"},{"id":"A413","pred":"fma_id","subj":"T413","obj":"http://purl.org/sig/ont/fma/fma84050"},{"id":"A414","pred":"fma_id","subj":"T414","obj":"http://purl.org/sig/ont/fma/fma264783"},{"id":"A415","pred":"fma_id","subj":"T415","obj":"http://purl.org/sig/ont/fma/fma284995"},{"id":"A416","pred":"fma_id","subj":"T416","obj":"http://purl.org/sig/ont/fma/fma63836"},{"id":"A417","pred":"fma_id","subj":"T417","obj":"http://purl.org/sig/ont/fma/fma284995"},{"id":"A418","pred":"fma_id","subj":"T418","obj":"http://purl.org/sig/ont/fma/fma284995"},{"id":"A419","pred":"fma_id","subj":"T419","obj":"http://purl.org/sig/ont/fma/fma63261"},{"id":"A420","pred":"fma_id","subj":"T420","obj":"http://purl.org/sig/ont/fma/fma284995"},{"id":"A421","pred":"fma_id","subj":"T421","obj":"http://purl.org/sig/ont/fma/fma7195"},{"id":"A422","pred":"fma_id","subj":"T422","obj":"http://purl.org/sig/ont/fma/fma7195"},{"id":"A423","pred":"fma_id","subj":"T423","obj":"http://purl.org/sig/ont/fma/fma7195"},{"id":"A424","pred":"fma_id","subj":"T424","obj":"http://purl.org/sig/ont/fma/fma67128"},{"id":"A425","pred":"fma_id","subj":"T425","obj":"http://purl.org/sig/ont/fma/fma63841"},{"id":"A426","pred":"fma_id","subj":"T426","obj":"http://purl.org/sig/ont/fma/fma284995"},{"id":"A427","pred":"fma_id","subj":"T427","obj":"http://purl.org/sig/ont/fma/fma68877"},{"id":"A428","pred":"fma_id","subj":"T428","obj":"http://purl.org/sig/ont/fma/fma63877"},{"id":"A429","pred":"fma_id","subj":"T429","obj":"http://purl.org/sig/ont/fma/fma62499"},{"id":"A430","pred":"fma_id","subj":"T430","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A431","pred":"fma_id","subj":"T431","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A432","pred":"fma_id","subj":"T432","obj":"http://purl.org/sig/ont/fma/fma63891"},{"id":"A433","pred":"fma_id","subj":"T433","obj":"http://purl.org/sig/ont/fma/fma68877"},{"id":"A434","pred":"fma_id","subj":"T434","obj":"http://purl.org/sig/ont/fma/fma7195"}],"text":"8. Autophagy Augmentation Strategies to Mitigate the Pathogenesis and Progression of Chronic Obstructive Lung Diseases\nAs 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. 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. 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]. 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]. 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]. 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. We and others have devised strategies such as nano/dendrimer-based formulations which can be efficiently delivered through intranasal inhalation [42,45,149]. 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]. 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.\nOur 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. 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]. 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]. 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. 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. 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]. 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]. 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.\nThe therapeutic potential of autophagy augmenting drugs has been extensively investigated in controlling chronic CF lung disease and associated pulmonary infection-related exacerbations. 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]. 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]. Tα1 possesses anti-inflammatory properties and is also known to induce autophagy [204], which could be its mechanism of action to rescue ΔF508-CFTR. Nonetheless, future pre-clinical and clinical studies will be essential before it could be any therapeutic benefit in CF-related autophagy dysfunction and exacerbations. 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]. However, a previously completed study of 10 patients with the ΔF508-CFTR mutation demonstrated a significant improvement in CFTR function with cysteamine treatment [208]. 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]. 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.\nIn 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]. Indeed, some recent studies have shown that autophagy mitigates IPF pathogenesis by regulating the fibroblast apoptosis and senescence of alveolar epithelial cells [209]. 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].\nTherefore, 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)."}

{"project":"LitCovid-PD-UBERON","denotations":[{"id":"T101","span":{"begin":105,"end":109},"obj":"Body_part"},{"id":"T102","span":{"begin":239,"end":243},"obj":"Body_part"},{"id":"T103","span":{"begin":559,"end":563},"obj":"Body_part"},{"id":"T104","span":{"begin":744,"end":748},"obj":"Body_part"},{"id":"T105","span":{"begin":830,"end":834},"obj":"Body_part"},{"id":"T106","span":{"begin":835,"end":841},"obj":"Body_part"},{"id":"T107","span":{"begin":1562,"end":1566},"obj":"Body_part"},{"id":"T108","span":{"begin":2608,"end":2612},"obj":"Body_part"},{"id":"T109","span":{"begin":4655,"end":4659},"obj":"Body_part"},{"id":"T110","span":{"begin":4810,"end":4814},"obj":"Body_part"},{"id":"T111","span":{"begin":4940,"end":4944},"obj":"Body_part"},{"id":"T112","span":{"begin":7051,"end":7055},"obj":"Body_part"}],"attributes":[{"id":"A101","pred":"uberon_id","subj":"T101","obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"id":"A102","pred":"uberon_id","subj":"T102","obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"id":"A103","pred":"uberon_id","subj":"T103","obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"id":"A104","pred":"uberon_id","subj":"T104","obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"id":"A105","pred":"uberon_id","subj":"T105","obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"id":"A106","pred":"uberon_id","subj":"T106","obj":"http://purl.obolibrary.org/obo/UBERON_0000479"},{"id":"A107","pred":"uberon_id","subj":"T107","obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"id":"A108","pred":"uberon_id","subj":"T108","obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"id":"A109","pred":"uberon_id","subj":"T109","obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"id":"A110","pred":"uberon_id","subj":"T110","obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"id":"A111","pred":"uberon_id","subj":"T111","obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"id":"A112","pred":"uberon_id","subj":"T112","obj":"http://purl.obolibrary.org/obo/UBERON_0002048"}],"text":"8. Autophagy Augmentation Strategies to Mitigate the Pathogenesis and Progression of Chronic Obstructive Lung Diseases\nAs 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. 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. 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]. 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]. 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]. 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. We and others have devised strategies such as nano/dendrimer-based formulations which can be efficiently delivered through intranasal inhalation [42,45,149]. 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]. 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.\nOur 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. 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]. 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]. 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. 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. 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]. 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]. 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.\nThe therapeutic potential of autophagy augmenting drugs has been extensively investigated in controlling chronic CF lung disease and associated pulmonary infection-related exacerbations. 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]. 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]. Tα1 possesses anti-inflammatory properties and is also known to induce autophagy [204], which could be its mechanism of action to rescue ΔF508-CFTR. Nonetheless, future pre-clinical and clinical studies will be essential before it could be any therapeutic benefit in CF-related autophagy dysfunction and exacerbations. 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]. However, a previously completed study of 10 patients with the ΔF508-CFTR mutation demonstrated a significant improvement in CFTR function with cysteamine treatment [208]. 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]. 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.\nIn 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]. Indeed, some recent studies have shown that autophagy mitigates IPF pathogenesis by regulating the fibroblast apoptosis and senescence of alveolar epithelial cells [209]. 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].\nTherefore, 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)."}

