Endoplasmic reticulum stress as a pro-fibrotic stimulus

Abstract

Current evidence suggests a prominent role for endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) in fibrotic conditions affecting a number of internal organs, including the lungs, liver, GI tract, kidney, and heart. ER stress enhances the susceptibility of structural cells, in most cases the epithelium, to pro-fibrotic stimuli. Studies suggest that ER stress facilitates fibrotic remodeling through activation of pro-apoptotic pathways, induction of epithelial-mesenchymal transition, and promotion of inflammatory responses. While genetic mutations that lead to ER stress underlie some cases of fibrosis, including lung fibrosis secondary to mutations in surfactant protein C (SFTPC), a variety of other factors can cause ER stress. These ER stress inducing factors include metabolic abnormalities, oxidative stress, viruses, and environmental exposures. Interestingly, the ability of the ER to maintain homeostasis under stress diminishes with age, potentially contributing to the fact that fibrotic disorders increase in incidence with aging. Taken together, underlying ER stress and UPR pathways are emerging as important determinants of fibrotic remodeling in different forms of tissue fibrosis. Further work is needed to better define the mechanisms by which ER stress facilitates progressive tissue fibrosis. In addition, it remains to be seen whether targeting ER stress and the UPR could have therapeutic benefit. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.

Figure 1

Schematic illustration of ER stress and the UPR. ATF = activating transcription factor; BiP = immunoglobulin heavy-chain-binding protein; EDEM = ER degradation enhancing α-mannosidase-like protein; eIF2α = eukaryotic initiation factor 2α; ER = endoplasmic reticulum; GADD34 = growth arrest and DNA damage protein 34; IRE = inositol-requiring enzyme 1 (IRE-1); PERK = PKR-like ER kinase; XBP1 = X-box binding protein 1; GADD34 = Growth arrest and DNA damage-inducible protein; PDI = Protein disulphide isomerase; GRP94 = Glucose-Regulated Protein 98; CHOP = C/enhancer binding protein (EBP) homologous protein; ASK1 = Apoptosis signal-regulating kinase 1; JNK = c-Jun N-terminal kinases; S1P = site-1 protease; S2P = site-2 protease; RIDD= regulated IRE1-dependent decay.

Figure 2

Schematic of proposed mechanisms by which ER stress may contribute to the development of pulmonary fibrosis.