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Angiotensin II type-2 receptor activation in alveolar macrophages mediates protection against cigarette smoke-induced chronic obstructive pulmonary disease.
Mei, Dan; Liao, Wupeng; Gan, Phyllis X L; Tran, Quy T N; Chan, Christabel C M Y; Heng, C K Matthew; Wong, W S Fred.
Afiliación
  • Mei D; Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, 117600, Singapore. Electronic address: meidan_nh@163.com.
  • Liao W; Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, 117600, Singapore; Singapore-HUJ Alliance for Research and Enterprise, National University of Singapore, 138602, Singapore.
  • Gan PXL; Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, 117600, Singapore.
  • Tran QTN; Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, 117600, Singapore; Singapore-HUJ Alliance for Research and Enterprise, National University of Singapore, 138602, Singapore.
  • Chan CCMY; Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, 117600, Singapore; Drug Discovery & Optimization Platform, Yong Loo Lin School of Medicine, National University Health System, 117600, Singapore.
  • Heng CKM; Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, 117600, Singapore; Singapore-HUJ Alliance for Research and Enterprise, National University of Singapore, 138602, Singapore.
  • Wong WSF; Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, 117600, Singapore; Singapore-HUJ Alliance for Research and Enterprise, National University of Singapore, 138602, Singapore; Drug Discovery & Optimization Platform, Yong Loo Lin School of Medicine, Nat
Pharmacol Res ; 184: 106469, 2022 10.
Article en En | MEDLINE | ID: mdl-36167278
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. Alveolar macrophages (AMs) are the first line immune defense in the respiratory system and play a critical role in the lung homeostasis. This study aimed to investigate the role of AMs in contributing to the protective effects of angiotensin II type-2 receptor (AT2R) activation in cigarette smoke (CS)-induced COPD. The AM polarization, phagocytosis and metabolism, and the underlying biochemical mechanisms of compound 21 (C21), a selective and potent non-peptide small molecule AT2R agonist, were evaluated in a two-week CS-induced COPD mouse model. C21 restored AM phagocytosis ability, reversing CS-induced AM phagocytosis impairment. CS exposure polarized AMs towards M1 phenotype, whereas, C21 skewed the CS-exposed AMs towards M2 phenotype. C21 reprogrammed CS-exposed AM metabolism from a high glycolysis-driven process to support inflammation energy demand to a high mitochondrial respiration process to limit inflammation. Besides, C21 upregulated AT2R and Mas receptor levels in CS-exposed AMs, favoring the anti-inflammatory Ang II/AT2R axis and Ang 1-7/Mas axis in the RAS. C21 restored the normal levels of sirtuin 1 (SIRT1) and MAPK phosphatase 1 (MKP1) in CS-exposed AMs, leading to the reduction of phospho-p38, phospho-ERK and p65 subunit of NF-κB levels in CS-exposed AMs. We report here for the first time that AT2R agonist C21 acts by boosting the protective functions of AMs against CS-induced COPD, and our results support the development of AT2R agonist for the treatment of COPD.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Enfermedad Pulmonar Obstructiva Crónica / Fumar Cigarrillos Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Animals Idioma: En Revista: Pharmacol Res Asunto de la revista: FARMACOLOGIA Año: 2022 Tipo del documento: Article

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Enfermedad Pulmonar Obstructiva Crónica / Fumar Cigarrillos Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Animals Idioma: En Revista: Pharmacol Res Asunto de la revista: FARMACOLOGIA Año: 2022 Tipo del documento: Article