TY - JOUR
T1 - ERK5 inhibition ameliorates pulmonary fibrosis via regulating Smad3 acetylation
AU - Kim, Suji
AU - Lim, Jae Hyang
AU - Woo, Chang Hoon
N1 - Funding Information:
Supported by the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea grant A111520 .
PY - 2013/12
Y1 - 2013/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84888261183&partnerID=8YFLogxK
U2 - 10.1016/j.ajpath.2013.08.014
DO - 10.1016/j.ajpath.2013.08.014
M3 - Article
C2 - 24095924
AN - SCOPUS:84888261183
SN - 0002-9440
VL - 183
SP - 1758
EP - 1768
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 6
ER -