Lipoxin A4 Preconditioning Attenuates Intestinal Ischemia Reperfusion Injury through Keap1/Nrf2 Pathway in a Lipoxin A4 Receptor Independent Manner.
Lipoxin A4 Preconditioning Attenuates Intestinal Ischemia Reperfusion Injury through Keap1/Nrf2 Pathway in a Lipoxin A4 Receptor Independent Manner.
复制标题
脂氧素 A4 预处理通过 Keap1/Nrf2 通路以脂氧素 A4 受体独立的方式减轻肠缺血再灌注损伤。
DOI：
10.1155/2016/9303606
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发表时间：
2016
影响因子：
--
通讯作者：
Xia Z
中科院分区：
文献类型：
--
作者：
Han X;Yao W;Liu Z;Li H;Zhang ZJ;Hei Z;Xia Z
氧化应激在肠缺血再灌注（IIR）损伤的发病机制中起重要作用。增强内源性脂氧素A4（LXA 4），一种有效的抗氧化剂和介质，与IIR的衰减。然而，LXA 4对IIR损伤的影响及其可能的机制尚不清楚。在大鼠IIR（缺血45分钟，随后再灌注6小时）模型中，IIR引起肠损伤，表现为血清二胺氧化酶、D-乳酸、脂肪酸型脂肪酸结合蛋白和氧化应激标志物15-F2 t-异前列烷增加。LXA 4治疗通过减少粘膜15-F2 t-异前列烷和提高内源性抗氧化剂超氧化物歧化酶活性，伴随Keap 1/Nrf 2途径激活，显著减轻IIR损伤。同时，LXA 4受体拮抗剂Boc-2逆转了LXA 4对肠损伤的保护作用，但未能影响氧化应激和相关的Nrf 2通路。Nrf 2拮抗剂Brusatol可逆转LXA 4的抗氧化作用，导致肠上皮细胞氧化应激和凋亡加剧，最终导致大鼠存活率下降。同时，LXA 4预处理可上调细胞核Nrf 2水平，减轻缺氧/复氧诱导的IEC-6细胞损伤，Nrf 2 siRNA可逆转LXA 4的这种保护作用。总之，这些发现表明，LXA 4通过以LXA 4受体非依赖性方式激活Keap 1/Nrf 2通路来改善IIR损伤。
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.