MEK-ERK Pathway Modulation Ameliorates Pulmonary Fibrosis Associated with Epidermal Growth Factor Receptor Activation

作者：Madala Satish K; Schmidt Stephanie; Davidson Cynthia; Ikegami Machiko; Wert Susan; Hardie William D^*

来源：American Journal of Respiratory Cell and Molecular Biology, 2012, 46(3): 380-388.

DOI：10.1165/rcmb.2011-0237OC

• pulmonary fibrosis
• transforming growth factor-alpha
• epidermal growth factor receptor
• mitogen-activated protein kinase/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase
• ARRY-142886

Pulmonary fibrosis remains a significant public health burden with no proven therapies. The mitogen-activated protein kinase (MAPK)/MAPK kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling cascade is a major pathway controlling cellular processes associated with fibrogenesis, including growth, proliferation, and survival. Activation of the MAPK/ERK pathway is detected in the lungs of human fibrosis samples; however, the effect of modulating the pathway in vivo is unknown. Overexpression of transforming growth factor (TGF)-alpha in the lung epithelium of transgenic mice causes a progressive pulmonary fibrosis associated with increased MEK/ERK activation localized primarily in mesenchymal cells. To determine the role of the MEK pathway in the induction of TGF-alpha-induced lung fibrosis, TGF-alpha was overexpressed for 4 weeks while mice were simultaneously treated with the specific MEK inhibitor, ARRY-142886 (ARRY). Treatment with ARRY prevented increases in lung cell proliferation and total lung collagen, attenuated production of extracellular matrix genes, and protected mice from changes in lung function. ARRY administered as a rescue treatment after fibrosis was already established inhibited fibrosis progression, as assessed by lung histology, changes in body weights, extracellular matrix gene expression, and lung mechanics. These findings demonstrate that MEK inhibition prevents progression of established fibrosis in the TGF-alpha model, and provides proof of concept of targeting the MEK pathway in fibrotic lung disease.

• 出版日期2012-3