NOGO-B promotes EMT in lung fibrosis via MMP14 mediates free TGF-beta1 formation.

Ye Xiong,Yunye Ning,Qiang Li,Guo-Wu Zhou,Jingyu Chen,Lingzhi Shi,Meng Yang,Si Chen,Jing Zhang,Ying Zhu

doi:10.18632/oncotarget.20297

Abstract

Idiopathic pulmonary fibrosis (IPF) is a lung disease with an extremely poor prognosis. Epithelial mesenchymal transition (EMT) appearing on the airway epithelial cell plays an essential role in the formation and development of Idiopathic pulmonary fibrosis. In this paper, Bleomycin (BLM)-induced mice model combined with bioinformatics analysis were employed to elucidate the potential mechanism of EMT in pulmonary fibrosis. The obtained results showed that endoplasmic reticulum protein Nogo-b may promote MMP14-mediated proprotein maturation of TGF-β1, accelerating the release of free TGF-β1 in type II airway epithelial cells A549, subsquently, induce the epithelial-mesenchymal transition (EMT) of the cell. In all, the overexpression of Nogo-b play a role in the course of pulmonary fibrosis by influencing the EMT ability of cells.

Highlights

Losing control of wound healing process in response to tissue injury may lead to tissue overgrowth, fibrosis, and organ failure, one of the adverse consequences of fibrotic diseases is that it can affect many organs, especially for lungs [1,2]
In order to determine whether protein expressions were associated with pulmonary fibrosis, Immunohistochemistry (IHC) was applied to examine the difference in the expression level of reticulon 4-b (Nogo-b) in lung samples of mice between the group treated with BLM and the untreated control, It was found that the lung mesenchyme in the mice treated with BLM showed a stronger brown staining for Nogo-b (Figure 1D) than that for the normal group (Figure 1C), indicating that high expression of Nogo-b is one of the features for the fibroblastic foci induced by BLM
Our study demonstrated that Matrix metalloproteinase 14 (MMP14) played a critical role in Epithelial mesenchymal transition (EMT) of pulmonary fibrosis, and the expression level of MMP14 determined the progress of EMT

Summary

Introduction

Losing control of wound healing process in response to tissue injury may lead to tissue overgrowth, fibrosis, and organ failure, one of the adverse consequences of fibrotic diseases is that it can affect many organs, especially for lungs [1,2]. Normal pulmonary fibrosis is pathologically featured with aberrant activation of epithelial mesenchymal transition (EMT) of airway epithelial cell accompanied by inflammation, fibroblast proliferation, and excessive collagen deposition [3,4,5,6,7,8,9]. EMT, as a leading factor for the pathogenesis of normal lung parenchyma replacement, is characterized by loss of epithelial characteristics (E-cadherin) and has acquired mesenchymal phenotype including N-cadherin, vimentin and smooth muscle actin (α-SMA) [10]. TGF-β1 induced disturbances of the homeostatic microenvironment resulted in Idiopathic pulmonary fibrosis (IPF) [12]. IPF suffers benefited few from these drugs. so it is urgent to develop new approaches to overcome this problem

Methods

Results

Conclusion