Down-regulation of toll-like receptor 4 alleviates intestinal ischemia reperfusion injury and acute lung injury in mice.

Qiankun Zhu,Tai Guo,Wei Chen,Jie Wang,Yukang Wang,Guizhen He

doi:10.18632/oncotarget.14624

Abstract

Intestinal ischemia reperfusion (IR) injury is a critical problem, which can cause intestinal injury locally and acute lung injury (ALI) distally by inflammatory responses and oxidative stress. Toll-like receptor 4 (TLR4) is involved in innate immune and inflammatory responses. This study was to determine whether TLR4 mutant can attenuate intestinal and lung injuries after intestinal IR. Wild type (WT) and TLR4 mutant mice were submitted to intestinal IR by occluding the superior mesenteric artery. Histological assessment of the intestine and the lung were conducted by HE staining. The levels of proinflammatory cytokines, oxidative stress markers, apoptotic index and other mediators were measured. In addition, a 24-hour survival study was performed. Histological assessment showed that intestinal IR caused serious injuries in the intestine and the lung, corroborated by increased proinflammatory cytokines in the circulation. TLR4 mutant suppressed the histological injuries as demonstrated by significantly decreased pathological scores. Consistent with the morphological results, the TLR4 mutant mice exhibited remarkably lowered cytokine expressions in the intestine (TNF-α, IL-6, IL-1β, and NF-κB) and the lung (NO, iNOS, MCP-1, MIP-2, NF-κB, and Caspase-3). ALT and creatinine were also significantly dampened in the liver and kidney, respectively. Furthermore, the survival rate over the course of 24 hours was significantly improved. Collectively, the findings reveal that TLR4 mutant significantly abated the intestinal IR injury and ALI at least in part by alleviating the inflammatory response and oxidative stress.

Highlights

Intestinal ischemia reperfusion (IR) injury occurs in a various clinical circumstances including mesenteric artery occlusion, small bowel transplantation, vascular surgery procedures, and trauma [1]
These results were reflected in increased pathological scores in the IR group of Wild type (WT) mice, where scores were significantly increased compared with WT sham group (Figure 1)
Pathological score of the intestine by hematoxylin and eosin (HE) staining in the Toll-like receptor 4 (TLR4) mutant mice after IR indicated that there was a significant decrement of histological injury score in comparison with the WT IR group, suggesting the protective effect of TLR4 knock-down in the intestinal IR injury (Figure 1)

Summary

Introduction

Intestinal ischemia reperfusion (IR) injury occurs in a various clinical circumstances including mesenteric artery occlusion, small bowel transplantation, vascular surgery procedures, and trauma [1]. Intestinal IR leads to the activation of the local inflammatory responses and changes of several mediators to induce bacterial translocation out of the gastrointestinal tract [2]. These phenomena contribute substantially to the multiple organ failure and systemic inflammatory responses [3, 4], and can damage distant organs, such as lung [5], heart [6], kidney [7] and liver [8], through circulation of many inflammatory factors. Therapies aiming at reducing inflammatory response or oxidative stress are, to some extent, theoretically reasonable to ameliorate the lung damage

Methods

Results

Conclusion