Heme Oxygenase-1 Reduces Sepsis-Induced Endoplasmic Reticulum Stress and Acute Lung Injury.

Xiaozhen Chen,Hongfei Chen,Hua Wei,Yinglin Wang,Qiqi Zhu,Jingshong Deng,Qingquan Lian,Zhengyuan Xia,Zhidong Ge,Xiang Xie

doi:10.1155/2018/9413876

Abstract

Background Sepsis leads to severe acute lung injury/acute respiratory distress syndrome (ALI/ARDS) that is associated with enhanced endoplasmic reticulum (ER) stress. Heme oxygenase-1 (HO-1), an ER-anchored protein, exerts antioxidant and protective functions under ALI. However, the role of HO-1 activation in the development of endoplasmic reticulum (ER) stress during sepsis remains unknown. Methods Cecal ligation and puncture (CLP) model was created to induce septic ALI. Lung tissue ER stress was measured 18 hours after CLP. The effects of HO-1 on ER stress during septic ALI were investigated in vivo using HO-1 agonist hemin and antagonist ZnPP. Results Compared with the sham group, ER stress in septic lung increased significantly 18 hours after CLP, which was significantly reduced by pretreatment with the ER inhibitor 4-phenylbutyrate (4-PBA). The lung injury score and the lung wet to dry (W/D) ratio in lungs were significantly reduced in septic rats after ER stress inhibition. Similarly, lung ER stress-related genes' (PERK, eIF2-α, ATF4, and CHOP) levels were attenuated after ER stress inhibition. Furthermore, HO-1 activation by hemin reduced p-PERK, p-eIF2-α, ATF4, and CHOP protein expression and oxidative stress and lung cell apoptosis. Additionally, HO-1 antagonist could aggregate the ER stress-related ALI. Conclusions ER stress was activated during CLP-induced ALI, which may represent a mechanism by which CLP induces ALI. HO-1 activation could inhibit CLP-induced lung ER stress and attenuate CLP-induced ALI.

Highlights

Sepsis and septic shock, caused by microorganisms such as bacteria, viruses, or parasites, are severe systemic inflammatory response syndromes in critically ill patients with severe trauma, burns, hemorrhage, and so on in the intensive care units (ICUs) [1,2,3]
There is convincing evidence indicating the role of endoplasmic reticulum (ER) stress in sepsis-associated acute lung injury (ALI) pathophysiology [16, 34, 35]
We discovered a previously unreported relationship between Heme oxygenase-1 (HO-1) and ER stress in the pathogenesis of ALI

Summary

Introduction

Sepsis and septic shock, caused by microorganisms such as bacteria, viruses, or parasites, are severe systemic inflammatory response syndromes in critically ill patients with severe trauma, burns, hemorrhage, and so on in the intensive care units (ICUs) [1,2,3]. Among the varieties of complications and MODS induced by sepsis, acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are frequent due to pulmonary susceptibility [10], which associated with an increased risk of in-hospital mortality in ICUs [11]. Researches regarding the pathogenesis process of ALI have been concentrated on uncontrolled inflammation activation, alveolar epithelial cell apoptosis, excessive oxidative stress, coagulation dysfunction, and so on [12, 13]. Sepsis leads to severe acute lung injury/acute respiratory distress syndrome (ALI/ARDS) that is associated with enhanced endoplasmic reticulum (ER) stress. HO-1 activation by hemin reduced p-PERK, p-eIF2-α, ATF4, and CHOP protein expression and oxidative stress and lung cell apoptosis. HO-1 activation could inhibit CLP-induced lung ER stress and attenuate CLP-induced ALI

Methods

Results

Conclusion