Endoplasmic reticulum stress enhances fibrotic remodeling in the lungs

Abstract

Evidence of endoplasmic reticulum (ER) stress has been found in lungs of patients with familial and sporadic idiopathic pulmonary fibrosis. We tested whether ER stress causes or exacerbates lung fibrosis by ( i ) conditional expression of a mutant form of surfactant protein C (L188Q SFTPC ) found in familial interstitial pneumonia and ( ii ) intratracheal treatment with the protein misfolding agent tunicamycin. We developed transgenic mice expressing L188Q SFTPC exclusively in type II alveolar epithelium by using the Tet-On system. Expression of L188Q SFTPC induced ER stress, as determined by increased expression of heavy-chain Ig binding protein (BiP) and splicing of X-box binding protein 1 (XBP1) mRNA, but no lung fibrosis was identified in the absence of a second profibrotic stimulus. After intratracheal bleomycin, L188Q SFTPC -expressing mice developed exaggerated lung fibrosis and reduced static lung compliance compared with controls. Bleomycin-treated L188Q SFTPC mice also demonstrated increased apoptosis of alveolar epithelial cells and greater numbers of fibroblasts in the lungs. With a complementary model, intratracheal tunicamycin treatment failed to induce lung remodeling yet resulted in augmentation of bleomycin-induced fibrosis. These data support the concept that ER stress produces a dysfunctional epithelial cell phenotype that facilitates fibrotic remodeling. ER stress pathways may serve as important therapeutic targets in idiopathic pulmonary fibrosis.

Oxidative and endoplasmic reticulum stress in respiratory disease

“…ER stress develops in airway cells in this model and is exacerbated by viral infection, and the UPR has been associated with the differentiation status of macrophages, and intrinsic ER stress within macrophages also occurs 16, 71, 75, 83, 84, 85, 86…”

“…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. Cultured type II pneumocytes and transfected cells carrying the Δexon‐4 SFTPC mutation show accumulation of the SFTPC precursor protein, UPR activation and increased cell death when infected with RSV, suggesting viral infection could be a trigger for development of IPF in susceptible individuals 76…”

Endoplasmic reticulum stress in lung disease

“…Several factors linked with an increased likelihood of pulmonary fibrosis, e.g. viral infection, asbestos, amiodarone and old age, each activate the UPR in the lung, which is consistent with a potential role for ER stress in the pathogenesis of pulmonary fibrosis [10][11][12][13][14]60]. However, the link between ER stress and interstitial lung disease appears to be complex.…”

“…However, the link between ER stress and interstitial lung disease appears to be complex. When L188Q SFTPC is expressed in murine type II pneumocytes the UPR is triggered, but this fails to cause pulmonary fibrosis [10]. However, mice expressing L188Q SFTPC show exaggerated pulmonary fibrosis when challenged with bleomycin.…”

“…However, mice expressing L188Q SFTPC show exaggerated pulmonary fibrosis when challenged with bleomycin. Likewise, co-administration of bleomycin and the ER stress-inducing drug tunicamycin enhances the degree of fibrosis [10].…”