BML-111通过抑制p38 MAPK／NF-κB通路减轻大鼠肠缺血再灌注早期急性肺损伤

摘要

Objective This study aims to investigate the effect of Lipoxin A4 receptor on acute lung injury (ALI) induced by intestine ischemia-reperfusion (IIR). Methods Thirty-two 8-week old SD rats were randomly divided into four groups: sham, intestine ischemia-reperfusion (IIR), IIR + BML111 (BML-111), Boc-2 + IIR +BML111 (Boc-2). BML-111 (1 mg/kg) was given intraperitoneally at the onset of reperfusion in the BML-111 and the Boc-2 group. Boc-2 (50 μg/kg) was given intraperitoneally after anesthesia in the Boc-2 group. Rats were subjected to superior mesenteric artery occlusion consisting of 45-min ischemia and 6-h reperfusion, and the sham laparotomy was served as controls. The lung pathology was assayed by the H&E staining. Lung water content was detected using dry/wet ratio. Concentrations of TNF-α, IL-1β, and IL-6 in lung tissue were determined by ELISA. The protein expression of p38 MAPK and NF-κB of lung was assayed by western blot. Results IIR induced serious ALI, with poor lung pathology and increased lung water content, elevation of TNF-α, IL-1β, and IL-6 levels in lung, accompanied with activation of p38 MAPK/NF-κB pathway. However, BML-111 could inhibit the activation of p38 MAPK/NF-κB pathway, leading to the reductions of TNF-α, IL-1β, and IL-6 in lung and attenuation of IIR-induced ALI. Conclusion BML-111 treatment could attenuate inflammation in lung after IIR injury via inactivating the p38 MAPK/NF-κB signaling pathway.%目的：探讨脂氧素受体激动剂 BML-111在肠缺血再灌注早期急性肺损伤中的作用及其机制。方法：32只8周龄健康雄性 SD 大鼠随机分为假手术组、缺血再灌注组、缺血再灌注＋BML-111处理组（BML-111组）和缺血再灌注＋ Boc-2＋ BML-111处理组（Boc-2组），BML-111组和 Boc-2组在再灌注开始时通过腹腔注射给予 BML-111（1mg／kg），Boc-2组在麻醉后通过腹腔注射给予 Boc-2（50μg／kg），另两组注入等量生理盐水。采用夹闭SD 大鼠肠系膜上动脉45 min 后再灌注6 h 的方法造成肠缺血再灌注损伤模型。处死大鼠取肺标本， HE 染色观察肺组织病理学改变，检测肺组织含水率；ELISA 检测肺组织 TNF-α、IL-1β和IL-6水平；蛋白质印迹法检测肺组织磷酸化p38 MAPK和NF-κB 蛋白表达水平。结果：肠缺血再灌注导致明显肺损伤，肺含水率增加，TNF-α、IL-1β和 IL-6含量明显升高，p38 MAPK／NF-κB 通路活化；BML-111可抑制肺组织 p38 MAPK／NF-κB 活化，减轻小肠缺血再灌注引起的肺损伤，并下调肺组织TNF-α、IL-1β和IL-6含量，当应用Boc-2处理后，BML-111的肺保护作用被取消。结论：BML-111通过抑制p38 MAPK／NF-κB通路活化促进肠缺血再灌注早期肺损伤炎症消退。