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CORD-19:85d7f47649ef43ff11b8d5196c98e4fdacd0f905 JSONTXT 9 Projects

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Id Subject Object Predicate Lexical cue
T1 0-305 Sentence denotes Angiotensin-converting enzyme 2 in lung diseases This review comes from a themed issue on Respiratory pharmacology Edited by Dale Hoyt and Daren Knoell as novel therapeutic agents to treat severe acute lung failure, a syndrome that currently affects millions of people without any effective drug treatment
T2 307-315 Sentence denotes Abstract
T3 316-445 Sentence denotes The renin-angiotensin system (RAS) plays a key role in maintaining blood pressure homeostasis, as well as fluid and salt balance.
T4 446-565 Sentence denotes Angiotensin II, a key effector peptide of the system, causes vasoconstriction and exerts multiple biological functions.
T5 566-805 Sentence denotes Angiotensin-converting enzyme (ACE) plays a central role in generating angiotensin II from angiotensin I, and capillary blood vessels in the lung are one of the major sites of ACE expression and angiotensin II production in the human body.
T6 806-989 Sentence denotes The RAS has been implicated in the pathogenesis of pulmonary hypertension and pulmonary fibrosis, both commonly seen in chronic lung diseases such as chronic obstructive lung disease.
T7 990-1132 Sentence denotes Recent studies indicate that the RAS also plays a critical role in acute lung diseases, especially acute respiratory distress syndrome (ARDS).
T8 1133-1330 Sentence denotes ACE2, a close homologue of ACE, functions as a negative regulator of the angiotensin system and was identified as a key receptor for SARS (severe acute respiratory syndrome) coronavirus infections.
T9 1331-1417 Sentence denotes In the lung, ACE2 protects against acute lung injury in several animal models of ARDS.
T10 1418-1505 Sentence denotes Thus, the RAS appears to play a critical role in the pathogenesis of acute lung injury.
T11 1506-1625 Sentence denotes Indeed, increasing ACE2 activity might be a novel approach for the treatment of acute lung failure in several diseases.
T12 1626-1794 Sentence denotes For many decades, the roles of the renin-angiotensin system (RAS) have been studied in physiology and multiple disorders, in particular cardiovascular diseases [1, 2] .
T13 1795-1981 Sentence denotes Angiotensin II (ANG II), a key effector peptide of the RAS, exerts multiple biological functions including the vasoconstriction and sodium balance involved in blood pressure homeostasis.
T14 1982-2208 Sentence denotes Angiotensin-converting enzyme (ACE) plays a central role in generating ANG II from angiotensin I (ANG I) [3, 4] (Figure 1 ), and ACE inhibitors or ANG II receptor blockers exhibit beneficial effects in cardiovascular diseases.
T15 2209-2299 Sentence denotes Capillary blood vessels in the lung are a major site of high-level expression of ACE [5] .
T16 2300-2428 Sentence denotes Thus, the lung is an important organ in generating circulating ANG II, acting as a classical circulation-borne endocrine system.
T17 2429-2538 Sentence denotes In contrast to this endocrine RAS model, numerous studies have highlighted the importance of local RASs [6] .
T18 2539-2763 Sentence denotes For example, an increase in endothelial ACE expression in the muscularized intraacinar arteries of lungs was shown both in patients with pulmonary hypertension [7] and in rats with hypoxiainduced pulmonary hypertension [8] .
T19 2764-2905 Sentence denotes In addition to ACE, other components of the RAS are expressed in lungs, including renin [9], angiotensinogen [10] and ANG II receptors [11] .
T20 2906-3031 Sentence denotes In 2000, ACE2, a homologue of ACE, was identified; its discovery instantaneously added a new complexity to the RAS [12, 13] .
T21 3032-3214 Sentence denotes Although ACE2 functions similarly to ACE as a carboxypeptidase, ACE2 has a different substrate specificity [12] [13] [14] , shown by in vitro analyses using recombinant ACE2 protein.
T22 3215-3510 Sentence denotes Whereas ACE removes dipeptides from the C-terminus of peptide substrates, generating the octapeptide ANG II from the decapeptide ANG I [3,15], ACE2 cleaves a single residue from ANG II, generating angiotensin-(1-9) [12, 13] , and a single residue from ANG II to generate angiotensin-(1-7) [12] .
T23 3511-3688 Sentence denotes Genetic inactivation of ACE using homologous recombination results in a phenotype characterized by spontaneous hypotension, reduced male fertility and kidney malformation [16] .
T24 3689-3836 Sentence denotes By contrast, targeted disruption of murine ACE2 resulted in increased systemic ANG II levels and impaired cardiac contractility in aged mice [17] .
T25 3837-3909 Sentence denotes Loss of ACE on an ACE2 background reversed this cardiac phenotype [17] .
T26 3910-4019 Sentence denotes Thus, ACE2 appears to be a negative regulator of the RAS and counterbalances the function of ACE (Figure 1 ).
T27 4020-4187 Sentence denotes The importance of the RAS in lung diseases has recently re-emerged since the identification of ACE2 as a severe acute respiratory syndrome (SARS) coronavirus receptor.
T28 4188-4340 Sentence denotes During several months of 2003, SARS -a newly identified illness -spread rapidly from China throughout the world, causing more than 800 deaths [18, 19] .
T29 4341-4490 Sentence denotes A novel coronavirus was identified as the SARS pathogen, which triggered atypical pneumonia characterized by high fever and severe dyspnea [18, 19] .
T30 4491-4654 Sentence denotes The death rate following SARS coronavirus exposure approached almost 10% of infected people owing to the development of acute respiratory distress syndrome (ARDS).
