Modafinil exerts anti-inflammatory and anti-fibrotic effects by upregulating adenosine A2A and A2B receptors

Abstract

Abstract Adenosine receptor (AR) suppresses inflammation and fibrosis by activating cyclic adenosine monophosphate (cAMP) signaling. We investigated whether altered AR expression contributes to the development of fibrotic diseases and whether A2A AR and A2B AR upregulation inhibits fibrotic responses. Murine models of fibrotic liver or pulmonary disease were developed by injecting thioacetamide intraperitoneally, by feeding a high-fat diet, or by intratracheal instillation of bleomycin. Modafinil was orally administered to inhibit fibrotic responses. The protein levels of A2A AR, A2B AR, and exchange protein directly activated by cAMP (Epac) were reduced, while collagen and α-smooth muscle actin (α-SMA) were elevated in diseased (idiopathic pulmonary fibrosis) human lung fibroblasts (HLFs) compared to normal HLFs. In liver or lung tissue from murine models of fibrotic diseases, A2A and A2B AR were downregulated, but A1 and A3 AR were not. Epac levels decreased, and levels of collagen, α-SMA, KCa2.3, and KCa3.1 increased compared to the control. Modafinil restored the levels of A2A AR, A2B AR, and Epac, and reduced collagen, α-SMA, KCa2.3, and KCa3.1 in murine models of fibrotic diseases. Transforming growth factor-β reduced the levels of A2A AR, A2B AR, and Epac, and elevated collagen, α-SMA, KCa2.3, and KCa3.1 in normal HLFs; however, these alterations were inhibited by modafinil. Our investigation revealed that downregulation of A2A AR and A2B AR reduced cAMP signaling and induced liver and lung fibrotic diseases while upregulation attenuated fibrotic responses, suggesting that A2A AR and A2B AR-upregulating agents, such as modafinil, may serve as novel therapies for fibrotic diseases.