Journal
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
Volume -, Issue -, Pages -Publisher
SPRINGER
DOI: 10.1007/s00210-023-02589-0
Keywords
Acute lung injury; Macrophage; Angiotensin II type2 receptor agonist; C21; Inflammation
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This study found that the angiotensin II type 2 receptor (AT2R) agonist C21 has a protective effect on the lipopolysaccharide (LPS)-induced acute lung injury (ALI) model. C21 significantly inhibits the production of inflammatory cytokines and oxidative stress, and alleviates lung damage caused by LPS. This study brings new hope for the early treatment of acute respiratory distress syndrome (ARDS).
Acute respiratory distress syndrome (ARDS) is a devastating respiratory disorder, characterized by overwhelming inflammation in the alveoli without effective pharmacological treatment. We aimed to investigate the effect and mechanism of angiotensin II type 2 receptor (AT2R) agonist, Compound 21 (C21), on the lipopolysaccharide (LPS)-induced acute lung injury (ALI) model. The protective effect of C21 was evaluated via enzyme-linked immunosorbent assay (ELISA), Western blot (WB), real-time PCR, and fluorescence microscopy in LPS-challenged THP1-derived macrophages. Besides, the in vivo efficacy of C21 was assessed using cell counting, ELISA, protein quantification, hematoxylin-eosin (H & E) staining, and WB in an LPS-induced ALI mouse model. The results showed that C21 significantly inhibited the secretion of pro-inflammatory cytokines (CCL-2, IL-6), overproduction of intracellular ROS, and activation of inflammatory pathways (NF-& kappa;B/NLRP3, p38/MAPK) in THP-1 cell-derived macrophages stimulated by LPS. In in vivo study, intraperitoneal injection of C21 could reduce airway leukocytes accumulation and chemokine/cytokine (keratinocyte chemoattractant (KC), IL-6) generation, as well as alleviate diffuse alveolar damage induced by LPS. Conclusively, the AT2R agonist C21 significantly inhibited LPS-stimulated excess inflammatory responses and oxidative stress in macrophages. Meanwhile, C21 could effectively alleviate acute inflammation and tissue damage in the lungs of ALI mice challenged by LPS. The results of this study bring new hope for the early treatment of ALI/ARDS.
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