T31 4655-4809 Sentence denotes ARDS is the most severe form of acute lung injury and is characterized by pulmonary oedema, accumulation of inflammatory cells and severe hypoxia [20,21].
T32 4810-4984 Sentence denotes Clinical as well as www.sciencedirect.com Current Opinion in Pharmacology 2006, 6:271-276 experimental animal studies have implicated ACE in the pathogenesis of ARDS [22-24].
T33 4985-5164 Sentence denotes ACE2 is expressed in the lungs of healthy and diseased humans [25], and recent ARDS and SARS studies have shown that ACE2 protects murine lungs from severe acute injury [26 ,27 ].
T34 5165-5295 Sentence denotes Importantly, these experiments also revealed that ACE2 is an essential receptor for SARS infections in vitro and in vivo [27 ,28].
T35 5296-5479 Sentence denotes In this review, we review the role of the RAS, in particular of the SARS receptor ACE2, in lung diseases, focusing on pulmonary hypertension, pulmonary fibrosis and acute lung injury.
T36 5480-5598 Sentence denotes The possible applications of blocking the RAS and/or modulating ACE2 for the treatment of lung diseases are discussed.
T37 5599-5871 Sentence denotes Pulmonary hypertension is characterized by elevations in pulmonary artery pressure and pulmonary vascular resistance caused by multiple etiologies, including primary pulmonary hypertension, chronic obstructive pulmonary disease (COPD), high altitude or pulmonary embolism.
T38 5872-6029 Sentence denotes Abnormal pulmonary vasoconstriction and pulmonary vascular remodeling are major pathological features seen in most forms of pulmonary hypertension [29, 30] .
T39 6030-6239 Sentence denotes Although ANG II is well known as a potent vasopressor peptide, in the pathogenesis of pulmonary hypertension ANG II seems to play a role in pulmonary vascular remodeling rather than pulmonary vasoconstriction.
T40 6240-6478 Sentence denotes In in vitro cell culture models, ANG II has been shown to directly cause growth/proliferation of pulmonary artery smooth muscle cells largely through ANG II type I (AT 1 ), rather than through type II (AT 2 ), receptors [31] ( Figure 1 ).
T41 6479-6632 Sentence denotes In pulmonary hypertension in vivo, the expression of ACE is increased in the endothelial layer of small, as well as elastic, pulmonary arteries [7, 32] .
T42 6633-6800 Sentence denotes In addition, in hypoxic, but not monocrotaline-treated [33], pulmonary hypertensive rats, both ANG II binding and the number of AT 1 receptors are increased [34, 35] .
T43 6801-7050 Sentence denotes In human patients, an association between an ACE insertion/deletion polymorphism (the D allele of the human ACE gene confers increased ACE activity in plasma) and pulmonary hypertension has been reported; this association is, however, controversial.
T44 7051-7272 Sentence denotes For instance, one study showed that the ACE D/D genotype is associated with less right ventricular hypertrophy [36] , whereas another reported a correlation between the ACE D/D genotype and the severity of symptoms [37] .
T45 7273-7550 Sentence denotes Pharmacologic treatment of animals with either an ACE blocker or an ANG II receptor antagonist inhibited pulmonary vascular remodeling associated with the development of pulmonary hypertension in chronically hypoxic rats or mice [38, 39] or in monocrotaline-treated rats [40] .
T46 7551-7758 Sentence denotes By contrast, tissue ACE-deficient mice, which exhibit undetectable lung ACE activity but retain 34% of the ACE activity in plasma, show the same remodeling of pulmonary arterioles as do wild-type mice [41] .
T47 7759-8127 Sentence denotes In addition, despite earlier studies of acute ACE inhibition [42] [43] [44] , a recent pilot study on patients with pulmonary hypertension secondary to COPD showed that treatment with the AT 1 receptor blocker losartan (50 mg) showed no statistically significant beneficial effect in terms of pulmonary artery pressure, exercise capacity or breathlessness score [45] .
T48 8128-8317 Sentence denotes The discrepancy between hypoxic rat studies and this human trial might be caused by differences in the pathogenesis of hypoxic rats versus patients with COPD-related pulmonary hypertension.
T49 8318-8379 Sentence denotes Further studies are required to solve these important issues.
T50 8380-8457 Sentence denotes Pulmonary fibrosis is a frequent response to insults or injuries to the lung.
T51 8458-8561 Sentence denotes Etiologies include idiopathic pulmonary fibrosis, sarcoidosis, irradiation-induced pneumonitis or ARDS.
T52 8562-8667 Sentence denotes Excess deposition of extracellular matrix proteins is a key feature of interstitial fibrosis in the lung.
T53 8668-8895 Sentence denotes The pathogenesis of pulmonary fibrosis includes endothelial and epithelial cell injury, influx of inflammatory cells and the production of chemical mediators leading to the proliferation and activation of fibroblasts [46, 47] .
T54 8896-9155 Sentence denotes Although there are various initiating mechanisms and etiologies, the terminal phases of fibrosis are commonly characterized by the proliferation and progressive 272 Respiratory Figure 1 Current view of the RAS in pulmonary hypertension and pulmonary fibrosis.
T55 9156-9206 Sentence denotes ANG I serves as a substrate for both ACE and ACE2.
T56 9207-9343 Sentence denotes ANG II is known to act as vasoconstrictor as well as a mitogen for smooth muscle cells or fibroblasts, mainly through the AT 1 receptor.
T57 9344-9401 Sentence denotes The function of angiotensin-(1-9) is not well understood.
