Activation of A2aR attenuates bleomycin-induced pulmonary fibrosis via the SDF-1/CXCR4 axis-related pathway.

Previous studies in our lab have demonstrated that Adenosine A2a receptor (A2aR) gene-knockout mice were vulnerable to pulmonary fibrosis induced by bleomycin (BLM). Inhibition of the SDF-1/CXCR4 axis has been reported to protect the lungs from fibrogenesis in BLM-exposed mice. Little is yet known about the relationships between A2aR and the SDF-1/CXCR4 axis in idiopathic pulmonary fibrosis (IPF). This study probes the role of A2aR in the fibrotic process and explores the relationship between A2aR and the SDF-1/CXCR4 axis in BLM-induced pulmonary fibrosis in mice. In the study, A2aR-/- and A2aR+/+ BALB/c mice were exposed to BLM by intratracheal instillation, and CGS-21680 (CGS), an A2aR agonist, was administered daily for 28 days to the A2aR+/+ mice in the BLM-induced fibrosis group. Activation of A2aR produced an anti-fibrotic effect as indicated by the evaluations of the lung architecture, microstructure and ultrastructure. The quantitative analysis indicated that treatment with CGS significantly reduced the collagen content in lungs. To explore the potential mechanisms, the expression levels of A2aR, SDF-1, and CXCR4 were subsequently determined using ELISA, in situ hybridization (ISH), immunohistochemical staining and western blotting techniques. Administration of CGS markedly suppressed the elevated expression levels of SDF-1 and CXCR4. Moreover, the A2aR-/- mice developed more severe pulmonary fibrosis than the normal mice when exposed to BLM. Furthermore, the SDF-1/CXCR4 axis was aberrantly uninhibited in the knockout mice. Together, these findings indicated that A2aR alleviated BLM-induced lung fibrosis, at least partially via the SDF-1/CXCR4 pathway, which could be a potential therapeutic target for the treatment of IPF.