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Activation of angiotensin II type‐2 receptor protects against cigarette smoke‐induced COPD
Author(s) -
Mei Dan,
Tan Wan Shun Daniel,
Liao Wupeng,
Heng Chew Kiat Matthew,
Wong Wai Shiu Fred
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.02640
Subject(s) - copd , bronchoalveolar lavage , receptor , agonist , lung , chemistry , angiotensin ii , pathogenesis , proinflammatory cytokine , mapk/erk pathway , medicine , endocrinology , immunology , inflammation , signal transduction , biochemistry
Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally. Cumulative evidence has implicated renin‐angiotensin system (RAS) in the pathogenesis of COPD. This study aimed to investigate potential protective effects of angiotensin II type‐2 receptor (AT2R) activation in cigarette smoke (CS)‐induced COPD models and alveolar macrophages. Compound 21 (C21), a selective and potent non‐peptide small molecule AT2R agonist, was evaluated for anti‐inflammatory, anti‐oxidative and anti‐remodeling activities in a two‐week (acute) and an eight‐week (chronic) CS‐induced COPD models. C21 inhibited CS‐induced increases in macrophage and neutrophil counts, pro‐inflammatory cytokines and oxidative damage markers in bronchoalveolar lavage (BAL) fluid, and TGF‐β1 in lung tissues, from COPD models. C21 restored phosphatase activities and reduced phospho‐p38 MAPK, phospho‐ERK and p65 subunit of NF‐κB levels in CS‐exposed lung tissues. C21 also suppressed CS‐induced increases in α‐Sma, Mmp9, Mmp12and hydroxyproline levels in lung tissues, and neutrophil elastase activity in BAL fluid. C21 modulated RAS in CS‐exposed lungs by downregulating Ang II but upregulating Ang‐(1‐7) and Mas receptor levels. C21 prevented CS‐induced emphysema and improved lung functions in chronic COPD model. In conclusion, AT2R agonist C21 facilitates protective effects against CS‐induced COPD, and provide strong evidence for further exploration of AT2R agonist effects on CS‐induced alveolar macrophages.