T58 9402-9496 Sentence denotes Both ACE and ACE2 are involved in the production of the vasodilator peptide angiotensin-(1-7).
T59 9497-9570 Sentence denotes accumulation of connective tissue replacing normal functional parenchyma.
T60 9571-9728 Sentence denotes ANG II immunoreactivity is also significantly increased within lung fibroblasts, macrophages and bronchiolar and alveolar epithelium after irradiation [48] .
T61 9729-9825 Sentence denotes In addition, angiotensinogen is produced by fibroblasts from fibrotic but not normal human lung.
T62 9826-10043 Sentence denotes ANG II upregulates the expression of the profibrotic cytokine transforming growth factor-b1, which is involved in both the conversion of fibroblasts to myofibroblasts and the accumulation of collagen [49] (Figure 1 ).
T63 10044-10180 Sentence denotes An in vivo role for ANG II in pulmonary fibrosis has been implied from animal models with bleomycin-or irradiation-mediated lung injury.
T64 10181-10377 Sentence denotes In bleomycin-induced pulmonary fibrosis in rats or mice, ACE inhibitors or AT 1 receptor blockers can attenuate epithelial apoptosis, interstitial fibrosis and collagen deposition [50] [51] [52] .
T65 10378-10492 Sentence denotes In irradiation-induced lung fibrosis, ACE inhibitors attenuate endothelial dysfunction and fibrosis in rats [53] .
T66 10493-10689 Sentence denotes Conversely, retrospective comparison of the incidence of irradiation-induced lung injury between subjects who took ACE inhibitors and those who did not, failed to reveal a protective effect [54] .
T67 10690-10869 Sentence denotes However, serum concentrations of ACE inhibitors used by subjects in the human study would be expected to be considerably less than those achieved in the animal models cited above.
T68 10870-11181 Sentence denotes As there are no published prospective or retrospective studies regarding the use of other ACE inhibitors or AT 1 receptor blockers in human pulmonary fibrosis induced by factors other than irradiation, it is therefore still unclear if inhibition of the RAS would indeed have beneficial effects on lung fibrosis.
T69 11182-11402 Sentence denotes Acute respiratory distress syndrome/acute lung injury ARDS is the most severe form of acute lung injury, and affects approximately one million individuals worldwide/ year with a mortality rate of at least 30-50% [20,21].
T70 11403-11596 Sentence denotes ARDS can be triggered by multiple diseases such as sepsis, aspiration, trauma, acute pancreatitis, or pneumonias following infections with SARS coronavirus or avian and human influenza viruses.
T71 11597-11758 Sentence denotes Recent cohort studies of ARDS showed a significant association between an ACE insertion/deletion polymorphism and the susceptibility and outcome of ARDS [23,24].
T72 11759-11858 Sentence denotes The D/D genotype frequency was increased in patients with ARDS compared with a control cohort [23].
T73 11859-11958 Sentence denotes In addition, the ACE D/D allele was significantly associated with mortality in the ARDS group [23].
T74 11959-12074 Sentence denotes Another study showed that patients carrying the ACE I/I genotype have a significantly increased survival rate [24].
T75 12075-12269 Sentence denotes Thus, from the results of inhibitor experiments in rodents [22] and ACE allelic correlation studies in humans [23,24], it has been suggested that the RAS could play a role in acute lung failure.
T76 12270-12350 Sentence denotes Our group has investigated the role of ACE2 in ARDS by using ace2 knockout mice.
T77 12351-12539 Sentence denotes In acid-aspiration-induced ARDS, endotoxin-induced ARDS and peritoneal sepsis-induced ARDS, ace2 knockout mice exhibited severe disease compared with control mice that express ACE2 [26 ] .
T78 12540-12696 Sentence denotes Loss of ACE2 expression in mutant mice resulted in enhanced vascular permeability, increased lung edema, neutrophil accumulation and worsened lung function.
T79 12697-12906 Sentence denotes Importantly, treatment with catalytically active, but not enzymatically inactive, recombinant ACE2 protein improved the symptoms of acute lung injury in wild-type mice, as well as in ace2 knockout mice [26 ] .
T80 12907-12963 Sentence denotes Thus, ACE2 plays a protective role in acute lung injury.
T81 12964-13093 Sentence denotes Mechanistically, the negative regulation of ANG II levels by ACE2 accounts, in part, for the protective function of ACE2 in ARDS.
T82 13094-13290 Sentence denotes For example, AT 1 receptor inhibitor treatment or additional ace gene deficiency on an ace2 knockout background rescues the severe phenotype of ace2 single mutant mice in acute lung injury [26 ] .
T83 13291-13408 Sentence denotes In addition, ace knockout mice and AT 1a receptor knockout mice showed improved symptoms of acute lung injury [26 ] .
T84 13409-13585 Sentence denotes Therefore, in acute lung injury, ACE, ANG II and AT 1 receptors function as lung injury-promoting factors [26 ,55], whereas ACE2 protects against lung injury [26 ] (Figure 2 ).
T85 13586-13844 Sentence denotes These findings suggest that the beneficial effects of ACE inhibitors or AT 1 receptor blockers in lung injury models induced by bleomycin or irradiation, observed in the earlier studies, derive largely from their effects on the acute phase of those injuries.
T86 13845-14005 Sentence denotes Within a few months following the publication of the SARS-CoV genome [56, 57] , ACE2 was identified as a potential receptor in cell line studies in vitro [28] .
