PMC:7556165 / 30691-33370 JSONTXT

{"target":"http://pubannotation.org/docs/sourcedb/PMC/sourceid/7556165","sourcedb":"PMC","sourceid":"7556165","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7556165","text":"ACE2 and Lung Injury\nACE2 is highly expressed in type I and II alveolar epithelial cells and in pulmonary small vessels (either endothelial cells or VSMC). The hypothesis that the ACE2 arm of the RAAS system could be of benefit in lung disease derives from the observation that ACE and angiotensin II are upregulated in acute lung injury (ALI), pulmonary fibrosis, pulmonary hypertension, and acute respiratory distress syndrome (ARDS) (Imai et al., 2005, 2010).\nARDS is an overly aggressive form of ALI and it is the final mechanism of lung injury in many diseases, including sepsis, acid aspiration, pancreatitis, anthrax and virus infections (Spanish flu, H5N1 avian flu and SARS). Imai et al. developed three ACE2 knockout mice models with severe ARDS induced by acid aspiration, endotoxin administration or peritoneal sepsis. They showed that ARDS was accompanied by increased vessel permeability, lung oedema, and infiltration of inflammation cells, with consequent impairment of respiratory function (Imai et al., 2005, 2007; Kuba et al., 2006). The phenotype was dramatically improved and rescued either administering ACE2 recombinant analogs or AT1Ra inhibitors (Imai et al., 2005, 2008).\nACE2 may also reduce lung inflammation via Ang1–7/MasR, since treatment with recombinant Ang1–7 in a model of allergic asthma reduced eosinophil mobilization, peri-bronchial inflammation, fibrosis and goblet cells metaplasia (El-Hashim et al., 2012). An anti-inflammatory effect with reduction of airway remodeling has also been demonstrated in another model of chronic asthma, after administration of Ang1–7 analog (Rodrigues-Machado et al., 2013). The underlying mechanism seems to be the modulation of the so-called cytokine storm and particularly the inhibition of transforming growth factor β (TGF- β) and NFkB signaling pathways (Li et al., 2015; Meng et al., 2015).\nACE2 might also modulate lung inflammation via the bradykinin-DABK/BKB1R axis. In fact, decreased ACE2 function in mouse lungs caused increased activity of the DABK axis and triggered a proinflammatory cytokine storm (CXCL5, MIP2, KC, and TNF-α), leading to pulmonary collapse (Sodhi et al., 2018).\nIn human, ACE/ACE2 imbalance may be related to genetic factors. In particular, a specific polymorphism of the ACE gene, namely ACE D, which determines increased ACE activity and decreased ACE2 activity has been correlated to ARDS susceptibility and mortality rate (Marshall et al., 2002). More recently, high levels of angiotensin II have been reported in patients infected with avian influenza viruses H5N1 and H7N9, and they were strongly predictive of a poor outcome (Huang et al., 2014; Zou et al., 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