{"project":"LitCovid-PD-MONDO","denotations":[{"id":"T437","span":{"begin":85,"end":118},"obj":"Disease"},{"id":"T438","span":{"begin":219,"end":252},"obj":"Disease"},{"id":"T439","span":{"begin":287,"end":297},"obj":"Disease"},{"id":"T440","span":{"begin":539,"end":572},"obj":"Disease"},{"id":"T441","span":{"begin":744,"end":757},"obj":"Disease"},{"id":"T442","span":{"begin":867,"end":883},"obj":"Disease"},{"id":"T443","span":{"begin":1161,"end":1170},"obj":"Disease"},{"id":"T444","span":{"begin":1567,"end":1573},"obj":"Disease"},{"id":"T445","span":{"begin":1579,"end":1583},"obj":"Disease"},{"id":"T446","span":{"begin":1584,"end":1593},"obj":"Disease"},{"id":"T447","span":{"begin":2436,"end":2440},"obj":"Disease"},{"id":"T448","span":{"begin":2441,"end":2450},"obj":"Disease"},{"id":"T449","span":{"begin":2596,"end":2620},"obj":"Disease"},{"id":"T450","span":{"begin":2608,"end":2620},"obj":"Disease"},{"id":"T451","span":{"begin":2820,"end":2824},"obj":"Disease"},{"id":"T452","span":{"begin":2825,"end":2834},"obj":"Disease"},{"id":"T453","span":{"begin":3079,"end":3083},"obj":"Disease"},{"id":"T454","span":{"begin":3084,"end":3093},"obj":"Disease"},{"id":"T455","span":{"begin":4514,"end":4518},"obj":"Disease"},{"id":"T456","span":{"begin":4519,"end":4528},"obj":"Disease"},{"id":"T457","span":{"begin":4652,"end":4654},"obj":"Disease"},{"id":"T458","span":{"begin":4655,"end":4667},"obj":"Disease"},{"id":"T459","span":{"begin":4693,"end":4702},"obj":"Disease"},{"id":"T460","span":{"begin":4799,"end":4801},"obj":"Disease"},{"id":"T461","span":{"begin":4815,"end":4825},"obj":"Disease"},{"id":"T462","span":{"begin":5091,"end":5093},"obj":"Disease"},{"id":"T463","span":{"begin":5428,"end":5430},"obj":"Disease"},{"id":"T464","span":{"begin":5594,"end":5596},"obj":"Disease"},{"id":"T465","span":{"begin":5983,"end":5985},"obj":"Disease"},{"id":"T466","span":{"begin":6210,"end":6214},"obj":"Disease"},{"id":"T467","span":{"begin":6219,"end":6221},"obj":"Disease"},{"id":"T468","span":{"begin":6230,"end":6240},"obj":"Disease"},{"id":"T469","span":{"begin":6324,"end":6337},"obj":"Disease"},{"id":"T470","span":{"begin":6338,"end":6342},"obj":"Disease"},{"id":"T471","span":{"begin":6347,"end":6349},"obj":"Disease"},{"id":"T472","span":{"begin":6444,"end":6447},"obj":"Disease"},{"id":"T474","span":{"begin":6555,"end":6558},"obj":"Disease"},{"id":"T476","span":{"begin":6643,"end":6646},"obj":"Disease"},{"id":"T478","span":{"begin":6841,"end":6853},"obj":"Disease"},{"id":"T479","span":{"begin":7031,"end":7063},"obj":"Disease"},{"id":"T480","span":{"begin":7039,"end":7063},"obj":"Disease"},{"id":"T481","span":{"begin":7051,"end":7063},"obj":"Disease"}],"attributes":[{"id":"A437","pred":"mondo_id","subj":"T437","obj":"http://purl.obolibrary.org/obo/MONDO_0005002"},{"id":"A438","pred":"mondo_id","subj":"T438","obj":"http://purl.obolibrary.org/obo/MONDO_0005002"},{"id":"A439","pred":"mondo_id","subj":"T439","obj":"http://purl.obolibrary.org/obo/MONDO_0005550"},{"id":"A440","pred":"mondo_id","subj":"T440","obj":"http://purl.obolibrary.org/obo/MONDO_0005002"},{"id":"A441","pred":"mondo_id","subj":"T441","obj":"http://purl.obolibrary.org/obo/MONDO_0005275"},{"id":"A442","pred":"mondo_id","subj":"T442","obj":"http://purl.obolibrary.org/obo/MONDO_0005108"},{"id":"A443","pred":"mondo_id","subj":"T443","obj":"http://purl.obolibrary.org/obo/MONDO_0005550"},{"id":"A444","pred":"mondo_id","subj":"T444","obj":"http://purl.obolibrary.org/obo/MONDO_0021178"},{"id":"A445","pred":"mondo_id","subj":"T445","obj":"http://purl.obolibrary.org/obo/MONDO_0005002"},{"id":"A446","pred":"mondo_id","subj":"T446","obj":"http://purl.obolibrary.org/obo/MONDO_0004849"},{"id":"A447","pred":"mondo_id","subj":"T447","obj":"http://purl.obolibrary.org/obo/MONDO_0005002"},{"id":"A448","pred":"mondo_id","subj":"T448","obj":"http://purl.obolibrary.org/obo/MONDO_0004849"},{"id":"A449","pred":"mondo_id","subj":"T449","obj":"http://purl.obolibrary.org/obo/MONDO_0002267"},{"id":"A450","pred":"mondo_id","subj":"T450","obj":"http://purl.obolibrary.org/obo/MONDO_0005275"},{"id":"A451","pred":"mondo_id","subj":"T451","obj":"http://purl.obolibrary.org/obo/MONDO_0005002"},{"id":"A452","pred":"mondo_id","subj":"T452","obj":"http://purl.obolibrary.org/obo/MONDO_0004849"},{"id":"A453","pred":"mondo_id","subj":"T453","obj":"http://purl.obolibrary.org/obo/MONDO_0005002"},{"id":"A454","pred":"mondo_id","subj":"T454","obj":"http://purl.obolibrary.org/obo/MONDO_0004849"},{"id":"A455","pred":"mondo_id","subj":"T455","obj":"http://purl.obolibrary.org/obo/MONDO_0005002"},{"id":"A456","pred":"mondo_id","subj":"T456","obj":"http://purl.obolibrary.org/obo/MONDO_0004849"},{"id":"A457","pred":"mondo_id","subj":"T457","obj":"http://purl.obolibrary.org/obo/MONDO_0009061"},{"id":"A458","pred":"mondo_id","subj":"T458","obj":"http://purl.obolibrary.org/obo/MONDO_0005275"},{"id":"A459","pred":"mondo_id","subj":"T459","obj":"http://purl.obolibrary.org/obo/MONDO_0005550"},{"id":"A460","pred":"mondo_id","subj":"T460","obj":"http://purl.obolibrary.org/obo/MONDO_0009061"},{"id":"A461","pred":"mondo_id","subj":"T461","obj":"http://purl.obolibrary.org/obo/MONDO_0005550"},{"id":"A462","pred":"mondo_id","subj":"T462","obj":"http://purl.obolibrary.org/obo/MONDO_0009061"},{"id":"A463","pred":"mondo_id","subj":"T463","obj":"http://purl.obolibrary.org/obo/MONDO_0009061"},{"id":"A464","pred":"mondo_id","subj":"T464","obj":"http://purl.obolibrary.org/obo/MONDO_0009061"},{"id":"A465","pred":"mondo_id","subj":"T465","obj":"http://purl.obolibrary.org/obo/MONDO_0009061"},{"id":"A466","pred":"mondo_id","subj":"T466","obj":"http://purl.obolibrary.org/obo/MONDO_0005002"},{"id":"A467","pred":"mondo_id","subj":"T467","obj":"http://purl.obolibrary.org/obo/MONDO_0009061"},{"id":"A468","pred":"mondo_id","subj":"T468","obj":"http://purl.obolibrary.org/obo/MONDO_0005550"},{"id":"A469","pred":"mondo_id","subj":"T469","obj":"http://purl.obolibrary.org/obo/MONDO_0005550"},{"id":"A470","pred":"mondo_id","subj":"T470","obj":"http://purl.obolibrary.org/obo/MONDO_0005002"},{"id":"A471","pred":"mondo_id","subj":"T471","obj":"http://purl.obolibrary.org/obo/MONDO_0009061"},{"id":"A472","pred":"mondo_id","subj":"T472","obj":"http://purl.obolibrary.org/obo/MONDO_0002429"},{"id":"A473","pred":"mondo_id","subj":"T472","obj":"http://purl.obolibrary.org/obo/MONDO_0008345"},{"id":"A474","pred":"mondo_id","subj":"T474","obj":"http://purl.obolibrary.org/obo/MONDO_0002429"},{"id":"A475","pred":"mondo_id","subj":"T474","obj":"http://purl.obolibrary.org/obo/MONDO_0008345"},{"id":"A476","pred":"mondo_id","subj":"T476","obj":"http://purl.obolibrary.org/obo/MONDO_0002429"},{"id":"A477","pred":"mondo_id","subj":"T476","obj":"http://purl.obolibrary.org/obo/MONDO_0008345"},{"id":"A478","pred":"mondo_id","subj":"T478","obj":"http://purl.obolibrary.org/obo/MONDO_0021166"},{"id":"A479","pred":"mondo_id","subj":"T479","obj":"http://purl.obolibrary.org/obo/MONDO_0005002"},{"id":"A480","pred":"mondo_id","subj":"T480","obj":"http://purl.obolibrary.org/obo/MONDO_0002267"},{"id":"A481","pred":"mondo_id","subj":"T481","obj":"http://purl.obolibrary.org/obo/MONDO_0005275"}],"text":"8. Autophagy Augmentation Strategies to Mitigate the Pathogenesis and Progression of Chronic Obstructive Lung Diseases\nAs 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. 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. 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]. 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]. 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]. 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. We and others have devised strategies such as nano/dendrimer-based formulations which can be efficiently delivered through intranasal inhalation [42,45,149]. 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]. 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.\nOur 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. 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]. 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]. 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. 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. 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]. 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]. 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.\nThe therapeutic potential of autophagy augmenting drugs has been extensively investigated in controlling chronic CF lung disease and associated pulmonary infection-related exacerbations. 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]. 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]. Tα1 possesses anti-inflammatory properties and is also known to induce autophagy [204], which could be its mechanism of action to rescue ΔF508-CFTR. Nonetheless, future pre-clinical and clinical studies will be essential before it could be any therapeutic benefit in CF-related autophagy dysfunction and exacerbations. 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]. However, a previously completed study of 10 patients with the ΔF508-CFTR mutation demonstrated a significant improvement in CFTR function with cysteamine treatment [208]. 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]. 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.\nIn 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]. Indeed, some recent studies have shown that autophagy mitigates IPF pathogenesis by regulating the fibroblast apoptosis and senescence of alveolar epithelial cells [209]. 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].\nTherefore, 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)."}