T87 14006-14217 Sentence denotes ACE2 has been demonstrated to bind SARS-CoV spike and to support 'syncytia formation', the fusion of spike-proteinexpressing cells into large multinucleated cells that can also be seen in 'real' SARS infections.
T88 14218-14371 Sentence denotes Using a mouse SARS infection model with ace2 knockout mice, our group provided evidence that ACE2 is indeed essential for SARS infections in vivo [27 ] .
T89 14372-14484 Sentence denotes When ace2 knockout mice are infected with the SARS coronavirus, they become resistant to virus infection [27 ] .
T90 14485-14650 Sentence denotes Virus titers from the lung tissues of infected ace2 knockout mice were 10 5 -fold lower than those isolated from the lung of SARS-CoV-infected wild-type mice [27 ] .
T91 14651-14887 Sentence denotes The lung histology from ace2 knockout mice challenged with SARS coronavirus showed no signs of inflammation [27 ], whereas some (but not all) SARS-infected wild-type mice displayed mild inflammation with leukocyte infiltration [27 ,58].
T92 14888-14952 Sentence denotes Thus, ACE2 is an essential receptor for SARS infections in vivo.
T93 14953-15132 Sentence denotes Despite many studies on SARS-CoV, the reasons why SARS-CoV infections trigger severe lung disease with such a high mortality, in contrast to other coronaviruses, remain a mystery.
T94 15133-15487 Sentence denotes Accumulating evidence indicates that severe SARS infections are dependent upon the burden of viral replication as well as on the immunopathologic Angiotensin-converting enzyme 2 in lung diseases Kuba, Imai and Penninger 273 www.sciencedirect.com Current Opinion in Pharmacology 2006, 6:271-276 consequences of the host response (for review, see [59,60]).
T95 15488-15860 Sentence denotes In addition to the aberrant activation of immune systems, our own studies have implicated the involvement of the RAS in SARS pathogenesis: firstly, ACE2 is a critical SARS receptor in vivo; and secondly, ACE2 and other components of the RAS play a central role in controlling the severity of acute lung failure once the disease process has been initiated [27 ] (Figure 2).
T96 15861-15974 Sentence denotes Intriguingly, wild-type mice infected with SARS-CoV showed markedly downregulated ACE2 expression in lungs [27 ].
T97 15975-16136 Sentence denotes Similarly, treatment with recombinant SARS-spike protein, in the absence of any other virus components, downregulates ACE2 expression in vitro and in vivo [27 ].
T98 16137-16349 Sentence denotes Thus, SARS-CoV-infected or spike proteintreated wild-type mice resemble ace2 knockout mice, and, similar to ace2 mutant mice, spike-treated wild-type mice show markedly more severe pathology of acute lung injury.
T99 16350-16524 Sentence denotes Additionally, in spike-treated mice, ANG II peptide levels were increased and the worsened ARDS symptoms could be partially reversed by AT 1 receptor blocker treatment [27 ].
T100 16525-16606 Sentence denotes By contrast, spike does not affect the ARDS symptoms in ace2 knockout mice [27 ].
T101 16607-16763 Sentence denotes Thus, the downregulation of ACE2 expression in SARS-CoV infections might play a causal role in SARS pathogenesis, especially in disease progression to ARDS.
T102 16764-16983 Sentence denotes ANG II plays roles in tissue remodeling and fibrotic changes through acting on fibroblasts or smooth muscle cells, thereby contributing to the pathogenesis or progression of pulmonary fibrosis or pulmonary hypertension.
T103 16984-17138 Sentence denotes This notion is strongly supported by the successful treatment of these disease conditions using ACE inhibitors or AT 1 receptor blockers in animal models.
T104 17139-17367 Sentence denotes However, pilot clinical trials have failed to observe significant beneficial effects of ACE inhibitors on radiation-induced pulmonary fibrosis or positive effects of AT 1 receptor blockers on COPD-related pulmonary hypertension.
T105 17368-17497 Sentence denotes Recently, the critical importance of the RAS in the pathogenesis of acute lung disease (i.e. ARDS/acute lung injury) has emerged.
T106 17498-17664 Sentence denotes Hypothetically, the RAS appears to contribute to the initial severity of lung diseases rather than to later stages that define chronic fibrosis and tissue remodeling.
T107 17665-17856 Sentence denotes In line with this notion, the D/D polymorphism of the ACE gene has been associated with the incidence of pneumonias in Japanese elderly patients [61] and mortality of ARDS patients [23, 24] .
T108 17857-18060 Sentence denotes Importantly, ACE2 has been identified as a key SARS receptor, and ACE2 protects murine lungs from acute lung injury induced by acid aspiration, endotoxin shock, peritoneal sepsis or SARS spike challenge.
T109 18061-18286 Sentence denotes These findings might provide the opportunity to develop ACE2 as a novel drug for ARDS that develops in emerging lung infectious diseases such as avian influenza A (H5N1) [62] or other diseases that affect lung function [63] .
T110 18287-18499 Sentence denotes Because ACE2 is an non-specific protease, it would also be interesting to investigate the role of ACE2 and its metabolites, including angiotensin-(1-7), des-Arg(9)-bradykinin, apelin and dynorphin, in ARDS [14] .
T111 18500-18622 Sentence denotes We look forward to the use of angiotensin system-modulating agents/molecules, in particular ACE2, 274 Respiratory Figure 2
T112 18623-18703 Sentence denotes Schematic diagram of the proposed role of the RAS in development of severe ARDS.
T113 18704-18848 Sentence denotes In acute lung injury such as SARS-CoV infections, acid aspiration, pneumonias or sepsis, the generation of ANG II from ANG I is enhanced by ACE.
