Role of MUC4 in idiopathic pulmonary fibrosis

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and irreversible form of fibrotic intersticial lung disease, characterized by uncontrolled fibroblast proliferative processes and alveolar type II epithelial dysfunction. MUC4, a multi-domain transmembrane glycoprotein, is often overexpressed in epithelial cancers, with consequences for the biological properties, involved in cellular processes related to IPF. However, the role of MUC4 in IPF has not beet studied yet. Objective: To analyze the implication of MUC4 in IPF Methods: Lung tissue from 14 healthy and 14 IPF patients was obtained. MUC4 expression was analyzed by western blot, RT-PCR and immunohistochemistry. The effect of MUC4 on TGFβ1-induced epithelial to mesenchymal transition (EMT) and fibroblast to myofibroblast transition (FMT) was determined in alveolar type II A549 cells and lung fibroblasts MRC5 silenced with siRNA-MUC4. HEK293 cells with MUC4-inducible overexpression construct was used to evaluate EMT process. Results: MUC4 protein and mRNA expression were increased in lung tissue of IPF patients and mainly located in hyperplastic alveolar type II cells and fibrotic foci areas. TGFβ1 promoted larger EMT by increasing alpha smooth muscle actin, collagen type I, SLUG and SNAIL, and decreasing E-cadherin expression in wild type cells than in siRNA-MUC4 cells. Similar results were observed in the TGFβ1-induced FMT process. Likewise, TGFβ1 induced larger EMT when MUC4 expression was over-induced, independent of TGFβ1 receptor expression Conclusions: MUC4 expression is increased in IPF lungs and collaborates with TGFβ1 to induce EMT and FMT cellular transformations. Pharmacologic targeting of MUC4 may be a promising option for the treatment of IPF.