Kr\xfcpple-like-factor 4 Attenuates Lung Fibrosis via Inhibiting Epithelial-mesenchymal Transition

Lianjun Lin,Qian Han,Xinmin Liu,Yanping Wu,Ting Li,Huiying Xu,Yan Xiong,Nanping Wang,Zhonghui Liu

doi:10.1038/s41598-017-14602-7

Abstract

Epithelial-mesenchymal transition (EMT) plays an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Krüpple-like-factor 4 (KLF4), has been suggested to play an important role in the phenotype transition. However, its function in pulmonary fibrosis and EMT of human alveolar epithelial cells (AECs) remains unclear. This study aimed to examine the role of KLF4 in pulmonary fibrosis and EMT. Decreased expression of KLF4 was first observed in human IPF lung tissues and models of bleomycin-induced pulmonary fibrosis. Transgenic mice with overexpression of KLF4 were subjected to bleomycin-induced pulmonary fibrosis model and showed attenuated lung fibrosis and EMT compared to wild type group. Furthermore, the effects overexpression and knockdown of KLF4 on TGF-β1-induced EMT were examined in AECs. Adenovirus-mediated overexpression of KLF4 attenuated TGF-β1-induced EMT and activation of Smad2/3 and Dvl in AECs. Conversely, knockdown of KLF4 promoted the activation of pathways above mentioned and TGF-β1-induced EMT. Our results demonstrates that KLF4 plays an important role in bleomycin-induced lung fibrosis through suppressing TGFβ1-induced EMT. Thus, it may serve as a potential target for the treatment of pulmonary fibrosis.

Highlights

Epithelial-mesenchymal transition (EMT) is a process in which fully differentiated epithelial cells are transformed into a mesenchymal phenotype, with the loss of epithelial markers, acquisition of mesenchymal property, reassembly of cytoskeleton with enhanced migratory
To further confirm the role of Krüpple-like-factor 4 (KLF4) in EMT of alveolar epithelial cells, we examined the effect of KLF4 on TGF-β1-induced EMT in AECs and A549 cells (Supplemental Figures)
We describe the novel finding that the expression of KLF4 was decreased in human idiopathic pulmonary fibrosis (IPF) lung tissues and mouse models of bleomycin-induced pulmonary fibrosis, when compared to the corresponding controls

Summary

Introduction

EMT is a process in which fully differentiated epithelial cells are transformed into a mesenchymal phenotype, with the loss of epithelial markers, acquisition of mesenchymal property, reassembly of cytoskeleton with enhanced migratory. Approximately one third of fibroblasts are of epithelial origin in bleomycin-induced pulmonary fibrosis[12]. A recent study demonstrated that KLF4 was down-regulated in TGF-β-induced EMT in human renal proximal tubule epithelial cells (HK-2 cells) and in mice www.nature.com/scientificreports/. The expression and function of KLF4 in pulmonary fibrosis and EMT of human lung alveolar epithelial cells (AECs) remains unclear. We demonstrated that the expression of KLF4 was decreased in lung tissues of human IPF and mouse models of bleomycin-induced pulmonary fibrosis. Overexpressing of KLF4 inhibited bleomycin-induced pulmonary fibrosis and EMT in vivo and attenuate TGF-β1-induced EMT in AECs in vitro. These results provide novel evidence that KLF4 represents a potential therapeutic target in IPF. Some of the results of this study have been previously reported in the form of an abstract[26]

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