Endoplasmic Reticulum Stress And Its Role In The Pathogenesis Of Idiopathic Pulmonary Brosis

Background Idiopathic pulmonary fibrosis (IPF) is a progressive and devastating chronic lung condition with poor prognosis, IPF is characterized by a progressive distortion of the alveolar architecture and replacement by fibrotic tissue, resulting in progressive dyspnea, decline in lung function, the mean length of survival from the time of diagnosis ranges from2.8to4.2years. IPF accounts for approximately20to30%of all interstitial lung diseases and probably affects500,000patients in the United States and the European Community (EC).No effective pharmacologic treatment exists, with lung transplantation being the only option for affected patients.While the factors that regulate the onset and progression of IPF are incompletely understood, Chronic inflammation has long been postulated to underlie this disease, but steroids and immunosuppressants are of limited or no help. An alternative theory of IPF, based on chronic epithelial injury and subsequent aberrant alveolar repair, has gained increasing attention. This hypothesis is supported by ultrastructural studies in which alveolar epithelial cell death was observed at an early stage of the disease.Increased apoptosis of type II alveolar epithelial cells (AEC lls)was observed primarily in the hyperplastic epithelium covering the fibroblast foci but also in regions of the lung with almost normal-appearing alveolar structures. Consistent with these results, blockade of apoptosis pathways was found to attenuate the extent of fibrosis in the bleomycin model of lung fibrosis. Endoplasmic reticulum stress is caused by conditions that perturb the processing and folding of proteins, resulting in the accumulation of misfolded proteins in the ER and activation of the unfolded protein response. Several diseases have been linked to misfolded proteins, recent investigations have revealed that endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) are prominent in alveolar epithelial cells in this disease, suggesting a role for ER stress in idiopathic pulmonary fibrosis.The ERS pathways are governed by three ER transmembrane proteins:PKR-like endoplasmic reticulum kinase (PERK), activating transcription factor6(ATF6) and inositol-requiring enzyme1(IRE1).This research is to analyze the activation of endoplasmic reticulum stress and its role in the pathogenesis of idiopathic pulmonary fibrosis.Objective To investigate the activation of endoplasmic reticulum stress and its role in the pathogenesis of idiopathic pulmonary fibrosis.Methods1. To investigate the activation of endoplasmic reticulum stress, Lung tissues from patients with sporadic IPF and lung fibrosis of mice after treatment with bleomycin were used for detecting expression of Grp78and CHOP by immunohistochemical staining.2. Tunicamycin.an inhibitor of glycosylation of proteins,can induce endoplasmic reticulum stress.we analyzed A549cell treated with Tunicamycin for expression of Grp78and CHOP by means of Western blot to investigate the activation of endoplasmic reticulum stress and cellular apoptosis.Results1. Of10lung tissues from patients with sporadic IPF, Positive staining of Grp78and CHOP were shown in all of them; Of16lung tissues from normal control group, Positive staining of Grp78and CHOP were shown in12.5%and18.8%of lung tissues, respectively.2. Of4lung tissues from lung fibrosis of mice after treatment with bleomycin, Positive staining of Grp78and CHOP were shown in all of them; Of4lung tissues from normal control group, none of them show positive staining of Grp78and CHOP.3. Endoplasmic reticulum stress was detected by the induction of Grp78and CHOP, and the ER stress response switched from UPR to a pro-apoptotic response as demonstrated by the upregulation of CHOP. Tunicamycin can induce the activation of ERS and initiate the apoptosis of A549cell, they are increased in a concentration-dependent manner and time-dependent manner. 4.Conclusions ERS can induce the apoptosis of alveolar epithelial cells,and it is prominent that regulate the onset and progression of IPF.