Lipoxin A4 Preconditioning Attenuates Intestinal Ischemia Reperfusion Injury through Keap1/Nrf2 Pathway in a Lipoxin A4 Receptor Independent Manner

Xue Han,Haobo Li,Zipeng Liu,Weifeng Yao,Zhong-Jun Zhang,Zhengyuan Xia,Ziqing Hei

doi:10.1155/2016/9303606

Abstract

Oxidative stress plays a critical role in the pathogenesis of intestinal ischemia reperfusion (IIR) injury. Enhancement in endogenous Lipoxin A4 (LXA4), a potent antioxidant and mediator, is associated with attenuation of IIR. However, the effects of LXA4 on IIR injury and the potential mechanisms are unknown. In a rat IIR (ischemia 45 minutes and subsequent reperfusion 6 hours) model, IIR caused intestinal injury, evidenced by increased serum diamine oxidase, D-lactic acid, intestinal-type fatty acid-binding protein, and the oxidative stress marker 15-F2t-Isoprostane. LXA4 treatment significantly attenuated IIR injury by reducing mucosal 15-F2t-Isoprostane and elevating endogenous antioxidant superoxide dismutase activity, accompanied with Keap1/Nrf2 pathway activation. Meanwhile, LXA4 receptor antagonist Boc-2 reversed the protective effects of LXA4 on intestinal injury but failed to affect the oxidative stress and the related Nrf2 pathway. Furthermore, Nrf2 antagonist brusatol reversed the antioxidant effects conferred by LXA4 and led to exacerbation of intestinal epithelium cells oxidative stress and apoptosis, finally resulting in a decrease of survival rate of rat. Meanwhile, LXA4 pretreatment upregulated nuclear Nrf2 level and reduced hypoxia/reoxygenation-induced IEC-6 cell damage and Nrf2 siRNA reversed this protective effect of LXA4 in vitro. In conclusion, these findings suggest that LXA4 ameliorates IIR injury by activating Keap1/Nrf2 pathway in a LXA4 receptor independent manner.

Highlights

Intestinal ischemia reperfusion (IIR), a critical condition usually caused by many clinical scenarios such as shock, acute mesenteric ischemia, sepsis, mesenteric thrombosis, or bowel transplantation [1], is closely related to high morbidity and mortality [2]
These results indicated that Lipoxin A4 preconditioning conferred protective effects against IIR injury, which involved the activation of ALXR
After blocking the ALXR by Boc-2, no change was exhibited in Kelch-like ECH associating protein 1 (Keap1)/NF-E2-related factor-2 (Nrf2) pathway and the associated 15-F2t-Isoprostane and superoxide dismutase (SOD) activity (p > 0.05 versus IIR+LXA4). These results suggested that the protective effects conferred by Lipoxin A4 preconditioning were associated with Keap1/Nrf2 pathway activation, which could be activated independent of ALXR

Summary

Introduction

Intestinal ischemia reperfusion (IIR), a critical condition usually caused by many clinical scenarios such as shock, acute mesenteric ischemia, sepsis, mesenteric thrombosis, or bowel transplantation [1], is closely related to high morbidity and mortality [2]. Interruption of blood supply to intestine could result in tissue damage. Far greater amounts of oxidants are produced after restoration of blood supply to the ischemic tissues. This causes damage to the intestinal mucosa and impairment of the local microvasculature, leading to high permeability of vascular and mucosa breakdown and subsequent systemic sepsis and multiple organ failure [5], which contributes to a high mortality in the critical care setting.

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Results

Conclusion