{"project":"LitCovid-PD-CLO","denotations":[{"id":"T701","span":{"begin":105,"end":109},"obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"id":"T702","span":{"begin":105,"end":109},"obj":"http://www.ebi.ac.uk/efo/EFO_0000934"},{"id":"T703","span":{"begin":149,"end":153},"obj":"http://purl.obolibrary.org/obo/PR_000001044"},{"id":"T704","span":{"begin":172,"end":173},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T705","span":{"begin":239,"end":243},"obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"id":"T706","span":{"begin":239,"end":243},"obj":"http://www.ebi.ac.uk/efo/EFO_0000934"},{"id":"T707","span":{"begin":469,"end":473},"obj":"http://purl.obolibrary.org/obo/PR_000001044"},{"id":"T708","span":{"begin":495,"end":496},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T709","span":{"begin":559,"end":563},"obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"id":"T710","span":{"begin":559,"end":563},"obj":"http://www.ebi.ac.uk/efo/EFO_0000934"},{"id":"T711","span":{"begin":744,"end":748},"obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"id":"T712","span":{"begin":744,"end":748},"obj":"http://www.ebi.ac.uk/efo/EFO_0000934"},{"id":"T713","span":{"begin":830,"end":834},"obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"id":"T714","span":{"begin":830,"end":834},"obj":"http://www.ebi.ac.uk/efo/EFO_0000934"},{"id":"T715","span":{"begin":998,"end":1002},"obj":"http://purl.obolibrary.org/obo/PR_000001044"},{"id":"T716","span":{"begin":1015,"end":1018},"obj":"http://purl.obolibrary.org/obo/CLO_0051582"},{"id":"T717","span":{"begin":1203,"end":1209},"obj":"http://purl.obolibrary.org/obo/UBERON_0000473"},{"id":"T718","span":{"begin":1263,"end":1264},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T719","span":{"begin":1328,"end":1329},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T720","span":{"begin":1562,"end":1566},"obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"id":"T721","span":{"begin":1562,"end":1566},"obj":"http://www.ebi.ac.uk/efo/EFO_0000934"},{"id":"T722","span":{"begin":1741,"end":1745},"obj":"http://purl.obolibrary.org/obo/PR_000001044"},{"id":"T723","span":{"begin":1803,"end":1807},"obj":"http://purl.obolibrary.org/obo/PR_000001044"},{"id":"T724","span":{"begin":1896,"end":1902},"obj":"http://purl.obolibrary.org/obo/UBERON_0001005"},{"id":"T725","span":{"begin":2397,"end":2398},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T726","span":{"begin":2608,"end":2612},"obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"id":"T727","span":{"begin":2608,"end":2612},"obj":"http://www.ebi.ac.uk/efo/EFO_0000934"},{"id":"T728","span":{"begin":2761,"end":2765},"obj":"http://purl.obolibrary.org/obo/PR_000001044"},{"id":"T729","span":{"begin":2940,"end":2950},"obj":"http://purl.obolibrary.org/obo/CLO_0001658"},{"id":"T730","span":{"begin":3025,"end":3029},"obj":"http://purl.obolibrary.org/obo/PR_000001044"},{"id":"T731","span":{"begin":3065,"end":3066},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T732","span":{"begin":3224,"end":3228},"obj":"http://purl.obolibrary.org/obo/PR_000001044"},{"id":"T733","span":{"begin":3406,"end":3412},"obj":"http://purl.obolibrary.org/obo/UBERON_0001005"},{"id":"T734","span":{"begin":3523,"end":3529},"obj":"http://purl.obolibrary.org/obo/UBERON_0000473"},{"id":"T735","span":{"begin":3533,"end":3534},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T736","span":{"begin":3576,"end":3580},"obj":"http://purl.obolibrary.org/obo/PR_000001044"},{"id":"T737","span":{"begin":3640,"end":3646},"obj":"http://purl.obolibrary.org/obo/UBERON_0000473"},{"id":"T738","span":{"begin":3750,"end":3758},"obj":"http://purl.obolibrary.org/obo/GO_0005764"},{"id":"T739","span":{"begin":4052,"end":4054},"obj":"http://purl.obolibrary.org/obo/CLO_0001302"},{"id":"T740","span":{"begin":4060,"end":4061},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T741","span":{"begin":4161,"end":4162},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T742","span":{"begin":4409,"end":4411},"obj":"http://purl.obolibrary.org/obo/CLO_0001000"},{"id":"T743","span":{"begin":4595,"end":4598},"obj":"http://purl.obolibrary.org/obo/CLO_0051582"},{"id":"T744","span":{"begin":4655,"end":4659},"obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"id":"T745","span":{"begin":4655,"end":4659},"obj":"http://www.ebi.ac.uk/efo/EFO_0000934"},{"id":"T746","span":{"begin":4810,"end":4814},"obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"id":"T747","span":{"begin":4810,"end":4814},"obj":"http://www.ebi.ac.uk/efo/EFO_0000934"},{"id":"T748","span":{"begin":4940,"end":4944},"obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"id":"T749","span":{"begin":4940,"end":4944},"obj":"http://www.ebi.ac.uk/efo/EFO_0000934"},{"id":"T750","span":{"begin":5011,"end":5018},"obj":"http://purl.obolibrary.org/obo/PR_000018263"},{"id":"T751","span":{"begin":5139,"end":5143},"obj":"http://purl.obolibrary.org/obo/PR_000001044"},{"id":"T752","span":{"begin":5155,"end":5162},"obj":"http://purl.obolibrary.org/obo/CLO_0009381"},{"id":"T753","span":{"begin":5304,"end":5308},"obj":"http://purl.obolibrary.org/obo/PR_000001044"},{"id":"T754","span":{"begin":5507,"end":5508},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T755","span":{"begin":5568,"end":5571},"obj":"http://purl.obolibrary.org/obo/CLO_0051582"},{"id":"T756","span":{"begin":5584,"end":5590},"obj":"http://purl.obolibrary.org/obo/UBERON_0000473"},{"id":"T757","span":{"begin":5670,"end":5675},"obj":"http://purl.obolibrary.org/obo/NCBITaxon_9606"},{"id":"T758","span":{"begin":5719,"end":5720},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T759","span":{"begin":5778,"end":5782},"obj":"http://purl.obolibrary.org/obo/PR_000001044"},{"id":"T760","span":{"begin":5805,"end":5806},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T761","span":{"begin":5834,"end":5838},"obj":"http://purl.obolibrary.org/obo/PR_000001044"},{"id":"T762","span":{"begin":6141,"end":6146},"obj":"http://www.ebi.ac.uk/efo/EFO_0000934"},{"id":"T763","span":{"begin":6148,"end":6150},"obj":"http://purl.obolibrary.org/obo/CLO_0050507"},{"id":"T764","span":{"begin":6386,"end":6389},"obj":"http://purl.obolibrary.org/obo/CLO_0051582"},{"id":"T765","span":{"begin":6418,"end":6419},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T766","span":{"begin":6678,"end":6688},"obj":"http://purl.obolibrary.org/obo/CL_0000057"},{"id":"T767","span":{"begin":6726,"end":6736},"obj":"http://purl.obolibrary.org/obo/CL_0000066"},{"id":"T768","span":{"begin":6737,"end":6742},"obj":"http://purl.obolibrary.org/obo/GO_0005623"},{"id":"T769","span":{"begin":6760,"end":6761},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T770","span":{"begin":6858,"end":6866},"obj":"http://purl.obolibrary.org/obo/CHEBI_3815"},{"id":"T771","span":{"begin":6888,"end":6893},"obj":"http://www.ebi.ac.uk/efo/EFO_0000934"},{"id":"T772","span":{"begin":7001,"end":7002},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T773","span":{"begin":7051,"end":7055},"obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"id":"T774","span":{"begin":7051,"end":7055},"obj":"http://www.ebi.ac.uk/efo/EFO_0000934"}],"text":"8. Autophagy Augmentation Strategies to Mitigate the Pathogenesis and Progression of Chronic Obstructive Lung Diseases\nAs 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. 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. 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]. 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]. 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]. 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. We and others have devised strategies such as nano/dendrimer-based formulations which can be efficiently delivered through intranasal inhalation [42,45,149]. 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]. 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.\nOur 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. 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]. 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]. 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. 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. 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]. 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]. 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.\nThe therapeutic potential of autophagy augmenting drugs has been extensively investigated in controlling chronic CF lung disease and associated pulmonary infection-related exacerbations. 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]. 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]. Tα1 possesses anti-inflammatory properties and is also known to induce autophagy [204], which could be its mechanism of action to rescue ΔF508-CFTR. Nonetheless, future pre-clinical and clinical studies will be essential before it could be any therapeutic benefit in CF-related autophagy dysfunction and exacerbations. 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]. However, a previously completed study of 10 patients with the ΔF508-CFTR mutation demonstrated a significant improvement in CFTR function with cysteamine treatment [208]. 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]. 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.\nIn 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]. Indeed, some recent studies have shown that autophagy mitigates IPF pathogenesis by regulating the fibroblast apoptosis and senescence of alveolar epithelial cells [209]. 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].\nTherefore, 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)."}

