乌司他丁对粘连性肠梗阻大鼠的作用机制研究

Mechanism of Ulinastatin in Treatment of Rats with Adhesive Intestinal Obstruction

目的研究乌司他丁对粘连性肠梗阻大鼠的作用机制。方法将60只SPF级Wistar大鼠随机分为对照组、模型组、乌司他丁组、抑制剂组,每组15只。粘连性肠梗阻大鼠模型制备成功后,乌司他丁组腹腔注射乌司他丁;抑制剂组大鼠术前给予丝裂原活化蛋白激酶2(MK2)抑制剂,成模后24 h给予乌司他丁;对照组及模型组大鼠接受腹腔注射等量的生理盐水,4组均连续干预7 d。比较各组大鼠一般情况、回盲部病理形态学变化及炎性浸润情况。比较各组大鼠白细胞介素-6(IL-6)、白细胞介素-1β(IL-1β)、肿瘤坏死因子-α(TNF-α)、单核细胞趋化蛋白-1(MCP-1)、巨噬细胞炎性蛋白-1α(MIP-1α)、细胞间黏附分子-1(ICAM-1)及MK2、p-MK2蛋白表达水平。结果乌司他丁组和抑制剂组可明显增加粘连性肠梗阻模型大鼠的体质量、进食量、舔毛次数、排便量,且抑制剂组较乌司他丁组变化更显著(P<0.05)。乌司他丁组和抑制剂组可改善粘连性肠梗阻模型大鼠回盲部病理形态学改变,减少炎性浸润,且抑制剂组改善效果更显著。与对照组比较,模型组大鼠外周血IL-6、IL-1β、TNF-α、MCP-1、MIP-1α、ICAM-1及p-MK2蛋白表达水平显著升高,MK2蛋白表达水平降低(P<0.05);与模型组比较,乌司他丁组及抑制剂组大鼠外周血IL-6、IL-1β、TNF-α、MCP-1、MIP-1α、ICAM-1及p-MK2蛋白表达水平明显下降,MK2蛋白表达水平明显升高,且抑制剂组上述指标较乌司他丁组变化更显著(P<0.05)。结论乌司他丁可明显改善粘连性肠梗阻,其作用机制可能与抑制p38-MK2信号通路有关。

Objective To study the mechanism of Ulinastatin in treatment of rats with adhesive intestinal obstruction(AIO).Methods A total of 60 SPF Wistar rats were randomly divided into control group(n=15),model group(n=15),Ulinastatin group(n=15)and inhibitor group(n=15).After successful preparation of the AIO rat models,Ulinastatin group was injected with Ulinastatin intraperitoneally,while Inhibitor group was given mitogen activated protein kinase 2(MK2)inhibitors before surgery,followed by Ulinastatin was given after modeling for 24 h.Control and model groups received intraperitoneal injection of the same volumes of normal saline.The four groups were treated for 7 d consecutively.General condition,pathomorphological changes of ileocecum,conditions of inflammatory infiltration and levels of interleukin-6(IL-6),interleukin-1β(IL-1β),tumor necrosis factor-α(TNF-α),monocyte chemoattractant protein-1(MCP-1),macrophage inflammatory protein-1α(MIP-1α),intercellular adhesion molecule-1(ICAM-1),MK2 and p-MK2 proteins were compared among groups.Results In Ulinastatin and inhibitor groups,the body weight,food intake,times of hair licking,and defecation volume in AIO rat models were significantly increased,and the changes in inhibitor group were more significant than those in Ulinastatin group(P<0.05).Pathomorphological changes of the ileocecum were improved,and conditions of inflammatory infiltration were reduced in AIO rat models in Ulinastatin and inhibitor groups,and the improvement conditions in inhibitor group were more significant.Compared with those in control group,expressions of IL-6,IL-1β,TNF-α,MCP-1,MIP-1α,ICAM-1 and p-MK2 protein in peripheral blood were significantly increased,while MK2 protein expression was significantly decreased in model group(P<0.05).Compared with those in model group,levels of IL-6,IL-1β,TNF-α,MCP-1,MIP-1α,ICAM-1 and p-MK2 protein in peripheral blood were significantly lower,while MK2 protein expressions were significantly increased in Ulinastatin and inhibitor groups;the changes in the above indexes in inhibitor group were more significant than those in Ulinastatin group(P<0.05).Conclusion Ulinastatin may significantly improve adhesive intestinal obstruction,and its mechanism may be related to the inhibition of P38-MK2 signaling pathway.