The ER Stress/UPR Axis in Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis

Abstract

Cellular protein homeostasis in the lungs is constantly disrupted by recurrent exposure to various external and internal stressors, which may cause considerable protein secretion pressure on the endoplasmic reticulum (ER), resulting in the survival and differentiation of these cell types to meet the increased functional demands. Cells are able to induce a highly conserved adaptive mechanism, known as the unfolded protein response (UPR), to manage such stresses. UPR dysregulation and ER stress are involved in numerous human illnesses, such as metabolic syndrome, fibrotic diseases, and neurodegeneration, and cancer. Therefore, effective and specific compounds targeting the UPR pathway are being considered as potential therapies. This review focuses on the impact of both external and internal stressors on the ER in idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) and discusses the role of the UPR signaling pathway activation in the control of cellular damage and specifically highlights the potential involvement of non-coding RNAs in COPD. Summaries of pathogenic mechanisms associated with the ER stress/UPR axis contributing to IPF and COPD, and promising pharmacological intervention strategies, are also presented.

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“…In a diseased state, the cell would be under a heavy burden of oxidative stress and inflammation that damages cell organelles [84] , [85] . Indeed, oxidative stress-induced endoplasmic reticulum (ER) stress is implicated in the unfolded protein response (UPR) pathophysiology in COPD, where protein translation and synthesis are downregulated to alleviate ER stress [86] , [87] . Analyzing lung fibroblasts of COPD patients has revealed deficient and disorganized ER and Golgi apparatus, which cannot heal despite being cultured for several weeks in the absence of cigarette smoke [88] .…”

Autophagy, Unfolded Protein Response, and Neuropilin-1 Cross-Talk in SARS-CoV-2 Infection: What Can Be Learned from Other Coronaviruses

“…Under normal cell conditions, it is a passive monomer that binds to GRP78. In contrast, GRP78 dissociates and PERK becomes oligomerized and activated during stress [ 22 ]. Activated PERK has two specific functions, activating eIF2α-ATF4, which inhibits protein synthesis as well as activating CHOP protein (C/EBP homologous protein), which activates cell death receptor 5 (DR5), and growth arrest- and DNA damage-inducible gene 153 (GADD153) which leads to cell growth arrest.…”

The Role of miRNAs during Endoplasmic Reticulum Stress Induced Apoptosis in Digestive Cancer

“…The three branches are composed of protein kinase R (PKR)-like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1) and activating transcription factor 6 (ATF6), orchestrate the major regulatory circuits to ensure ER homeostasis [5]. A growing number of studies indicate that ER stress involves numerous diseases including but not limited to neurodegenerative disease [6] like Alzheimer's Ivyspring International Publisher disease [7], Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis [8], disease of immune system [2], diabetes [9], cardiovascular disease [10], as well as various cancer. Digestive cancer is one of the common malignant tumors with very poor overall survival worldwide, including esophageal cancer, gastric cancer, colorectal cancer, pancreatic cancer and liver cancer.…”