{"project":"LitCovid-PD-CHEBI","denotations":[{"id":"T73","span":{"begin":1061,"end":1063},"obj":"Chemical"},{"id":"T91727","span":{"begin":1115,"end":1117},"obj":"Chemical"},{"id":"T38305","span":{"begin":1251,"end":1261},"obj":"Chemical"},{"id":"T134","span":{"begin":1457,"end":1459},"obj":"Chemical"},{"id":"T56457","span":{"begin":1618,"end":1628},"obj":"Chemical"},{"id":"T80","span":{"begin":1678,"end":1689},"obj":"Chemical"},{"id":"T73677","span":{"begin":1705,"end":1714},"obj":"Chemical"},{"id":"T72726","span":{"begin":1783,"end":1785},"obj":"Chemical"},{"id":"T49800","span":{"begin":1972,"end":1981},"obj":"Chemical"},{"id":"T62899","span":{"begin":2139,"end":2148},"obj":"Chemical"},{"id":"T47656","span":{"begin":2155,"end":2160},"obj":"Chemical"},{"id":"T15350","span":{"begin":2346,"end":2356},"obj":"Chemical"},{"id":"T54058","span":{"begin":2369,"end":2378},"obj":"Chemical"},{"id":"T77653","span":{"begin":2656,"end":2660},"obj":"Chemical"},{"id":"T90481","span":{"begin":2688,"end":2706},"obj":"Chemical"},{"id":"T28575","span":{"begin":2688,"end":2700},"obj":"Chemical"},{"id":"T41830","span":{"begin":2695,"end":2700},"obj":"Chemical"},{"id":"T97","span":{"begin":2701,"end":2706},"obj":"Chemical"},{"id":"T18880","span":{"begin":2750,"end":2752},"obj":"Chemical"},{"id":"T99","span":{"begin":2883,"end":2887},"obj":"Chemical"},{"id":"T100","span":{"begin":2936,"end":2939},"obj":"Chemical"},{"id":"T38467","span":{"begin":3037,"end":3039},"obj":"Chemical"},{"id":"T23686","span":{"begin":3137,"end":3139},"obj":"Chemical"},{"id":"T105","span":{"begin":3144,"end":3146},"obj":"Chemical"},{"id":"T44313","span":{"begin":3413,"end":3417},"obj":"Chemical"},{"id":"T97111","span":{"begin":3488,"end":3492},"obj":"Chemical"},{"id":"T108","span":{"begin":3565,"end":3567},"obj":"Chemical"},{"id":"T109","span":{"begin":3611,"end":3621},"obj":"Chemical"},{"id":"T111","span":{"begin":3626,"end":3630},"obj":"Chemical"},{"id":"T112","span":{"begin":3702,"end":3707},"obj":"Chemical"},{"id":"T54131","span":{"begin":3717,"end":3728},"obj":"Chemical"},{"id":"T17954","span":{"begin":3730,"end":3733},"obj":"Chemical"},{"id":"T48946","span":{"begin":3774,"end":3781},"obj":"Chemical"},{"id":"T116","span":{"begin":3798,"end":3800},"obj":"Chemical"},{"id":"T117","span":{"begin":3886,"end":3888},"obj":"Chemical"},{"id":"T16262","span":{"begin":4020,"end":4023},"obj":"Chemical"},{"id":"T83227","span":{"begin":4024,"end":4031},"obj":"Chemical"},{"id":"T14089","span":{"begin":4294,"end":4305},"obj":"Chemical"},{"id":"T9718","span":{"begin":4306,"end":4313},"obj":"Chemical"},{"id":"T93835","span":{"begin":4338,"end":4340},"obj":"Chemical"},{"id":"T87765","span":{"begin":4589,"end":4594},"obj":"Chemical"},{"id":"T5256","span":{"begin":4774,"end":4783},"obj":"Chemical"},{"id":"T13696","span":{"begin":5011,"end":5018},"obj":"Chemical"},{"id":"T67833","span":{"begin":5151,"end":5153},"obj":"Chemical"},{"id":"T129","span":{"begin":5495,"end":5505},"obj":"Chemical"},{"id":"T27730","span":{"begin":5516,"end":5527},"obj":"Chemical"},{"id":"T79502","span":{"begin":5528,"end":5532},"obj":"Chemical"},{"id":"T133","span":{"begin":5853,"end":5863},"obj":"Chemical"},{"id":"T17243","span":{"begin":6028,"end":6038},"obj":"Chemical"},{"id":"T137","span":{"begin":6059,"end":6061},"obj":"Chemical"},{"id":"T8987","span":{"begin":6109,"end":6117},"obj":"Chemical"},{"id":"T140","span":{"begin":6292,"end":6300},"obj":"Chemical"},{"id":"T96107","span":{"begin":6801,"end":6803},"obj":"Chemical"},{"id":"T144","span":{"begin":6823,"end":6832},"obj":"Chemical"}],"attributes":[{"id":"A50541","pred":"chebi_id","subj":"T73","obj":"http://purl.obolibrary.org/obo/CHEBI_73462"},{"id":"A52905","pred":"chebi_id","subj":"T91727","obj":"http://purl.obolibrary.org/obo/CHEBI_73462"},{"id":"A97506","pred":"chebi_id","subj":"T38305","obj":"http://purl.obolibrary.org/obo/CHEBI_17141"},{"id":"A65796","pred":"chebi_id","subj":"T38305","obj":"http://purl.obolibrary.org/obo/CHEBI_58029"},{"id":"A20102","pred":"chebi_id","subj":"T134","obj":"http://purl.obolibrary.org/obo/CHEBI_73462"},{"id":"A3839","pred":"chebi_id","subj":"T56457","obj":"http://purl.obolibrary.org/obo/CHEBI_17141"},{"id":"A86585","pred":"chebi_id","subj":"T56457","obj":"http://purl.obolibrary.org/obo/CHEBI_58029"},{"id":"A68902","pred":"chebi_id","subj":"T80","obj":"http://purl.obolibrary.org/obo/CHEBI_22586"},{"id":"A17988","pred":"chebi_id","subj":"T73677","obj":"http://purl.obolibrary.org/obo/CHEBI_77034"},{"id":"A45432","pred":"chebi_id","subj":"T72726","obj":"http://purl.obolibrary.org/obo/CHEBI_73462"},{"id":"A88149","pred":"chebi_id","subj":"T49800","obj":"http://purl.obolibrary.org/obo/CHEBI_51338"},{"id":"A51215","pred":"chebi_id","subj":"T49800","obj":"http://purl.obolibrary.org/obo/CHEBI_61483"},{"id":"A95232","pred":"chebi_id","subj":"T62899","obj":"http://purl.obolibrary.org/obo/CHEBI_51338"},{"id":"A26385","pred":"chebi_id","subj":"T62899","obj":"http://purl.obolibrary.org/obo/CHEBI_61483"},{"id":"A18690","pred":"chebi_id","subj":"T47656","obj":"http://purl.obolibrary.org/obo/CHEBI_23888"},{"id":"A39103","pred":"chebi_id","subj":"T15350","obj":"http://purl.obolibrary.org/obo/CHEBI_17141"},{"id":"A97824","pred":"chebi_id","subj":"T15350","obj":"http://purl.obolibrary.org/obo/CHEBI_58029"},{"id":"A68811","pred":"chebi_id","subj":"T54058","obj":"http://purl.obolibrary.org/obo/CHEBI_51338"},{"id":"A12885","pred":"chebi_id","subj":"T54058","obj":"http://purl.obolibrary.org/obo/CHEBI_61483"},{"id":"A13130","pred":"chebi_id","subj":"T77653","obj":"http://purl.obolibrary.org/obo/CHEBI_50091"},{"id":"A48128","pred":"chebi_id","subj":"T90481","obj":"http://purl.obolibrary.org/obo/CHEBI_50566"},{"id":"A65775","pred":"chebi_id","subj":"T28575","obj":"http://purl.obolibrary.org/obo/CHEBI_16480"},{"id":"A57482","pred":"chebi_id","subj":"T41830","obj":"http://purl.obolibrary.org/obo/CHEBI_25741"},{"id":"A75103","pred":"chebi_id","subj":"T41830","obj":"http://purl.obolibrary.org/obo/CHEBI_29356"},{"id":"A65706","pred":"chebi_id","subj":"T97","obj":"http://purl.obolibrary.org/obo/CHEBI_17891"},{"id":"A70114","pred":"chebi_id","subj":"T18880","obj":"http://purl.obolibrary.org/obo/CHEBI_73462"},{"id":"A3910","pred":"chebi_id","subj":"T99","obj":"http://purl.obolibrary.org/obo/CHEBI_50091"},{"id":"A55539","pred":"chebi_id","subj":"T100","obj":"http://purl.obolibrary.org/obo/CHEBI_26523"},{"id":"A71781","pred":"chebi_id","subj":"T38467","obj":"http://purl.obolibrary.org/obo/CHEBI_141444"},{"id":"A8734","pred":"chebi_id","subj":"T38467","obj":"http://purl.obolibrary.org/obo/CHEBI_16410"},{"id":"A90599","pred":"chebi_id","subj":"T38467","obj":"http://purl.obolibrary.org/obo/CHEBI_53551"},{"id":"A9412","pred":"chebi_id","subj":"T23686","obj":"http://purl.obolibrary.org/obo/CHEBI_73462"},{"id":"A34169","pred":"chebi_id","subj":"T105","obj":"http://purl.obolibrary.org/obo/CHEBI_73462"},{"id":"A66549","pred":"chebi_id","subj":"T44313","obj":"http://purl.obolibrary.org/obo/CHEBI_50091"},{"id":"A48260","pred":"chebi_id","subj":"T97111","obj":"http://purl.obolibrary.org/obo/CHEBI_50091"},{"id":"A77896","pred":"chebi_id","subj":"T108","obj":"http://purl.obolibrary.org/obo/CHEBI_73462"},{"id":"A99217","pred":"chebi_id","subj":"T109","obj":"http://purl.obolibrary.org/obo/CHEBI_17141"},{"id":"A71432","pred":"chebi_id","subj":"T109","obj":"http://purl.obolibrary.org/obo/CHEBI_58029"},{"id":"A30980","pred":"chebi_id","subj":"T111","obj":"http://purl.obolibrary.org/obo/CHEBI_50091"},{"id":"A74383","pred":"chebi_id","subj":"T112","obj":"http://purl.obolibrary.org/obo/CHEBI_23888"},{"id":"A34654","pred":"chebi_id","subj":"T54131","obj":"http://purl.obolibrary.org/obo/CHEBI_5296"},{"id":"A96669","pred":"chebi_id","subj":"T17954","obj":"http://purl.obolibrary.org/obo/CHEBI_5296"},{"id":"A92604","pred":"chebi_id","subj":"T48946","obj":"http://purl.obolibrary.org/obo/CHEBI_42567"},{"id":"A79532","pred":"chebi_id","subj":"T116","obj":"http://purl.obolibrary.org/obo/CHEBI_73462"},{"id":"A3075","pred":"chebi_id","subj":"T117","obj":"http://purl.obolibrary.org/obo/CHEBI_73462"},{"id":"A14641","pred":"chebi_id","subj":"T16262","obj":"http://purl.obolibrary.org/obo/CHEBI_5296"},{"id":"A48236","pred":"chebi_id","subj":"T83227","obj":"http://purl.obolibrary.org/obo/CHEBI_42567"},{"id":"A29259","pred":"chebi_id","subj":"T14089","obj":"http://purl.obolibrary.org/obo/CHEBI_22586"},{"id":"A94858","pred":"chebi_id","subj":"T9718","obj":"http://purl.obolibrary.org/obo/CHEBI_42567"},{"id":"A71835","pred":"chebi_id","subj":"T93835","obj":"http://purl.obolibrary.org/obo/CHEBI_73462"},{"id":"A55901","pred":"chebi_id","subj":"T87765","obj":"http://purl.obolibrary.org/obo/CHEBI_23888"},{"id":"A18661","pred":"chebi_id","subj":"T5256","obj":"http://purl.obolibrary.org/obo/CHEBI_9168"},{"id":"A76454","pred":"chebi_id","subj":"T13696","obj":"http://purl.obolibrary.org/obo/CHEBI_16670"},{"id":"A41354","pred":"chebi_id","subj":"T67833","obj":"http://purl.obolibrary.org/obo/CHEBI_141444"},{"id":"A13220","pred":"chebi_id","subj":"T67833","obj":"http://purl.obolibrary.org/obo/CHEBI_16410"},{"id":"A94585","pred":"chebi_id","subj":"T67833","obj":"http://purl.obolibrary.org/obo/CHEBI_53551"},{"id":"A82908","pred":"chebi_id","subj":"T129","obj":"http://purl.obolibrary.org/obo/CHEBI_17141"},{"id":"A4237","pred":"chebi_id","subj":"T129","obj":"http://purl.obolibrary.org/obo/CHEBI_58029"},{"id":"A80675","pred":"chebi_id","subj":"T27730","obj":"http://purl.obolibrary.org/obo/CHEBI_22586"},{"id":"A36533","pred":"chebi_id","subj":"T79502","obj":"http://purl.obolibrary.org/obo/CHEBI_23888"},{"id":"A16317","pred":"chebi_id","subj":"T133","obj":"http://purl.obolibrary.org/obo/CHEBI_17141"},{"id":"A16935","pred":"chebi_id","subj":"T133","obj":"http://purl.obolibrary.org/obo/CHEBI_58029"},{"id":"A72621","pred":"chebi_id","subj":"T17243","obj":"http://purl.obolibrary.org/obo/CHEBI_17141"},{"id":"A87014","pred":"chebi_id","subj":"T17243","obj":"http://purl.obolibrary.org/obo/CHEBI_58029"},{"id":"A73529","pred":"chebi_id","subj":"T137","obj":"http://purl.obolibrary.org/obo/CHEBI_73462"},{"id":"A28340","pred":"chebi_id","subj":"T8987","obj":"http://purl.obolibrary.org/obo/CHEBI_17761"},{"id":"A58129","pred":"chebi_id","subj":"T8987","obj":"http://purl.obolibrary.org/obo/CHEBI_52639"},{"id":"A16025","pred":"chebi_id","subj":"T140","obj":"http://purl.obolibrary.org/obo/CHEBI_17761"},{"id":"A99481","pred":"chebi_id","subj":"T140","obj":"http://purl.obolibrary.org/obo/CHEBI_52639"},{"id":"A78663","pred":"chebi_id","subj":"T96107","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A1260","pred":"chebi_id","subj":"T96107","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A21623","pred":"chebi_id","subj":"T144","obj":"http://purl.obolibrary.org/obo/CHEBI_22907"}],"text":"8. Autophagy Augmentation Strategies to Mitigate the Pathogenesis and Progression of Chronic Obstructive Lung Diseases\nAs 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. 