T114 18849-19036 Sentence denotes ANG II contributes to acute lung failure through stimulation of the AT 1 receptor, whereas ACE2 and the AT 2 receptor negatively regulate this pathway and protect from acute lung failure.
T115 19037-19138 Sentence denotes However, additional ACE2-regulated, but ANG II-independent, pathways seem to also contribute to ARDS.
T116 19140-19269 Sentence denotes The renin-angiotensin system (RAS) plays a key role in maintaining blood pressure homeostasis, as well as fluid and salt balance.
T117 19270-19389 Sentence denotes Angiotensin II, a key effector peptide of the system, causes vasoconstriction and exerts multiple biological functions.
T118 19390-19629 Sentence denotes Angiotensin-converting enzyme (ACE) plays a central role in generating angiotensin II from angiotensin I, and capillary blood vessels in the lung are one of the major sites of ACE expression and angiotensin II production in the human body.
T119 19630-19813 Sentence denotes The RAS has been implicated in the pathogenesis of pulmonary hypertension and pulmonary fibrosis, both commonly seen in chronic lung diseases such as chronic obstructive lung disease.
T120 19814-19956 Sentence denotes Recent studies indicate that the RAS also plays a critical role in acute lung diseases, especially acute respiratory distress syndrome (ARDS).
T121 19957-20154 Sentence denotes ACE2, a close homologue of ACE, functions as a negative regulator of the angiotensin system and was identified as a key receptor for SARS (severe acute respiratory syndrome) coronavirus infections.
T122 20155-20241 Sentence denotes In the lung, ACE2 protects against acute lung injury in several animal models of ARDS.
T123 20242-20329 Sentence denotes Thus, the RAS appears to play a critical role in the pathogenesis of acute lung injury.
T124 20330-20449 Sentence denotes Indeed, increasing ACE2 activity might be a novel approach for the treatment of acute lung failure in several diseases.
T125 20450-20618 Sentence denotes For many decades, the roles of the renin-angiotensin system (RAS) have been studied in physiology and multiple disorders, in particular cardiovascular diseases [1, 2] .
T126 20619-20805 Sentence denotes Angiotensin II (ANG II), a key effector peptide of the RAS, exerts multiple biological functions including the vasoconstriction and sodium balance involved in blood pressure homeostasis.
T127 20806-21032 Sentence denotes Angiotensin-converting enzyme (ACE) plays a central role in generating ANG II from angiotensin I (ANG I) [3, 4] (Figure 1 ), and ACE inhibitors or ANG II receptor blockers exhibit beneficial effects in cardiovascular diseases.
T128 21033-21123 Sentence denotes Capillary blood vessels in the lung are a major site of high-level expression of ACE [5] .
T129 21124-21252 Sentence denotes Thus, the lung is an important organ in generating circulating ANG II, acting as a classical circulation-borne endocrine system.
T130 21253-21362 Sentence denotes In contrast to this endocrine RAS model, numerous studies have highlighted the importance of local RASs [6] .
T131 21363-21587 Sentence denotes For example, an increase in endothelial ACE expression in the muscularized intraacinar arteries of lungs was shown both in patients with pulmonary hypertension [7] and in rats with hypoxiainduced pulmonary hypertension [8] .
T132 21588-21730 Sentence denotes In addition to ACE, other components of the RAS are expressed in lungs, including renin [9] , angiotensinogen [10] and ANG II receptors [11] .
T133 21731-21856 Sentence denotes In 2000, ACE2, a homologue of ACE, was identified; its discovery instantaneously added a new complexity to the RAS [12, 13] .
T134 21857-22039 Sentence denotes Although ACE2 functions similarly to ACE as a carboxypeptidase, ACE2 has a different substrate specificity [12] [13] [14] , shown by in vitro analyses using recombinant ACE2 protein.
T135 22040-22337 Sentence denotes Whereas ACE removes dipeptides from the C-terminus of peptide substrates, generating the octapeptide ANG II from the decapeptide ANG I [3, 15] , ACE2 cleaves a single residue from ANG II, generating angiotensin-(1-9) [12, 13] , and a single residue from ANG II to generate angiotensin-(1-7) [12] .
T136 22338-22515 Sentence denotes Genetic inactivation of ACE using homologous recombination results in a phenotype characterized by spontaneous hypotension, reduced male fertility and kidney malformation [16] .
T137 22516-22663 Sentence denotes By contrast, targeted disruption of murine ACE2 resulted in increased systemic ANG II levels and impaired cardiac contractility in aged mice [17] .
T138 22664-22736 Sentence denotes Loss of ACE on an ACE2 background reversed this cardiac phenotype [17] .
T139 22737-22847 Sentence denotes Thus, ACE2 appears to be a negative regulator of the RAS and counterbalances the function of ACE ( Figure 1 ).
T140 22848-23015 Sentence denotes The importance of the RAS in lung diseases has recently re-emerged since the identification of ACE2 as a severe acute respiratory syndrome (SARS) coronavirus receptor.
T141 23016-23168 Sentence denotes During several months of 2003, SARS -a newly identified illness -spread rapidly from China throughout the world, causing more than 800 deaths [18, 19] .
T142 23169-23318 Sentence denotes A novel coronavirus was identified as the SARS pathogen, which triggered atypical pneumonia characterized by high fever and severe dyspnea [18, 19] .
T143 23319-23482 Sentence denotes The death rate following SARS coronavirus exposure approached almost 10% of infected people owing to the development of acute respiratory distress syndrome (ARDS).
