MEK-ERK pathway modulation ameliorates pulmonary fibrosis associated with epidermal growth factor receptor activation

SK Madala, S Schmidt, C Davidson… - American journal of …, 2012 - atsjournals.org
SK Madala, S Schmidt, C Davidson, M Ikegami, S Wert, WD Hardie
American journal of respiratory cell and molecular biology, 2012atsjournals.org
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 …
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)-α 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-α–induced lung fibrosis, TGF-α 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-α model, and provides proof of concept of targeting the MEK pathway in fibrotic lung disease.
ATS Journals