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. 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]. 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]. 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]. 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. We and others have devised strategies such as nano/dendrimer-based formulations which can be efficiently delivered through intranasal inhalation [42,45,149]. 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]. 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.\nOur 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. 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]. 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]. 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. 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. 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]. 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]. 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.\nThe therapeutic potential of autophagy augmenting drugs has been extensively investigated in controlling chronic CF lung disease and associated pulmonary infection-related exacerbations. 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]. 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]. Tα1 possesses anti-inflammatory properties and is also known to induce autophagy [204], which could be its mechanism of action to rescue ΔF508-CFTR. Nonetheless, future pre-clinical and clinical studies will be essential before it could be any therapeutic benefit in CF-related autophagy dysfunction and exacerbations. 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]. However, a previously completed study of 10 patients with the ΔF508-CFTR mutation demonstrated a significant improvement in CFTR function with cysteamine treatment [208]. 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]. 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.\nIn 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]. Indeed, some recent studies have shown that autophagy mitigates IPF pathogenesis by regulating the fibroblast apoptosis and senescence of alveolar epithelial cells [209]. 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].\nTherefore, 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)."}

{"project":"LitCovid-PubTator","denotations":[{"id":"1477","span":{"begin":85,"end":118},"obj":"Disease"},{"id":"1500","span":{"begin":1741,"end":1745},"obj":"Gene"},{"id":"1501","span":{"begin":627,"end":633},"obj":"Species"},{"id":"1502","span":{"begin":1098,"end":1104},"obj":"Species"},{"id":"1503","span":{"begin":1251,"end":1261},"obj":"Chemical"},{"id":"1504","span":{"begin":1298,"end":1308},"obj":"Chemical"},{"id":"1505","span":{"begin":1618,"end":1628},"obj":"Chemical"},{"id":"1506","span":{"begin":2346,"end":2356},"obj":"Chemical"},{"id":"1507","span":{"begin":149,"end":165},"obj":"Disease"},{"id":"1508","span":{"begin":219,"end":252},"obj":"Disease"},{"id":"1509","span":{"begin":287,"end":297},"obj":"Disease"},{"id":"1510","span":{"begin":363,"end":372},"obj":"Disease"},{"id":"1511","span":{"begin":469,"end":485},"obj":"Disease"},{"id":"1512","span":{"begin":539,"end":572},"obj":"Disease"},{"id":"1513","span":{"begin":744,"end":757},"obj":"Disease"},{"id":"1514","span":{"begin":867,"end":883},"obj":"Disease"},{"id":"1515","span":{"begin":998,"end":1014},"obj":"Disease"},{"id":"1516","span":{"begin":1147,"end":1170},"obj":"Disease"},{"id":"1517","span":{"begin":1562,"end":1573},"obj":"Disease"},{"id":"1518","span":{"begin":1579,"end":1593},"obj":"Disease"},{"id":"1519","span":{"begin":1803,"end":1819},"obj":"Disease"},{"id":"1520","span":{"begin":2436,"end":2450},"obj":"Disease"},{"id":"1521","span":{"begin":2596,"end":2620},"obj":"Disease"},{"id":"1550","span":{"begin":3025,"end":3029},"obj":"Gene"},{"id":"1551","span":{"begin":3224,"end":3228},"obj":"Gene"},{"id":"1552","span":{"begin":3576,"end":3580},"obj":"Gene"},{"id":"1553","span":{"begin":3901,"end":3905},"obj":"Gene"},{"id":"1554","span":{"begin":4036,"end":4040},"obj":"Gene"},{"id":"1555","span":{"begin":2750,"end":2752},"obj":"Gene"},{"id":"1556","span":{"begin":2898,"end":2913},"obj":"Gene"},{"id":"1557","span":{"begin":3094,"end":3100},"obj":"Species"},{"id":"1558","span":{"begin":4248,"end":4261},"obj":"Species"},{"id":"1559","span":{"begin":4384,"end":4397},"obj":"Species"},{"id":"1560","span":{"begin":2656,"end":2660},"obj":"Chemical"},{"id":"1561","span":{"begin":2688,"end":2700},"obj":"Chemical"},{"id":"1562","span":{"begin":2883,"end":2887},"obj":"Chemical"},{"id":"1563","span":{"begin":3413,"end":3417},"obj":"Chemical"},{"id":"1564","span":{"begin":3488,"end":3492},"obj":"Chemical"},{"id":"1565","span":{"begin":3611,"end":3621},"obj":"Chemical"},{"id":"1566","span":{"begin":3626,"end":3630},"obj":"Chemical"},{"id":"1567","span":{"begin":3717,"end":3728},"obj":"Chemical"},{"id":"1568","span":{"begin":3730,"end":3733},"obj":"Chemical"},{"id":"1569","span":{"begin":4020,"end":4023},"obj":"Chemical"},{"id":"1570","span":{"begin":4024,"end":4031},"obj":"Chemical"},{"id":"1571","span":{"begin":4306,"end":4313},"obj":"Chemical"},{"id":"1572","span":{"begin":2761,"end":2777},"obj":"Disease"},{"id":"1573","span":{"begin":2820,"end":2834},"obj":"Disease"},{"id":"1574","span":{"begin":3079,"end":3093},"obj":"Disease"},{"id":"1575","span":{"begin":4185,"end":4205},"obj":"Disease"},{"id":"1576","span":{"begin":4349,"end":4368},"obj":"Disease"},{"id":"1577","span":{"begin":4514,"end":4528},"obj":"Disease"},{"id":"1602","span":{"begin":5034,"end":5037},"obj":"Gene"},{"id":"1603","span":{"begin":5139,"end":5143},"obj":"Gene"},{"id":"1604","span":{"begin":5161,"end":5164},"obj":"Gene"},{"id":"1605","span":{"begin":5304,"end":5308},"obj":"Gene"},{"id":"1606","span":{"begin":5778,"end":5782},"obj":"Gene"},{"id":"1607","span":{"begin":5834,"end":5838},"obj":"Gene"},{"id":"1608","span":{"begin":5670,"end":5675},"obj":"Species"},{"id":"1609","span":{"begin":5754,"end":5762},"obj":"Species"},{"id":"1610","span":{"begin":6134,"end":6140},"obj":"Species"},{"id":"1611","span":{"begin":4774,"end":4783},"obj":"Chemical"},{"id":"1612","span":{"begin":5495,"end":5505},"obj":"Chemical"},{"id":"1613","span":{"begin":5853,"end":5863},"obj":"Chemical"},{"id":"1614","span":{"begin":5921,"end":5931},"obj":"Chemical"},{"id":"1615","span":{"begin":6028,"end":6038},"obj":"Chemical"},{"id":"1616","span":{"begin":6109,"end":6117},"obj":"Chemical"},{"id":"1617","span":{"begin":6292,"end":6300},"obj":"Chemical"},{"id":"1618","span":{"begin":4644,"end":4667},"obj":"Disease"},{"id":"1619","span":{"begin":4683,"end":4702},"obj":"Disease"},{"id":"1620","span":{"begin":4810,"end":4825},"obj":"Disease"},{"id":"1621","span":{"begin":4940,"end":4953},"obj":"Disease"},{"id":"1622","span":{"begin":6210,"end":6214},"obj":"Disease"},{"id":"1623","span":{"begin":6219,"end":6240},"obj":"Disease"},{"id":"1624","span":{"begin":6314,"end":6334},"obj":"Disease"},{"id":"1625","span":{"begin":6338,"end":6342},"obj":"Disease"},{"id":"1630","span":{"begin":6908,"end":6916},"obj":"Gene"},{"id":"1631","span":{"begin":6881,"end":6887},"obj":"Species"},{"id":"1632","span":{"begin":6823,"end":6832},"obj":"Chemical"},{"id":"1633","span":{"begin":6841,"end":6853},"obj":"Disease"},{"id":"1637","span":{"begin":7162,"end":7169},"obj":"Species"},{"id":"1638","span":{"begin":7031,"end":7063},"obj":"Disease"},{"id":"1639","span":{"begin":7170,"end":7179},"obj":"Disease"}],"attributes":[{"id":"A1477","pred":"tao:has_database_id","subj":"1477","obj":"MESH:D029424"},{"id":"A1500","pred":"tao:has_database_id","subj":"1500","obj":"Gene:1080"},{"id":"A1501","pred":"tao:has_database_id","subj":"1501","obj":"Tax:10090"},{"id":"A1502","pred":"tao:has_database_id","subj":"1502","obj":"Tax:10090"},{"id":"A1503","pred":"tao:has_database_id","subj":"1503","obj":"MESH:D003543"},{"id":"A1505","pred":"tao:has_database_id","subj":"1505","obj":"MESH:D003543"},{"id":"A1506","pred":"tao:has_database_id","subj":"1506","obj":"MESH:D003543"},{"id":"A1507","pred":"tao:has_database_id","subj":"1507","obj":"MESH:D009461"},{"id":"A1508","pred":"tao:has_database_id","subj":"1508","obj":"MESH:D029424"},{"id":"A1509","pred":"tao:has_database_id","subj":"1509","obj":"MESH:D007239"},{"id":"A1510","pred":"tao:has_database_id","subj":"1510","obj":"MESH:D003643"},{"id":"A1511","pred":"tao:has_database_id","subj":"1511","obj":"MESH:D009461"},{"id":"A1512","pred":"tao:has_database_id","subj":"1512","obj":"MESH:D029424"},{"id":"A1513","pred":"tao:has_database_id","subj":"1513","obj":"MESH:D008171"},{"id":"A1514","pred":"tao:has_database_id","subj":"1514","obj":"MESH:D001102"},{"id":"A1515","pred":"tao:has_database_id","subj":"1515","obj":"MESH:D009461"},{"id":"A1516","pred":"tao:has_database_id","subj":"1516","obj":"MESH:D060085"},{"id":"A1517","pred":"tao:has_database_id","subj":"1517","obj":"MESH:D055370"},{"id":"A1518","pred":"tao:has_database_id","subj":"1518","obj":"MESH:D029424"},{"id":"A1519","pred":"tao:has_database_id","subj":"1519","obj":"MESH:D009461"},{"id":"A1520","pred":"tao:has_database_id","subj":"1520","obj":"MESH:D029424"},{"id":"A1521","pred":"tao:has_database_id","subj":"1521","obj":"MESH:D008173"},{"id":"A1550","pred":"tao:has_database_id","subj":"1550","obj":"Gene:1080"},{"id":"A1551","pred":"tao:has_database_id","subj":"1551","obj":"Gene:12638"},{"id":"A1552","pred":"tao:has_database_id","subj":"1552","obj":"Gene:12638"},{"id":"A1553","pred":"tao:has_database_id","subj":"1553","obj":"Gene:7942"},{"id":"A1554","pred":"tao