T144 23483-23639 Sentence denotes ARDS is the most severe form of acute lung injury and is characterized by pulmonary oedema, accumulation of inflammatory cells and severe hypoxia [20, 21] .
T145 23640-23752 Sentence denotes Clinical as well as experimental animal studies have implicated ACE in the pathogenesis of ARDS [22] [23] [24] .
T146 23753-23934 Sentence denotes ACE2 is expressed in the lungs of healthy and diseased humans [25] , and recent ARDS and SARS studies have shown that ACE2 protects murine lungs from severe acute injury [26 ,27 ] .
T147 23935-24066 Sentence denotes Importantly, these experiments also revealed that ACE2 is an essential receptor for SARS infections in vitro and in vivo [27 ,28] .
T148 24067-24250 Sentence denotes In this review, we review the role of the RAS, in particular of the SARS receptor ACE2, in lung diseases, focusing on pulmonary hypertension, pulmonary fibrosis and acute lung injury.
T149 24251-24369 Sentence denotes The possible applications of blocking the RAS and/or modulating ACE2 for the treatment of lung diseases are discussed.
T150 24370-24642 Sentence denotes Pulmonary hypertension is characterized by elevations in pulmonary artery pressure and pulmonary vascular resistance caused by multiple etiologies, including primary pulmonary hypertension, chronic obstructive pulmonary disease (COPD), high altitude or pulmonary embolism.
T151 24643-24800 Sentence denotes Abnormal pulmonary vasoconstriction and pulmonary vascular remodeling are major pathological features seen in most forms of pulmonary hypertension [29, 30] .
T152 24801-25010 Sentence denotes Although ANG II is well known as a potent vasopressor peptide, in the pathogenesis of pulmonary hypertension ANG II seems to play a role in pulmonary vascular remodeling rather than pulmonary vasoconstriction.
T153 25011-25249 Sentence denotes In in vitro cell culture models, ANG II has been shown to directly cause growth/proliferation of pulmonary artery smooth muscle cells largely through ANG II type I (AT 1 ), rather than through type II (AT 2 ), receptors [31] ( Figure 1 ).
T154 25250-25403 Sentence denotes In pulmonary hypertension in vivo, the expression of ACE is increased in the endothelial layer of small, as well as elastic, pulmonary arteries [7, 32] .
T155 25404-25572 Sentence denotes In addition, in hypoxic, but not monocrotaline-treated [33] , pulmonary hypertensive rats, both ANG II binding and the number of AT 1 receptors are increased [34, 35] .
T156 25573-25822 Sentence denotes In human patients, an association between an ACE insertion/deletion polymorphism (the D allele of the human ACE gene confers increased ACE activity in plasma) and pulmonary hypertension has been reported; this association is, however, controversial.
T157 25823-26044 Sentence denotes For instance, one study showed that the ACE D/D genotype is associated with less right ventricular hypertrophy [36] , whereas another reported a correlation between the ACE D/D genotype and the severity of symptoms [37] .
T158 26045-26322 Sentence denotes Pharmacologic treatment of animals with either an ACE blocker or an ANG II receptor antagonist inhibited pulmonary vascular remodeling associated with the development of pulmonary hypertension in chronically hypoxic rats or mice [38, 39] or in monocrotaline-treated rats [40] .
T159 26323-26530 Sentence denotes By contrast, tissue ACE-deficient mice, which exhibit undetectable lung ACE activity but retain 34% of the ACE activity in plasma, show the same remodeling of pulmonary arterioles as do wild-type mice [41] .
T160 26531-26899 Sentence denotes In addition, despite earlier studies of acute ACE inhibition [42] [43] [44] , a recent pilot study on patients with pulmonary hypertension secondary to COPD showed that treatment with the AT 1 receptor blocker losartan (50 mg) showed no statistically significant beneficial effect in terms of pulmonary artery pressure, exercise capacity or breathlessness score [45] .
T161 26900-27089 Sentence denotes The discrepancy between hypoxic rat studies and this human trial might be caused by differences in the pathogenesis of hypoxic rats versus patients with COPD-related pulmonary hypertension.
T162 27090-27151 Sentence denotes Further studies are required to solve these important issues.
T163 27152-27229 Sentence denotes Pulmonary fibrosis is a frequent response to insults or injuries to the lung.
T164 27230-27333 Sentence denotes Etiologies include idiopathic pulmonary fibrosis, sarcoidosis, irradiation-induced pneumonitis or ARDS.
T165 27334-27439 Sentence denotes Excess deposition of extracellular matrix proteins is a key feature of interstitial fibrosis in the lung.
T166 27440-27667 Sentence denotes The pathogenesis of pulmonary fibrosis includes endothelial and epithelial cell injury, influx of inflammatory cells and the production of chemical mediators leading to the proliferation and activation of fibroblasts [46, 47] .
T167 27668-27927 Sentence denotes Although there are various initiating mechanisms and etiologies, the terminal phases of fibrosis are commonly characterized by the proliferation and progressive 272 Respiratory Figure 1 Current view of the RAS in pulmonary hypertension and pulmonary fibrosis.
T168 27928-27978 Sentence denotes ANG I serves as a substrate for both ACE and ACE2.
T169 27979-28115 Sentence denotes ANG II is known to act as vasoconstrictor as well as a mitogen for smooth muscle cells or fibroblasts, mainly through the AT 1 receptor.
T170 28116-28173 Sentence denotes The function of angiotensin-(1-9) is not well understood.
T171 28174-28268 Sentence denotes Both ACE and ACE2 are involved in the production of the vasodilator peptide angiotensin-(1-7).
