Modafinil exerts anti-inflammatory and anti-fibrotic effects by upregulating adenosine A 2A and A 2B receptors.

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 A _2A AR and A _2B AR upregulation inhibits fibrotic responses. Primary human lung fibroblasts (HLFs) from normal (NHLFs) or patients with idiopathic pulmonary fibrosis (DHLF) were used for in vitro testing. 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, which activates cAMP signaling via A _2A AR and A _2B AR, was administered orally. The protein amounts of A _2A AR, A _2B AR, and exchange protein directly activated by cAMP (Epac) were reduced, while collagen and α-smooth muscle actin (α-SMA) were elevated in DHLFs compared to NHLFs. In liver or lung tissue from murine models of fibrotic diseases, A _2A AR and A _2B AR were downregulated, but A ₁ AR and A ₃ AR were not. Epac amounts decreased, and amounts of collagen, α-SMA, K _Ca 2.3, and K _Ca 3.1 increased compared to the control. Modafinil restored the amounts of A _2A AR, A _2B AR, and Epac, and reduced collagen, α-SMA, K _Ca 2.3, and K _Ca 3.1 in murine models of fibrotic diseases. Transforming growth factor-β reduced the amounts of A _2A AR, A _2B AR, and Epac, and elevated collagen, α-SMA, K _Ca 2.3, and K _Ca 3.1 in NHLFs; however, these alterations were inhibited by modafinil. Our investigation revealed that A _2A AR and A _2B AR downregulation induced liver and lung fibrotic diseases while upregulation attenuated fibrotic responses, suggesting that A _2A AR and A _2B AR-upregulating agents, such as modafinil, may serve as novel therapies for fibrotic diseases.
(© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)