ERK5 inhibition ameliorates pulmonary fibrosis via regulating Smad3 acetylation

Suji Kim, Jae Hyang Lim, Chang-Hoon Woo
American Journal of Pathology 2013, 183 (6): 1758-68
Idiopathic pulmonary fibrosis is a progressive and chronic lung disease of unknown cause. Pathologically, the interstitium of the lungs becomes thick and stiff, which eventually cause the symptom of breathlessness. It has been established that the transforming growth factor-β1 (TGF-β1)/Smad signaling pathway plays a critical role in the pathogenesis of lung fibrosis. TGF-β1-mediated activation of the mitogen-activated protein kinase family affects Smad signaling. Extracellular signal-regulated kinase (ERK) 5, an atypical member of mitogen-activated protein kinase, promotes cardiac hypertrophy characterized with increased expression of fibrotic and extracellular matrix genes. However, the role of ERK5 in pulmonary fibrosis remains unknown. Herein, we investigated whether ERK5 regulates the pathogenesis of pulmonary fibrosis in both in vitro and in vivo systems. Pharmacological inhibition of mitogen activated protein kinase kinase 5/ERK5 with BIX02189 and depletion of ERK5 with siRNA-ERK5 inhibited TGF-β1-induced extracellular matrix production in lung epithelial cells and fibroblasts. Inhibition of ERK5 also blocked the TGF-β1 signal to Smad3 transcriptional activity. However, TGF-β1-induced Smad3 phosphorylation and nuclear translocation were not affected by inhibition of ERK5. Notably, ERK5 regulates TGF-β1-induced fibrogenic signaling via Smad3 acetylation. Furthermore, ERK5 inhibitor, BIX02189, inhibited lung fibrosis and improved survival rate in the bleomycin-induced lung fibrosis model. Our findings indicate that ERK5 plays a critical role in TGF-β1-induced pulmonary fibrosis via enhancing Smad3 acetylation. This study may lead to a novel therapeutic strategy for treating lung fibrosis.

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