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

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