Inhibition of ERK5 protects pulmonary fibrosis via downregulation of TGF‐b1‐Smad signaling

Abstract

TGF‐b1‐Smad signaling plays an important role in pulmonary fibrosis. TGF‐b1‐mediated MAPK family activation affects Smad signaling. ERK5 are also involved in promoting hypertrophic remodeling which lead to fibrotic and ECM gene expression in cardiomyocytes. However, the role of ERK5 in pulmonary fibrosis remains not known. Herein, we identified whether ERK5 regulates TGF‐b1‐induced fibrogenic gene expression in both in vitro and in vivo system. Pharmacological inhibitor of MEK5/ERK5, BIX02189 and depletion of ERK5 with siRNA inhibited TGF‐b1‐induced ECM molecules in lung epithelial cells and fibroblasts. Inhibition of ERK5 also blocked TGF‐b1 signal to smad3 transcriptional activity and PAI‐1 promoter activity. TGF‐b1‐induced Smad3 phosphorylation and nuclear translocation was not regulated by ERK5 signaling. Notably, ERK5 is involved in Smad2 phosphorylation at linker region and Smad3 acetylation. In bleomycin‐induced lung fibrosis, we found that BIX02189 treatment improved survival rate and inhibited lung fibrosis of mice after bleomycin. Our results demonstrate ERK5 plays a major role in TGF‐b1‐induced Smad3 acetylation, PAI‐1 transcription, and ECM molecules.