MitoQ Modulates Lipopolysaccharide-Induced Intestinal Barrier Dysfunction via Regulating Nrf2 Signaling.

Shengfeng Zhang,Youcheng Li,Yunli Zhang,Qingniao Zhou,Yinmei Wu

doi:10.1155/2020/3276148

Abstract

Background Gut barrier dysfunction with alterant mucosal permeability during sepsis is a challenge problem in clinical practice. Intestinal epithelial cells (IECs) are strongly involved in mucosal oxidative stress and inflammatory response. The current study aimed at investigating the effect of MitoQ, a mitochondrial targeted antioxidant, in the treatment of intestinal injury and its potential mechanism during sepsis. Methods 30 minutes before sepsis induction by lipopolysaccharide (LPS) treatment, mice were treated with MitoQ. Intestinal histopathology, mucosal permeability, inflammatory cytokines, and mucosal barrier proteins were evaluated in the present study. Results MitoQ pretreatment significantly decreased the levels of plasma diamine oxidase, D-lactate, and intestinal histological damage and markedly restored the levels of tight junction proteins (ZO-1 and occludin) following LPS challenge. Furthermore, MitoQ inhibited the LPS-induced intestinal oxidative stress and inflammatory response, evidenced by increased levels of intestinal superoxide dismutase and glutathione, and decreased levels of intestinal IL-1, IL-6, TNF-α, and nitric oxide levels. Mechanically, we found that MitoQ inhibited the oxidative stress via activating nuclear factor E2-related factor 2 (Nrf2) signaling pathway and its downstream antioxidant genes, including HO-1, NQO-1, and GCLM. Conclusions MitoQ exerts antioxidative and anti-inflammatory effects against sepsis-associated gut barrier injury by promoting Nrf2 signaling pathway.

Highlights

Sepsis is a challenge problem that usually induces multiple organ injuries and is the major cause of death in the critical care units [1]
LPS stimulation induced a significant increase in plasma D-lac, diamine oxidase (DAO), and lactic dehydrogenase (LDH), while MitoQ pretreatment reduced the up-regulation of these tissue injury biomarkers following LPS injection (Figure 1(b))
Increased gut permeability was directly associated with bacterial translocation, systemic inflammatory response, and multiple organ failure (MOF) [16]

Summary

Introduction

Sepsis is a challenge problem that usually induces multiple organ injuries and is the major cause of death in the critical care units [1]. Increased evidence indicated that mitochondrial oxidative injury could disrupt mitochondrial integrity and inhibit the production of mitochondrial ATP, which play a critical role in inducing cell death and MOF during sepsis [4]. Increased oxidative stress could activate various signaling pathways, and Mediators of Inflammation excessive reactive oxygen species (ROS) can induce the death of intestinal epithelial cells, amplify inflammation, and damage gut barrier during the progress of sepsis [6]. The current study aimed at investigating the effect of MitoQ, a mitochondrial targeted antioxidant, in the treatment of intestinal injury and its potential mechanism during sepsis. MitoQ inhibited the LPS-induced intestinal oxidative stress and inflammatory response, evidenced by increased levels of intestinal superoxide dismutase and glutathione, and decreased levels of intestinal IL-1, IL-6, TNF-α, and nitric oxide levels. MitoQ exerts antioxidative and anti-inflammatory effects against sepsis-associated gut barrier injury by promoting Nrf signaling pathway

Methods

Results

Conclusion