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. In previous studies we showed that MUC4 is overexpressed in IPF lungs and collaborates with TGFβ1 to induce epithelial to mesenchymal transition (EMT) and fibroblast to myofibroblast transition (FMT). However the exact participation of MUC4 in IPF is currently unknown. Objective: To explore the mechanisms which explain the role of MUC4 in IPF in different cellular and animal models. Methods: The influence of MUC4 in IPF was evaluated in vitro by measure of senescence and cell proliferation in alveolar type II (ATII) A549 cells and lung fibroblasts MRC5 silenced with siRNA-MUC4 and HEK293 cells with MUC4-inducible overexpression construct. Otherwise, the intracellular mechanism of MUC4 was evaluated by immunoprecipitation and immunofluorescence in A549 and MRC5, and in IPF primary ATII cells stimulated with TGFβ1. Lung tissue from human healthy/IPF patients and bleomycin mice wild type (WT)/ knockout MUC4 (KO-MUC4) were analyzed to explore in vivo the influence of MUC4 in IPF progression, and the MUC4 intracellular interactions by immunofluorescence. Results: Senescence and proliferation in IPF are induced by MUC4. A multi-protein complex is formed among pSmad2/3, pTGFβ type I receptor (pTGFβRI) and MUC4, which migrates into the nucleus to activate fibrotic genes in human cells and human and animal lung tissue. Unlike WT, KO-MUC4 mice were protected against IPF. Conclusions: MUC4 collaborates with pSmad2/3 and pTGFβRI inducing IPF progression. Therefore, pharmacologic targeting of MUC4 may be a potential target to design new therapies for IPF.