:has_database_id","subj":"1554","obj":"Gene:7942"},{"id":"A1555","pred":"tao:has_database_id","subj":"1555","obj":"Gene:1431"},{"id":"A1556","pred":"tao:has_database_id","subj":"1556","obj":"Gene:1431"},{"id":"A1557","pred":"tao:has_database_id","subj":"1557","obj":"Tax:10090"},{"id":"A1558","pred":"tao:has_database_id","subj":"1558","obj":"Tax:287"},{"id":"A1559","pred":"tao:has_database_id","subj":"1559","obj":"Tax:287"},{"id":"A1561","pred":"tao:has_database_id","subj":"1561","obj":"MESH:D009569"},{"id":"A1565","pred":"tao:has_database_id","subj":"1565","obj":"MESH:D003543"},{"id":"A1567","pred":"tao:has_database_id","subj":"1567","obj":"MESH:D015248"},{"id":"A1568","pred":"tao:has_database_id","subj":"1568","obj":"MESH:D015248"},{"id":"A1569","pred":"tao:has_database_id","subj":"1569","obj":"MESH:D015248"},{"id":"A1570","pred":"tao:has_database_id","subj":"1570","obj":"MESH:C017875"},{"id":"A1571","pred":"tao:has_database_id","subj":"1571","obj":"MESH:C017875"},{"id":"A1572","pred":"tao:has_database_id","subj":"1572","obj":"MESH:D009461"},{"id":"A1573","pred":"tao:has_database_id","subj":"1573","obj":"MESH:D029424"},{"id":"A1574","pred":"tao:has_database_id","subj":"1574","obj":"MESH:D029424"},{"id":"A1575","pred":"tao:has_database_id","subj":"1575","obj":"MESH:D000014"},{"id":"A1576","pred":"tao:has_database_id","subj":"1576","obj":"MESH:D000014"},{"id":"A1577","pred":"tao:has_database_id","subj":"1577","obj":"MESH:D029424"},{"id":"A1602","pred":"tao:has_database_id","subj":"1602","obj":"Gene:134864"},{"id":"A1603","pred":"tao:has_database_id","subj":"1603","obj":"Gene:1080"},{"id":"A1604","pred":"tao:has_database_id","subj":"1604","obj":"Gene:134864"},{"id":"A1605","pred":"tao:has_database_id","subj":"1605","obj":"Gene:1080"},{"id":"A1606","pred":"tao:has_database_id","subj":"1606","obj":"Gene:1080"},{"id":"A1607","pred":"tao:has_database_id","subj":"1607","obj":"Gene:1080"},{"id":"A1608","pred":"tao:has_database_id","subj":"1608","obj":"Tax:9606"},{"id":"A1609","pred":"tao:has_database_id","subj":"1609","obj":"Tax:9606"},{"id":"A1610","pred":"tao:has_database_id","subj":"1610","obj":"Tax:10090"},{"id":"A1611","pred":"tao:has_database_id","subj":"1611","obj":"MESH:D020123"},{"id":"A1612","pred":"tao:has_database_id","subj":"1612","obj":"MESH:D003543"},{"id":"A1613","pred":"tao:has_database_id","subj":"1613","obj":"MESH:D003543"},{"id":"A1614","pred":"tao:has_database_id","subj":"1614","obj":"MESH:D003543"},{"id":"A1615","pred":"tao:has_database_id","subj":"1615","obj":"MESH:D003543"},{"id":"A1616","pred":"tao:has_database_id","subj":"1616","obj":"MESH:D002518"},{"id":"A1617","pred":"tao:has_database_id","subj":"1617","obj":"MESH:D002518"},{"id":"A1618","pred":"tao:has_database_id","subj":"1618","obj":"MESH:D003550"},{"id":"A1619","pred":"tao:has_database_id","subj":"1619","obj":"MESH:D012141"},{"id":"A1620","pred":"tao:has_database_id","subj":"1620","obj":"MESH:D012141"},{"id":"A1621","pred":"tao:has_database_id","subj":"1621","obj":"MESH:D008171"},{"id":"A1622","pred":"tao:has_database_id","subj":"1622","obj":"MESH:D029424"},{"id":"A1623","pred":"tao:has_database_id","subj":"1623","obj":"MESH:D003550"},{"id":"A1624","pred":"tao:has_database_id","subj":"1624","obj":"MESH:D012141"},{"id":"A1625","pred":"tao:has_database_id","subj":"1625","obj":"MESH:D029424"},{"id":"A1630","pred":"tao:has_database_id","subj":"1630","obj":"Gene:56208"},{"id":"A1631","pred":"tao:has_database_id","subj":"1631","obj":"Tax:10090"},{"id":"A1632","pred":"tao:has_database_id","subj":"1632","obj":"MESH:D001761"},{"id":"A1633","pred":"tao:has_database_id","subj":"1633","obj":"MESH:D007249"},{"id":"A1637","pred":"tao:has_database_id","subj":"1637","obj":"Tax:9606"},{"id":"A1638","pred":"tao:has_database_id","subj":"1638","obj":"MESH:D029424"},{"id":"A1639","pred":"tao:has_database_id","subj":"1639","obj":"MESH:D003643"}],"namespaces":[{"prefix":"Tax","uri":"https://www.ncbi.nlm.nih.gov/taxonomy/"},{"prefix":"MESH","uri":"https://id.nlm.nih.gov/mesh/"},{"prefix":"Gene","uri":"https://www.ncbi.nlm.nih.gov/gene/"},{"prefix":"CVCL","uri":"https://web.expasy.org/cellosaurus/CVCL_"}],"text":"8. Autophagy Augmentation Strategies to Mitigate the Pathogenesis and Progression of Chronic Obstructive Lung Diseases\nAs 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. 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. 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]. 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]. 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]. 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. We and others have devised strategies such as nano/dendrimer-based formulations which can be efficiently delivered through intranasal inhalation [42,45,149]. 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]. 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.\nOur 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. 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]. 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]. 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. 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. 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]. 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]. 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.\nThe therapeutic potential of autophagy augmenting drugs has been extensively investigated in controlling chronic CF lung disease and associated pulmonary infection-related exacerbations. 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]. 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]. Tα1 possesses anti-inflammatory properties and is also known to induce autophagy [204], which could be its mechanism of action to rescue ΔF508-CFTR. Nonetheless, future pre-clinical and clinical studies will be essential before it could be any therapeutic benefit in CF-related autophagy dysfunction and exacerbations. 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]. However, a previously completed study of 10 patients with the ΔF508-CFTR mutation demonstrated a significant improvement in CFTR function with cysteamine treatment [208]. 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]. 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.\nIn 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]. Indeed, some recent studies have shown that autophagy mitigates IPF pathogenesis by regulating the fibroblast apoptosis and senescence of alveolar epithelial cells [209]. 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].\nTherefore, 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)."}

{"project":"LitCovid-PD-HP","denotations":[{"id":"T188","span":{"begin":93,"end":118},"obj":"Phenotype"},{"id":"T189","span":{"begin":227,"end":252},"obj":"Phenotype"},{"id":"T190","span":{"begin":277,"end":297},"obj":"Phenotype"},{"id":"T191","span":{"begin":547,"end":572},"obj":"Phenotype"},{"id":"T192","span":{"begin":736,"end":757},"obj":"Phenotype"},{"id":"T193","span":{"begin":780,"end":796},"obj":"Phenotype"},{"id":"T194","span":{"begin":1492,"end":1508},"obj":"Phenotype"},{"id":"T195","span":{"begin":1579,"end":1583},"obj":"Phenotype"},{"id":"T196","span":{"begin":1584,"end":1593},"obj":"Phenotype"},{"id":"T197","span":{"begin":2436,"end":2440},"obj":"Phenotype"},{"id":"T198","span":{"begin":2441,"end":2450},"obj":"Phenotype"},{"id":"T199","span":{"begin":2596,"end":2620},"obj":"Phenotype"},{"id":"T200","span":{"begin":2820,"end":2824},"obj":"Phenotype"},{"id":"T201","span":{"begin":2825,"end":2834},"obj":"Phenotype"},{"id":"T202","span":{"begin":3079,"end":3083},"obj":"Phenotype"},{"id":"T203","span":{"begin":3084,"end":3093},"obj":"Phenotype"},{"id":"T204","span":{"begin":3941,"end":3957},"obj":"Phenotype"},{"id":"T205","span":{"begin":4514,"end":4518},"obj":"Phenotype"},{"id":"T206","span":{"begin":4519,"end":4528},"obj":"Phenotype"},{"id":"T207","span":{"begin":4655,"end":4667},"obj":"Phenotype"},{"id":"T208","span":{"begin":4683,"end":4702},"obj":"Phenotype"},{"id":"T209","span":{"begin":6210,"end":6214},"obj":"Phenotype"},{"id":"T210","span":{"begin":6314,"end":6334},"obj":"Phenotype"},{"id":"T211","span":{"begin":6338,"end":6342},"obj":"Phenotype"},{"id":"T212","span":{"begin":7039,"end":7063},"obj":"Phenotype"}],"attributes":[{"id":"A188","pred":"hp_id","subj":"T188","obj":"http://purl.obolibrary.org/obo/HP_0006536"},{"id":"A189","pred":"hp_id","subj":"T189","obj":"http://purl.obolibrary.org/obo/HP_0006536"},{"id":"A190","pred":"hp_id","subj":"T190","obj":"http://purl.obolibrary.org/obo/HP_0002719"},{"id":"A191","pred":"hp_id","subj":"T191","obj":"http://purl.obolibrary.org/obo/HP_0006536"},{"id":"A192","pred":"hp_id","subj":"T192","obj":"http://purl.obolibrary.org/obo/HP_0006528"},{"id":"A193","pred":"hp_id","subj":"T193","obj":"http://purl.obolibrary.org/obo/HP_0025464"},{"id":"A194","pred":"hp_id","subj":"T194","obj":"http://purl.obolibrary.org/obo/HP_0025464"},{"id":"A195","pred":"hp_id","subj":"T195","obj":"http://purl.obolibrary.org/obo/HP_0006510"},{"id":"A196","pred":"hp_id","subj":"T196","obj":"http://purl.obolibrary.org/obo/HP_0002097"},{"id":"A197","pred":"hp_id","subj":"T197","obj":"http://purl.obolibrary.org/obo/HP_0006510"},{"id":"A198","pred":"hp_id","subj":"T198","obj":"http://purl.obolibrary.org/obo/HP_0002097"},{"id":"A199","pred":"hp_id","subj":"T199","obj":"http://purl.obolibrary.org/obo/HP_0006536"},{"id":"A200","pred":"hp_id","subj":"T200","obj":"http://purl.obolibrary.org/obo/HP_0006510"},{"id":"A201","pred":"hp_id","subj":"T201","obj":"http://purl.obolibrary.org/obo/HP_0002097"},{"id":"A202","pred":"hp_id","subj":"T202","obj":"http://purl.obolibrary.org/obo/HP_0006510"},{"id":"A203","pred":"hp_id","subj":"T203","obj":"http://purl.obolibrary.org/obo/HP_0002097"},{"id":"A204","pred":"hp_id","subj":"T204","obj":"http://purl.obolibrary.org/obo/HP_0025464"},{"id":"A205","pred":"hp_id","subj":"T205","obj":"http://purl.obolibrary.org/obo/HP_0006510"},{"id":"A206","pred":"hp_id","subj":"T206","obj":"http://purl.obolibrary.org/obo/HP_0002097"},{"id":"A207","pred":"hp_id","subj":"T207","obj":"http://purl.obolibrary.org/obo/HP_0002088"},{"id":"A208","pred":"hp_id","subj":"T208","obj":"http://purl.obolibrary.org/obo/HP_0006532"},{"id":"A209","pred":"hp_id","subj":"T209","obj":"http://purl.obolibrary.org/obo/HP_0006510"},{"id":"A210","pred":"hp_id","subj":"T210","obj":"http://purl.obolibrary.org/obo/HP_0006532"},{"id":"A211","pred":"hp_id","subj":"T211","obj":"http://purl.obolibrary.org/obo/HP_0006510"},{"id":"A212","pred":"hp_id","subj":"T212","obj":"http://purl.obolibrary.org/obo/HP_0006536"}],"text":"8. Autophagy Augmentation Strategies to Mitigate the Pathogenesis and Progression of Chronic Obstructive Lung Diseases\nAs 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. 