Endoplasmic Reticulum Stress Induces HRD1 to Protect Alveolar Type II Epithelial Cells from Apoptosis Induced by Cigarette Smoke Extract

Abstract

Background/Aims: Cigarette smoking is a major risk factor of chronic obstructive pulmonary disease. This study aimed to examine the effects of cigarette smoke extract (CSE) on alveolar type II epithelial cells (AECII) and investigate the underlying mechanism. Methods: Primary AECII were isolated from rat lung tissues and exposed to CSE. Apoptosis was detected by flow cytometry. Protein expression was detected by Western blot analysis. Results: Primary rat AECII maintained morphological and physiological characteristic after 3 passages. CSE increased the expression of ER specific pro-apoptosis factors CHOP and caspase 12, and the phosphorylation of JNK in AECII. CSE activated ER stress signaling and increased the phosphorylation of PERK, eIF2α and IRE1. Furthermore, CSE induced the expression of Hrd1, a key factor of ER-associated degradation, in AECII. Knockdown of Hrd1 led to more than 2 fold increase of apoptosis, while overexpression of Hrd1 attenuated CSE induced apoptosis of AECII. Conclusions: Our results suggest that ER stress induces HRD1 to protect alveolar type II epithelial cells from apoptosis induced by CSE.

Cigarette smoke extract alters genome‐wide profiles of circular RNAs and mRNAs in primary human small airway epithelial cells

“…In the top GO processes of increased mRNAs, autophagy identified in BP was reported to promote lung epithelial cell death, airway dysfunction in the experimental models of COPD exposed to cigarette smoke in vivo and in vitro . In addition, as a part of endoplasmic reticulum stress, IRE1‐mediated unfolded protein response was suggested involved in CSE‐induced apoptosis in alveolar type II epithelial cells . In the GO processes of decreased mRNAs, regulation of signal transduction by p53 class mediator process and extracellular matrix organisation process were identified in BP whereas histone serine kinase activity and RAGE receptor binding were found in MF, which is corresponding to the previous studies .…”

“…27 In addition, as a part of endoplasmic reticulum stress, IRE1-mediated unfolded protein response was suggested involved in CSE-induced apoptosis in alveolar type II epithelial cells. 28 In the GO processes of decreased mRNAs, regulation of signal transduction by p53…”

Pulmonary Exposure to Particulate Matter (PM2.5) Affects the Sensitivity to Myocardial Ischemia/Reperfusion Injury Through Farnesoid-X-Receptor-Induced Autophagy

“…Some literatures showed that autophagy could augment cell apoptosis, and autophagy inhibition could reduce apoptosis [63, 64]. Most studies have shown that PM 2.5 exposure can induce autophagy, which leads to endothelial apoptosis and dysfunction [19-21, 65]. In the process of autophagy, the expression of protein 1 light chain 3I (LC3I) and protein 1 light chain 3II (LC3II) is increased, and these changes reflect the extent of the autophagy [66].…”

The integrated stress response in pulmonary disease

“…It has long been known that primary bronchial epithelial cells exposed to cigarette smoke display a transient PERK-dependent phosphorylation of eIF2α followed by induction of ATF4 and PPP1R15A [134]. Indeed, PERK-dependent eIF2α phosphorylation is a consistent feature of cells exposed to cigarette smoke or smoke extract and at least some of the cytotoxicity is mediated by ER stress-induced cell death [135,145]. For example, the aldehyde acrolein found in smoke induces ER stress-mediated cell death in A549 cells through multiple pathways including perturbed ER calcium homeostasis [146].…”