Endoplasmic reticulum stress in alveolar epithelial cells is prominent in IPF: association with altered surfactant protein processing and herpesvirus infection

Abstract

Recent evidence suggests that dysfunctional type II alveolar epithelial cells (AECs) contribute to the pathogenesis of idiopathic pulmonary fibrosis (IPF). Based on the hypothesis that disease-causing mutations in surfactant protein C ( SFTPC) provide an important paradigm for studying IPF, we investigated a potential mechanism of AEC dysfunction suggested to result from mutant SFTPC expression: induction of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). We evaluated biopsies from 23 IPF patients (including 3 family members with L188Q SFTPC mutations, 10 individuals with familial interstitial pneumonia without SFTPC mutations, and 10 individuals with sporadic IPF) and sections from 10 control lungs. After demonstrating UPR activation in cultured A549 cells expressing mutant SFTPC, we identified prominent expression of UPR markers in AECs in the lungs of patients with SFTPC mutation-associated fibrosis. In individuals with familial interstitial pneumonia without SFTPC mutations and patients with sporadic IPF, we also found UPR activation selectively in AECs lining areas of fibrotic remodeling. Because herpesviruses are found frequently in IPF lungs and can induce ER stress, we investigated expression of viral proteins in lung biopsies. Herpesvirus protein expression was found in AECs from 15/23 IPF patients and colocalized with UPR markers in AECs from these patients. ER stress and UPR activation are found in the alveolar epithelium in patients with IPF and could contribute to disease progression. Activation of these pathways may result from altered surfactant protein processing or chronic herpesvirus infection.

Oxidative and endoplasmic reticulum stress in respiratory disease

“…Evidence for ER stress in human respiratory epithelial cells, particularly in type II pneumocytes, includes high expression of CHOP,71 activation of ATF6, XBP1 and ATF4 14. Activation of the UPR has been found in both inherited and sporadic IPF and associated with viral infection 13. Additionally, fibroblasts from the lungs of IPF patients show increased ER stress in response to TGFβ 72.…”

“…Additionally, fibroblasts from the lungs of IPF patients show increased ER stress in response to TGFβ 72. IPF‐linked mutations in SFTPC and SFTPA2 cause misfolding of the encoded surfactant proteins and ER stress in type II pneumocytes, providing a direct mechanistic driver for the ER stress in these forms of IPF 13, 73. Interestingly, there is substantial evidence for the importance of environmental triggers, and mice transgenic for the Δexon‐4 SFTPC mutation develop spontaneous lung disease,74 whereas those expressing L188Q SFTPC mutations only develop disease when exposed to low dose bleomycin 75.…”

“…Prolonged ER stress can eventually lead to inflammatory signalling and premature apoptosis through several different mechanisms 6. The UPR has been linked to the pathogenesis of diabetes, inflammatory bowel disease, Alzheimer's disease, Parkinson's disease and many respiratory conditions including cystic fibrosis (CF),7, 8, 9, 10 chronic obstructive pulmonary disease (COPD),11 asthma,12 idiopathic pulmonary fibrosis (IPF)13, 14 and infection 15, 16, 17…”

Endoplasmic reticulum stress in lung disease

“…When expressed in cultured cells, some of these mutant proteins trigger the UPR. Prompted by this, ER stress was sought in lung tissue from patients with pulmonary fibrosis [58,59]. UPR activation was detected in the AECII of individuals with the L188Q SFTPC mutation and also in the alveolar epithelium of patients with sporadic idiopathic pulmonary fibrosis.…”

Gene Expression Profiling of Pulmonary Fibrosis Identifies Twist1 as an Antiapoptotic Molecular “Rectifier” of Growth Factor Signaling

“…Various apoptotic stimuli are present in IPF lungs, including oxidants, 2 endoplasmic reticulum (ER) stress, 26,27 Fas ligand, and TNF-␣. 28,29 Remarkably, fibroblasts in IPF lungs exhibit few signs of apoptosis.…”