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. 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]. 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]. 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]. 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. We and others have devised strategies such as nano/dendrimer-based formulations which can be efficiently delivered through intranasal inhalation [42,45,149]. 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]. 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.\nOur 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. 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]. 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]. 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. 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. 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]. 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]. 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.\nThe therapeutic potential of autophagy augmenting drugs has been extensively investigated in controlling chronic CF lung disease and associated pulmonary infection-related exacerbations. 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]. 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]. Tα1 possesses anti-inflammatory properties and is also known to induce autophagy [204], which could be its mechanism of action to rescue ΔF508-CFTR. Nonetheless, future pre-clinical and clinical studies will be essential before it could be any therapeutic benefit in CF-related autophagy dysfunction and exacerbations. 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]. However, a previously completed study of 10 patients with the ΔF508-CFTR mutation demonstrated a significant improvement in CFTR function with cysteamine treatment [208]. 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]. 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.\nIn 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]. Indeed, some recent studies have shown that autophagy mitigates IPF pathogenesis by regulating the fibroblast apoptosis and senescence of alveolar epithelial cells [209]. 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].\nTherefore, 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)."}

{"project":"LitCovid-PD-GO-BP","denotations":[{"id":"T791","span":{"begin":3,"end":12},"obj":"http://purl.obolibrary.org/obo/GO_0016236"},{"id":"T792","span":{"begin":3,"end":12},"obj":"http://purl.obolibrary.org/obo/GO_0006914"},{"id":"T793","span":{"begin":53,"end":65},"obj":"http://purl.obolibrary.org/obo/GO_0009405"},{"id":"T794","span":{"begin":139,"end":148},"obj":"http://purl.obolibrary.org/obo/GO_0016236"},{"id":"T795","span":{"begin":139,"end":148},"obj":"http://purl.obolibrary.org/obo/GO_0006914"},{"id":"T796","span":{"begin":149,"end":153},"obj":"http://purl.obolibrary.org/obo/GO_0005260"},{"id":"T797","span":{"begin":203,"end":215},"obj":"http://purl.obolibrary.org/obo/GO_0009405"},{"id":"T798","span":{"begin":459,"end":468},"obj":"http://purl.obolibrary.org/obo/GO_0016236"},{"id":"T799","span":{"begin":459,"end":468},"obj":"http://purl.obolibrary.org/obo/GO_0006914"},{"id":"T800","span":{"begin":469,"end":473},"obj":"http://purl.obolibrary.org/obo/GO_0005260"},{"id":"T801","span":{"begin":573,"end":585},"obj":"http://purl.obolibrary.org/obo/GO_0009405"},{"id":"T802","span":{"begin":672,"end":681},"obj":"http://purl.obolibrary.org/obo/GO_0016236"},{"id":"T803","span":{"begin":672,"end":681},"obj":"http://purl.obolibrary.org/obo/GO_0006914"},{"id":"T804","span":{"begin":798,"end":807},"obj":"http://purl.obolibrary.org/obo/GO_0097194"},{"id":"T805","span":{"begin":798,"end":807},"obj":"http://purl.obolibrary.org/obo/GO_0006915"},{"id":"T806","span":{"begin":809,"end":828},"obj":"http://purl.obolibrary.org/obo/GO_0090398"},{"id":"T807","span":{"begin":867,"end":883},"obj":"http://purl.obolibrary.org/obo/GO_0016032"},{"id":"T808","span":{"begin":988,"end":997},"obj":"http://purl.obolibrary.org/obo/GO_0016236"},{"id":"T809","span":{"begin":988,"end":997},"obj":"http://purl.obolibrary.org/obo/GO_0006914"},{"id":"T810","span":{"begin":998,"end":1002},"obj":"http://purl.obolibrary.org/obo/GO_0005260"},{"id":"T811","span":{"begin":1353,"end":1362},"obj":"http://purl.obolibrary.org/obo/GO_0016236"},{"id":"T812","span":{"begin":1353,"end":1362},"obj":"http://purl.obolibrary.org/obo/GO_0006914"},{"id":"T813","span":{"begin":1386,"end":1409},"obj":"http://purl.obolibrary.org/obo/GO_0000045"},{"id":"T814","span":{"begin":1400,"end":1409},"obj":"http://purl.obolibrary.org/obo/GO_0009058"},{"id":"T815","span":{"begin":1465,"end":1470},"obj":"http://purl.obolibrary.org/obo/GO_0007568"},{"id":"T816","span":{"begin":1510,"end":1519},"obj":"http://purl.obolibrary.org/obo/GO_0097194"},{"id":"T817","span":{"begin":1510,"end":1519},"obj":"http://purl.obolibrary.org/obo/GO_0006915"},{"id":"T818","span":{"begin":1521,"end":1540},"obj":"http://purl.obolibrary.org/obo/GO_0090398"},{"id":"T819","span":{"begin":1741,"end":1745},"obj":"http://purl.obolibrary.org/obo/GO_0005260"},{"id":"T820","span":{"begin":1803,"end":1807},"obj":"http://purl.obolibrary.org/obo/GO_0005260"},{"id":"T821","span":{"begin":2761,"end":2765},"obj":"http://purl.obolibrary.org/obo/GO_0005260"},{"id":"T822","span":{"begin":2786,"end":2795},"obj":"http://purl.obolibrary.org/obo/GO_0016236"},{"id":"T823","span":{"begin":2786,"end":2795},"obj":"http://purl.obolibrary.org/obo/GO_0006914"},{"id":"T824","span":{"begin":2835,"end":2847},"obj":"http://purl.obolibrary.org/obo/GO_0009405"},{"id":"T825","span":{"begin":2955,"end":2964},"obj":"http://purl.obolibrary.org/obo/GO_0016236"},{"id":"T826","span":{"begin":2955,"end":2964},"obj":"http://purl.obolibrary.org/obo/GO_0006914"},{"id":"T827","span":{"begin":3025,"end":3029},"obj":"http://purl.obolibrary.org/obo/GO_0005260"},{"id":"T828","span":{"begin":3213,"end":3222},"obj":"http://purl.obolibrary.org/obo/GO_0009058"},{"id":"T829","span":{"begin":3224,"end":3228},"obj":"http://purl.obolibrary.org/obo/GO_0005260"},{"id":"T830","span":{"begin":3239,"end":3251},"obj":"http://purl.obolibrary.org/obo/GO_0051179"},{"id":"T831","span":{"begin":3287,"end":3296},"obj":"http://purl.obolibrary.org/obo/GO_0097194"},{"id":"T832","span":{"begin":3287,"end":3296},"obj":"http://purl.obolibrary.org/obo/GO_0006915"},{"id":"T833","span":{"begin":3576,"end":3580},"obj":"http://purl.obolibrary.org/obo/GO_0005260"},{"id":"T834","span":{"begin":3581,"end":3590},"obj":"http://purl.obolibrary.org/obo/GO_0016236"},{"id":"T835","span":{"begin":3581,"end":3590},"obj":"http://purl.obolibrary.org/obo/GO_0006914"},{"id":"T836","span":{"begin":3683,"end":3692},"obj":"http://purl.obolibrary.org/obo/GO_0016236"},{"id":"T837","span":{"begin":3683,"end":3692},"obj":"http://purl.obolibrary.org/obo/GO_0006914"},{"id":"T838","span":{"begin":3759,"end":3768},"obj":"http://purl.obolibrary.org/obo/GO_0009058"},{"id":"T839","span":{"begin":3809,"end":3818},"obj":"http://purl.obolibrary.org/obo/GO_0016236"},{"id":"T840","span":{"begin":3809,"end":3818},"obj":"http://purl.obolibrary.org/obo/GO_0006914"},{"id":"T841","span":{"begin":3906,"end":3915},"obj":"http://purl.obolibrary.org/obo/GO_0016236"},{"id":"T842","span":{"begin":3906,"end":3915},"obj":"http://purl.obolibrary.org/obo/GO_0006914"},{"id":"T843","span":{"begin":3959,"end":3968},"obj":"http://purl.obolibrary.org/obo/GO_0097194"},{"id":"T844","span":{"begin":3959,"end":3968},"obj":"http://purl.obolibrary.org/obo/GO_0006915"},{"id":"T845","span":{"begin":4121,"end":4130},"obj":"http://purl.obolibrary.org/obo/GO_0016236"},{"id":"T846","span":{"begin":4121,"end":4130},"obj":"http://purl.obolibrary.org/obo/GO_0006914"},{"id":"T847","span":{"begin":4185,"end":4197},"obj":"http://purl.obolibrary.org/obo/GO_0006909"},{"id":"T848","span":{"begin":4275,"end":4284},"obj":"http://purl.obolibrary.org/obo/GO_0016236"},{"id":"T849","span":{"begin":4275,"end":4284},"obj":"http://purl.obolibrary.org/obo/GO_0006914"},{"id":"T850","span":{"begin":4349,"end":4361},"obj":"http://purl.obolibrary.org/obo/GO_0006909"},{"id":"T851","span":{"begin":4442,"end":4451},"obj":"http://purl.obolibrary.org/obo/GO_0016236"},{"id":"T852","span":{"begin":4442,"end":4451},"obj":"http://purl.obolibrary.org/obo/GO_0006914"},{"id":"T853","span":{"begin":4568,"end":4577},"obj":"http://purl.obolibrary.org/obo/GO_0016236"},{"id":"T854","span":{"begin":4568,"end":4577},"obj":"http://purl.obolibrary.org/obo/GO_0006914"},{"id":"T855","span":{"begin":5139,"end":5143},"obj":"http://purl.obolibrary.org/obo/GO_0005260"},{"id":"T856","span":{"begin":5232,"end":5241},"obj":"http://purl.obolibrary.org/obo/GO_0016236"},{"id":"T857