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

Abstract

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.

Unique and Redundant Functions of p70 Ribosomal S6 Kinase Isoforms Regulate Mesenchymal Cell Proliferation and Migration in Pulmonary Fibrosis

“…Similar to our findings in isolated lung mesenchymal cells, we observed a significant reduction in the intensity of S6 phosphorylation in the total lung lysates of CCSP/TGF-a/S6K2 2/2 mice compared with control, CCSP/TGF-a WT, and CCSP/TGF-a/S6K1 2/2 mice, with no differences in phosphorylated Akt expression (Figure 4). The dampened increase in Akt and S6 phosphorylation between control and CCSP/TGF-a groups seen at 8 weeks of Dox is consistent with previous work showing diminished phosphorylation of signaling intermediates of the PI3K/mTOR pathway after continuous and prolonged TGF-a expression in the lung (23). Together, these findings show differential responses in vivo between the p70S6K isoforms in downstream S6 phosphorylation and proliferative responses in fibrotic lesions.…”

“…Our previous studies examining the progression of subpleural fibrosis in the TGF-a transgenic model confirmed that selective pharmacologic inhibition of the mTORC1, mitogen-activated protein kinase (MAPK), or PI3K pathways reversed or prevented the progression of the subpleural lesions (14,15,22,23). Pharmacologically targeting the p70S6K is a logical target, as it may represent a crucial converging downstream pathway of these known fibroproliferative signaling pathways that regulate subpleural fibroproliferative disease.…”

“…Paraffin sections were immunostained with Ki67 antigen (Dako, Glostrup, Denmark) and the proliferation index determined (21,22). Lung mechanics were assessed on mice with a computerized flexiVent system (SCIREQ, Montreal, PQ, Canada), and lung hydroxyproline levels determined as previously described (23 …”

Animal Models of Fibrotic Lung Disease

“…This model illustrates the importance of regulatory crosstalk between lung epithelial cells and mesenchymal cells. For example, the overexpression of TGF-a in the lung epithelium results in a persistent up-regulation of the mitogen-activated protein kinase kinase (MEK)/extracellular regulated kinase signaling pathway in lung mesenchyme (69). When the inducible expression of TGF-a is discontinued, lung remodeling is partly reversed, allowing for studies of the mediators involved in this reversal process (67).…”

The wound healing, chronic fibrosis, and cancer progression triad

“…Under physiological conditions, EGFR signaling drives wound healing, and controlled activity of EGFR by HB-EGF has been proposed as a therapeutic approach to prompt and accelerate cutaneous wounds healing (161,363). Of note, aberrant EGFR activation is known to promote fibrosis in tissues such as lung, heart, and pancreas (128,214,229,245). EGFR activity has been implicated in the progression of malignancies such as colon and lung cancer (94,134,314).…”