T172 28269-28342 Sentence denotes accumulation of connective tissue replacing normal functional parenchyma.
T173 28343-28500 Sentence denotes ANG II immunoreactivity is also significantly increased within lung fibroblasts, macrophages and bronchiolar and alveolar epithelium after irradiation [48] .
T174 28501-28597 Sentence denotes In addition, angiotensinogen is produced by fibroblasts from fibrotic but not normal human lung.
T175 28598-28815 Sentence denotes ANG II upregulates the expression of the profibrotic cytokine transforming growth factor-b1, which is involved in both the conversion of fibroblasts to myofibroblasts and the accumulation of collagen [49] (Figure 1 ).
T176 28816-28952 Sentence denotes An in vivo role for ANG II in pulmonary fibrosis has been implied from animal models with bleomycin-or irradiation-mediated lung injury.
T177 28953-29149 Sentence denotes In bleomycin-induced pulmonary fibrosis in rats or mice, ACE inhibitors or AT 1 receptor blockers can attenuate epithelial apoptosis, interstitial fibrosis and collagen deposition [50] [51] [52] .
T178 29150-29264 Sentence denotes In irradiation-induced lung fibrosis, ACE inhibitors attenuate endothelial dysfunction and fibrosis in rats [53] .
T179 29265-29461 Sentence denotes Conversely, retrospective comparison of the incidence of irradiation-induced lung injury between subjects who took ACE inhibitors and those who did not, failed to reveal a protective effect [54] .
T180 29462-29641 Sentence denotes However, serum concentrations of ACE inhibitors used by subjects in the human study would be expected to be considerably less than those achieved in the animal models cited above.
T181 29642-29953 Sentence denotes As there are no published prospective or retrospective studies regarding the use of other ACE inhibitors or AT 1 receptor blockers in human pulmonary fibrosis induced by factors other than irradiation, it is therefore still unclear if inhibition of the RAS would indeed have beneficial effects on lung fibrosis.
T182 29954-30122 Sentence denotes ARDS is the most severe form of acute lung injury, and affects approximately one million individuals worldwide/ year with a mortality rate of at least 30-50% [20, 21] .
T183 30123-30316 Sentence denotes ARDS can be triggered by multiple diseases such as sepsis, aspiration, trauma, acute pancreatitis, or pneumonias following infections with SARS coronavirus or avian and human influenza viruses.
T184 30317-30480 Sentence denotes Recent cohort studies of ARDS showed a significant association between an ACE insertion/deletion polymorphism and the susceptibility and outcome of ARDS [23, 24] .
T185 30481-30581 Sentence denotes The D/D genotype frequency was increased in patients with ARDS compared with a control cohort [23] .
T186 30582-30682 Sentence denotes In addition, the ACE D/D allele was significantly associated with mortality in the ARDS group [23] .
T187 30683-30799 Sentence denotes Another study showed that patients carrying the ACE I/I genotype have a significantly increased survival rate [24] .
T188 30800-30996 Sentence denotes Thus, from the results of inhibitor experiments in rodents [22] and ACE allelic correlation studies in humans [23, 24] , it has been suggested that the RAS could play a role in acute lung failure.
T189 30997-31077 Sentence denotes Our group has investigated the role of ACE2 in ARDS by using ace2 knockout mice.
T190 31078-31266 Sentence denotes In acid-aspiration-induced ARDS, endotoxin-induced ARDS and peritoneal sepsis-induced ARDS, ace2 knockout mice exhibited severe disease compared with control mice that express ACE2 [26 ] .
T191 31267-31423 Sentence denotes Loss of ACE2 expression in mutant mice resulted in enhanced vascular permeability, increased lung edema, neutrophil accumulation and worsened lung function.
T192 31424-31633 Sentence denotes Importantly, treatment with catalytically active, but not enzymatically inactive, recombinant ACE2 protein improved the symptoms of acute lung injury in wild-type mice, as well as in ace2 knockout mice [26 ] .
T193 31634-31690 Sentence denotes Thus, ACE2 plays a protective role in acute lung injury.
T194 31691-31820 Sentence denotes Mechanistically, the negative regulation of ANG II levels by ACE2 accounts, in part, for the protective function of ACE2 in ARDS.
T195 31821-32017 Sentence denotes For example, AT 1 receptor inhibitor treatment or additional ace gene deficiency on an ace2 knockout background rescues the severe phenotype of ace2 single mutant mice in acute lung injury [26 ] .
T196 32018-32135 Sentence denotes In addition, ace knockout mice and AT 1a receptor knockout mice showed improved symptoms of acute lung injury [26 ] .
T197 32136-32313 Sentence denotes Therefore, in acute lung injury, ACE, ANG II and AT 1 receptors function as lung injury-promoting factors [26 ,55] , whereas ACE2 protects against lung injury [26 ] (Figure 2 ).
T198 32314-32572 Sentence denotes These findings suggest that the beneficial effects of ACE inhibitors or AT 1 receptor blockers in lung injury models induced by bleomycin or irradiation, observed in the earlier studies, derive largely from their effects on the acute phase of those injuries.
T199 32573-32733 Sentence denotes Within a few months following the publication of the SARS-CoV genome [56, 57] , ACE2 was identified as a potential receptor in cell line studies in vitro [28] .
T200 32734-32945 Sentence denotes ACE2 has been demonstrated to bind SARS-CoV spike and to support 'syncytia formation', the fusion of spike-proteinexpressing cells into large multinucleated cells that can also be seen in 'real' SARS infections.
T201 32946-33099 Sentence denotes Using a mouse SARS infection model with ace2 knockout mice, our group provided evidence that ACE2 is indeed essential for SARS infections in vivo [27 ] .