","span":{"begin":5232,"end":5241},"obj":"http://purl.obolibrary.org/obo/GO_0006914"},{"id":"T858","span":{"begin":5304,"end":5308},"obj":"http://purl.obolibrary.org/obo/GO_0005260"},{"id":"T859","span":{"begin":5439,"end":5448},"obj":"http://purl.obolibrary.org/obo/GO_0016236"},{"id":"T860","span":{"begin":5439,"end":5448},"obj":"http://purl.obolibrary.org/obo/GO_0006914"},{"id":"T861","span":{"begin":5538,"end":5547},"obj":"http://purl.obolibrary.org/obo/GO_0016236"},{"id":"T862","span":{"begin":5538,"end":5547},"obj":"http://purl.obolibrary.org/obo/GO_0006914"},{"id":"T863","span":{"begin":5778,"end":5782},"obj":"http://purl.obolibrary.org/obo/GO_0005260"},{"id":"T864","span":{"begin":5834,"end":5838},"obj":"http://purl.obolibrary.org/obo/GO_0005260"},{"id":"T865","span":{"begin":6070,"end":6079},"obj":"http://purl.obolibrary.org/obo/GO_0061724"},{"id":"T866","span":{"begin":6364,"end":6373},"obj":"http://purl.obolibrary.org/obo/GO_0016236"},{"id":"T867","span":{"begin":6364,"end":6373},"obj":"http://purl.obolibrary.org/obo/GO_0006914"},{"id":"T868","span":{"begin":6480,"end":6489},"obj":"http://purl.obolibrary.org/obo/GO_0016236"},{"id":"T869","span":{"begin":6480,"end":6489},"obj":"http://purl.obolibrary.org/obo/GO_0006914"},{"id":"T870","span":{"begin":6559,"end":6571},"obj":"http://purl.obolibrary.org/obo/GO_0009405"},{"id":"T871","span":{"begin":6623,"end":6632},"obj":"http://purl.obolibrary.org/obo/GO_0016236"},{"id":"T872","span":{"begin":6623,"end":6632},"obj":"http://purl.obolibrary.org/obo/GO_0006914"},{"id":"T873","span":{"begin":6647,"end":6659},"obj":"http://purl.obolibrary.org/obo/GO_0009405"},{"id":"T874","span":{"begin":6663,"end":6698},"obj":"http://purl.obolibrary.org/obo/GO_2000269"},{"id":"T875","span":{"begin":6678,"end":6698},"obj":"http://purl.obolibrary.org/obo/GO_0044346"},{"id":"T876","span":{"begin":6689,"end":6698},"obj":"http://purl.obolibrary.org/obo/GO_0097194"},{"id":"T877","span":{"begin":6689,"end":6698},"obj":"http://purl.obolibrary.org/obo/GO_0006915"},{"id":"T878","span":{"begin":6841,"end":6853},"obj":"http://purl.obolibrary.org/obo/GO_0006954"},{"id":"T879","span":{"begin":6927,"end":6936},"obj":"http://purl.obolibrary.org/obo/GO_0016236"},{"id":"T880","span":{"begin":6927,"end":6936},"obj":"http://purl.obolibrary.org/obo/GO_0006914"},{"id":"T881","span":{"begin":6955,"end":6964},"obj":"http://purl.obolibrary.org/obo/GO_0016236"},{"id":"T882","span":{"begin":6955,"end":6964},"obj":"http://purl.obolibrary.org/obo/GO_0006914"},{"id":"T883","span":{"begin":7064,"end":7076},"obj":"http://purl.obolibrary.org/obo/GO_0009405"}],"text":"8. Autophagy Augmentation Strategies to Mitigate the Pathogenesis and Progression of Chronic Obstructive Lung Diseases\nAs 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. 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. 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]. 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]. 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]. 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. We and others have devised strategies such as nano/dendrimer-based formulations which can be efficiently delivered through intranasal inhalation [42,45,149]. 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]. 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.\nOur 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. 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]. 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]. 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. 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. 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]. 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]. 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.\nThe therapeutic potential of autophagy augmenting drugs has been extensively investigated in controlling chronic CF lung disease and associated pulmonary infection-related exacerbations. 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]. 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]. Tα1 possesses anti-inflammatory properties and is also known to induce autophagy [204], which could be its mechanism of action to rescue ΔF508-CFTR. Nonetheless, future pre-clinical and clinical studies will be essential before it could be any therapeutic benefit in CF-related autophagy dysfunction and exacerbations. 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]. However, a previously completed study of 10 patients with the ΔF508-CFTR mutation demonstrated a significant improvement in CFTR function with cysteamine treatment [208]. 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]. 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.\nIn 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]. Indeed, some recent studies have shown that autophagy mitigates IPF pathogenesis by regulating the fibroblast apoptosis and senescence of alveolar epithelial cells [209]. 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].\nTherefore, 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)."}

{"project":"LitCovid-sentences","denotations":[{"id":"T308","span":{"begin":0,"end":2},"obj":"Sentence"},{"id":"T309","span":{"begin":3,"end":118},"obj":"Sentence"},{"id":"T310","span":{"begin":119,"end":373},"obj":"Sentence"},{"id":"T311","span":{"begin":374,"end":586},"obj":"Sentence"},{"id":"T312","span":{"begin":587,"end":916},"obj":"Sentence"},{"id":"T313","span":{"begin":917,"end":1182},"obj":"Sentence"},{"id":"T314","span":{"begin":1183,"end":1605},"obj":"Sentence"},{"id":"T315","span":{"begin":1606,"end":1920},"obj":"Sentence"},{"id":"T316","span":{"begin":1921,"end":2078},"obj":"Sentence"},{"id":"T317","span":{"begin":2079,"end":2329},"obj":"Sentence"},{"id":"T318","span":{"begin":2330,"end":2621},"obj":"Sentence"},{"id":"T319","span":{"begin":2622,"end":2848},"obj":"Sentence"},{"id":"T320","span":{"begin":2849,"end":3045},"obj":"Sentence"},{"id":"T321","span":{"begin":3046,"end":3430},"obj":"Sentence"},{"id":"T322","span":{"begin":3431,"end":3599},"obj":"Sentence"},{"id":"T323","span":{"begin":3600,"end":3863},"obj":"Sentence"},{"id":"T324","span":{"begin":3864,"end":4056},"obj":"Sentence"},{"id":"T325","span":{"begin":4057,"end":4270},"obj":"Sentence"},{"id":"T326","span":{"begin":4271,"end":4538},"obj":"Sentence"},{"id":"T327","span":{"begin":4539,"end":4725},"obj":"Sentence"},{"id":"T328","span":{"begin":4726,"end":4975},"obj":"Sentence"},{"id":"T329","span":{"begin":4976,"end":5160},"obj":"Sentence"},{"id":"T330","span":{"begin":5161,"end":5309},"obj":"Sentence"},{"id":"T331","span":{"begin":5310,"end":5479},"obj":"Sentence"},{"id":"T332","span":{"begin":5480,"end":5709},"obj":"Sentence"},{"id":"T333","span":{"begin":5710,"end":5880},"obj":"Sentence"},{"id":"T334","span":{"begin":5881,"end":6152},"obj":"Sentence"},{"id":"T335","span":{"begin":6153,"end":6350},"obj":"Sentence"},{"id":"T336","span":{"begin":6351,"end":6578},"obj":"Sentence"},{"id":"T337","span":{"begin":6579,"end":6749},"obj":"Sentence"},{"id":"T338","span":{"begin":6750,"end":6943},"obj":"Sentence"},{"id":"T339","span":{"begin":6944,"end":7191},"obj":"Sentence"}],"namespaces":[{"prefix":"_base","uri":"http://pubannotation.org/ontology/tao.owl#"}],"text":"8. Autophagy Augmentation Strategies to Mitigate the Pathogenesis and Progression of Chronic Obstructive Lung Diseases\nAs 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. 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. 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]. 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]. 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]. 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. We and others have devised strategies such as nano/dendrimer-based formulations which can be efficiently delivered through intranasal inhalation [42,45,149]. 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]. 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.\nOur 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. 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]. 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]. 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. 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. 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]. 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]. 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.\nThe therapeutic potential of autophagy augmenting drugs has been extensively investigated in controlling chronic CF lung disease and associated pulmonary infection-related exacerbations. 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]. 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]. Tα1 possesses anti-inflammatory properties and is also known to induce autophagy [204], which could be its mechanism of action to rescue ΔF508-CFTR. Nonetheless, future pre-clinical and clinical studies will be essential before it could be any therapeutic benefit in CF-related autophagy dysfunction and exacerbations. 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]. However, a previously completed study of 10 patients with the ΔF508-CFTR mutation demonstrated a significant improvement in CFTR function with cysteamine treatment [208]. 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]. 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.\nIn 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]. Indeed, some recent studies have shown that autophagy mitigates IPF pathogenesis by regulating the fibroblast apoptosis and senescence of alveolar epithelial cells [209]. 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].\nTherefore, 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)."}