Remifentanil Promotes PDIA3 Expression by Activating p38MAPK to Inhibit Intestinal Ischemia/Reperfusion-Induced Oxidative and Endoplasmic Reticulum Stress.

Wenqi Huang,Kunhe Li,Qiulan He,Shihong Wen,Qiwen Deng,Jiantong Shen,Yaqing Zhan

doi:10.3389/fcell.2022.818513

Abstract

Background: Remifentanil protects against intestinal ischemia/reperfusion (I/R) injury; however, its exact mechanism remains to be elucidated. The objective of this study was to investigate the underlying molecular mechanism of remifentanil in intestinal I/R injury in mice. Methods: We evaluated the intestine-protective effect of remifentanil in adult male mice with 45 min superior mesenteric artery occlusion followed by 4 h reperfusion by determining the following: intestinal Chiu’s scores, diamine oxidase, and intestinal fatty acid binding protein in serum; the apoptotic index, lipid peroxidation product malondialdehyde (MDA), and superoxide dismutase (SOD) activity in the intestinal mucosa; and the intestinal mRNA and protein expressions of Bip, CHOP, caspase-12, and cleaved caspase-3, reflecting endoplasmic reticulum (ER) stress. Furthermore, conditional knockout mice, in which the protein disulfide isomerase A3 (PDIA3) gene was deleted from the intestinal epithelium, and SB203580 (a selective p38MAPK inhibitor) were used to determine the role of PDIA3 and p38MAPK in I/R progression and intestinal protection by remifentanil. Results: Our data showed that intestinal I/R induced obvious oxidative stress and endoplasmic reticulum stress–related cell apoptosis, as evidenced by an increase in the intestinal mucosal malondialdehyde, a decrease in the intestinal mucosal SOD, and an increase in the apoptotic index and the mRNA and protein expression of Bip, CHOP, caspase-12, and cleaved caspase-3. Remifentanil significantly improved these changes. Moreover, the deletion of intestinal epithelium PDIA3 blocked the protective effects of remifentanil. SB203580 also abolished the intestinal protection of remifentanil and downregulated the mRNA and protein expression of PDIA3. Conclusion: Remifentanil appears to act via p38MAPK to protect the small intestine from intestinal I/R injury by its PDIA3-mediated antioxidant and anti-ER stress properties.

Highlights

Intestinal ischemia/reperfusion (I/R) injury, a serious clinical event accompanied by high morbidity and mortality, is one of the main causes of multiple organ failure in the perioperative period (Mallick et al, 2004)
We evaluated the intestine-protective effect of remifentanil in adult male mice with 45 min superior mesenteric artery occlusion followed by 4 h reperfusion by determining the following: intestinal Chiu’s scores, diamine oxidase, and intestinal fatty acid binding protein in serum; the apoptotic index, lipid peroxidation product malondialdehyde (MDA), and superoxide dismutase (SOD) activity in the intestinal mucosa; and the intestinal mRNA and protein expressions of Bip, CHOP, caspase-12, and cleaved caspase-3, reflecting endoplasmic reticulum (ER) stress
The deletion of intestinal epithelium protein disulfide isomerase A3 (PDIA3) blocked the protective effects of remifentanil

Summary

Introduction

Intestinal ischemia/reperfusion (I/R) injury, a serious clinical event accompanied by high morbidity and mortality, is one of the main causes of multiple organ failure in the perioperative period (Mallick et al, 2004). We (Shen et al, 2016) and others (Cho et al, 2013; Sayan-Ozacmak et al, 2015) have previously demonstrated that remifentanil may protect the intestine against intestinal I/R injury. The exact protective mechanisms of remifentanil need to be explored further. PDIA3 is a classic member of the protein disulfide isomerase family and mainly exists in the endoplasmic reticulum (ER) (Frickel et al, 2004). Prior research (Yoo et al, 2017) has demonstrated that PDIA3 protein levels are significantly altered during transient spinal cord ischemia, which further was identified as a candidate therapeutic agent against spinal cord ischemic damage. Remifentanil protects against intestinal ischemia/reperfusion (I/R) injury; its exact mechanism remains to be elucidated. The objective of this study was to investigate the underlying molecular mechanism of remifentanil in intestinal I/R injury in mice

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Results

Discussion

Conclusion