T202 33100-33212 Sentence denotes When ace2 knockout mice are infected with the SARS coronavirus, they become resistant to virus infection [27 ] .
T203 33213-33378 Sentence denotes Virus titers from the lung tissues of infected ace2 knockout mice were 10 5 -fold lower than those isolated from the lung of SARS-CoV-infected wild-type mice [27 ] .
T204 33379-33617 Sentence denotes The lung histology from ace2 knockout mice challenged with SARS coronavirus showed no signs of inflammation [27 ] , whereas some (but not all) SARS-infected wild-type mice displayed mild inflammation with leukocyte infiltration [27 ,58] .
T205 33618-33682 Sentence denotes Thus, ACE2 is an essential receptor for SARS infections in vivo.
T206 33683-33862 Sentence denotes Despite many studies on SARS-CoV, the reasons why SARS-CoV infections trigger severe lung disease with such a high mortality, in contrast to other coronaviruses, remain a mystery.
T207 33863-34071 Sentence denotes Accumulating evidence indicates that severe SARS infections are dependent upon the burden of viral replication as well as on the immunopathologic consequences of the host response (for review, see [59, 60] ).
T208 34072-34445 Sentence denotes In addition to the aberrant activation of immune systems, our own studies have implicated the involvement of the RAS in SARS pathogenesis: firstly, ACE2 is a critical SARS receptor in vivo; and secondly, ACE2 and other components of the RAS play a central role in controlling the severity of acute lung failure once the disease process has been initiated [27 ] (Figure 2) .
T209 34446-34560 Sentence denotes Intriguingly, wild-type mice infected with SARS-CoV showed markedly downregulated ACE2 expression in lungs [27 ] .
T210 34561-34723 Sentence denotes Similarly, treatment with recombinant SARS-spike protein, in the absence of any other virus components, downregulates ACE2 expression in vitro and in vivo [27 ] .
T211 34724-34936 Sentence denotes Thus, SARS-CoV-infected or spike proteintreated wild-type mice resemble ace2 knockout mice, and, similar to ace2 mutant mice, spike-treated wild-type mice show markedly more severe pathology of acute lung injury.
T212 34937-35112 Sentence denotes Additionally, in spike-treated mice, ANG II peptide levels were increased and the worsened ARDS symptoms could be partially reversed by AT 1 receptor blocker treatment [27 ] .
T213 35113-35195 Sentence denotes By contrast, spike does not affect the ARDS symptoms in ace2 knockout mice [27 ] .
T214 35196-35352 Sentence denotes Thus, the downregulation of ACE2 expression in SARS-CoV infections might play a causal role in SARS pathogenesis, especially in disease progression to ARDS.
T215 35353-35572 Sentence denotes ANG II plays roles in tissue remodeling and fibrotic changes through acting on fibroblasts or smooth muscle cells, thereby contributing to the pathogenesis or progression of pulmonary fibrosis or pulmonary hypertension.
T216 35573-35727 Sentence denotes This notion is strongly supported by the successful treatment of these disease conditions using ACE inhibitors or AT 1 receptor blockers in animal models.
T217 35728-35956 Sentence denotes However, pilot clinical trials have failed to observe significant beneficial effects of ACE inhibitors on radiation-induced pulmonary fibrosis or positive effects of AT 1 receptor blockers on COPD-related pulmonary hypertension.
T218 35957-36086 Sentence denotes Recently, the critical importance of the RAS in the pathogenesis of acute lung disease (i.e. ARDS/acute lung injury) has emerged.
T219 36087-36253 Sentence denotes Hypothetically, the RAS appears to contribute to the initial severity of lung diseases rather than to later stages that define chronic fibrosis and tissue remodeling.
T220 36254-36445 Sentence denotes In line with this notion, the D/D polymorphism of the ACE gene has been associated with the incidence of pneumonias in Japanese elderly patients [61] and mortality of ARDS patients [23, 24] .
T221 36446-36649 Sentence denotes Importantly, ACE2 has been identified as a key SARS receptor, and ACE2 protects murine lungs from acute lung injury induced by acid aspiration, endotoxin shock, peritoneal sepsis or SARS spike challenge.
T222 36650-36875 Sentence denotes These findings might provide the opportunity to develop ACE2 as a novel drug for ARDS that develops in emerging lung infectious diseases such as avian influenza A (H5N1) [62] or other diseases that affect lung function [63] .
T223 36876-37088 Sentence denotes Because ACE2 is an non-specific protease, it would also be interesting to investigate the role of ACE2 and its metabolites, including angiotensin-(1-7), des-Arg(9)-bradykinin, apelin and dynorphin, in ARDS [14] .
T224 37089-37267 Sentence denotes We look forward to the use of angiotensin system-modulating agents/molecules, in particular ACE2, Schematic diagram of the proposed role of the RAS in development of severe ARDS.
T225 37268-37412 Sentence denotes In acute lung injury such as SARS-CoV infections, acid aspiration, pneumonias or sepsis, the generation of ANG II from ANG I is enhanced by ACE.
T226 37413-37600 Sentence denotes ANG II contributes to acute lung failure through stimulation of the AT 1 receptor, whereas ACE2 and the AT 2 receptor negatively regulate this pathway and protect from acute lung failure.
T227 37601-37857 Sentence denotes However, additional ACE2-regulated, but ANG II-independent, pathways seem to also contribute to ARDS. as novel therapeutic agents to treat severe acute lung failure, a syndrome that currently affects millions of people without any effective drug treatment.