Roxadustat Alleviates Cigarette-Induced COPD via the VEGF-A Pathway

Roxadustat, an inhibitor of hypoxia-inducible factor prolyl hydroxylase, exhibits recognized anti-inflammatory and antioxidant properties. Its application and underlying mechanisms in COPD remain unclear. Mice were treated with cigarette smoke and/or Roxadustat. Bronchoalveolar lavage fluid (BALF) and serum were collected to quantify IL-6 and TNF-α via ELISA. Western blot and immunohistochemistry staining were conducted on lung tissues to assess endothelial cell cleaved caspase 3 expression levels. CD31&TUNEL and NG2&TUNEL fluorescent double staining were employed to evaluate apoptosis of vascular endothelial cells and pericytes. The expression of VEGF-A in mouse lung tissues and BALF was assessed by RT-qPCR, western blot, and ELISA, while the expression and phosphorylation levels of VEGFR2 in mouse lung tissues were evaluated by immunofluorescence staining. The treatment of Roxadustat exhibited reduced inflammatory cell counts and IL-6 and TNF-α levels in BALF as compared to CS. Roxadustat treatment ameliorated cigarette-induced emphysema, notably reducing cleaved caspase 3 expression in pulmonary vascular endothelial cells. Furthermore, it significantly counteracted the decrease in CD31(+) pulmonary vascular endothelial cells and NG2(+) pericytes induced by cigarette smoke exposure, mitigating vascular endothelial cell apoptosis. Notably, Roxadustat treatment reversed the compromised expression of VEGF-A caused by cigarette smoke exposure and enhanced VEGFR2 expression and activation. In summary, roxadustat treatment mitigates cigarette-induced inflammation and inhibits pulmonary vascular endothelial cell apoptosis by promoting the VEGF-A pathway.