Asiaticoside might attenuate bleomycin-induced pulmonary fibrosis by activating cAMP and Rap1 signalling pathway assisted by A2AR

Abstract

Asiaticoside (AS) has been reported to have protective effect on pulmonary fibrosis (PF). In this study, we aimed to explore the potential mechanism of the therapeutic role of AS and its relationship with A2AR in PF. Adenosine 2A receptor gene knockout (A2AR^-/- ) mice and wild-type (WT) mice were used to establish bleomycin (BLM)-induced PF models and were then treated with AS (50 mg/kg/d). Pulmonary inflammation and fibrosis were observed in the PF model with much higher severity in A2AR^-/- mice than that in WT mice and AS significantly alleviated lung inflammation and fibrosis; however, it was less effective in A2AR^-/- mice than in WT mice via histopathological analysis. Using RNA sequencing analysis, we found up-regulated differentially expressed genes (DEGs) in BLM group were enriched in immune and inflammation-associated pathways compared with control group. There were 242 common DEGs between down-regulated in BLM vs control group and up-regulated in BLM + AS vs BLM group, which were enriched in cAMP and Rap1 signalling pathways. Furthermore, the expression of five key factors of these two pathways including adenylate cyclase (ADCY1, ADCY5, ADCY8, cAMP and Rap1) were confirmed up-regulated by AS with the presence of A2AR. Therefore, AS might attenuate BLM-induced PF by activating cAMP and Rap1 signalling pathways which is assisted by A2AR, making it a promising therapeutic optional for PF.

Keywords: adenosine A2A receptor; adenylate cyclase; asiaticoside; cAMP and Rap1 signalling pathway; pulmonary fibrosis.