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目的:探讨巨噬细胞移动抑制因子(MIF)抑制剂(S，R)-3-(4-羟苯基)-4，5-二氢-5-异噁唑乙酸甲酯(ISO-1)对重症急性胰腺炎(SAP)大鼠肝内胆管细胞损伤的保护作用及其机制。方法:采用随机数字法，将48只无特定病原体(SPF)级雄性SD大鼠随机分为4组，假手术(SO)组、SAP组、ISO-1处理组(ISO-1)和ISO-1对照组(ISO-1con)，每组12只。采用逆行胰胆管注射牛黄胆酸钠法制作SAP大鼠模型，各组于造模后12 h剖杀取材。苏木精-伊红(HE)染色观察胰腺、肝内胆管细胞病理学变化。电镜观察肝内胆管细胞超微结构变化。分别应用免疫组织化学法检测肝内胆管细胞中巨噬细胞移动抑制因子(MIF)、p38的表达，实时定量聚合酶链反应(Real-time PCR)检测MIF mRNA、肿瘤坏死因子-α(TNF-α) mRNA表达，蛋白质印迹法(Western blot)检测肝内胆管细胞p38、磷酸化(p)-p38、核因子-κB(NF-κB) p65、TNF-α的蛋白表达水平，酶联免疫吸附试验(ELISA)检测肝内胆管TNF-α、白细胞介素(IL)-1β、IL-6的含量，组间比较采用n t检验或方差分析。n 结果:给予ISO-1预处理后，苏木精-伊红(HE)染色结果显示SAP大鼠胰腺及肝内胆管细胞病理损伤程度明显减轻，电镜下见肝内胆管细胞超微结构损伤也明显缓解，两组病理损伤评分比较，ISO-1处理组评分明显低于SAP组，差异有统计学意义[(5.00±0.84)分比(12.50±0.45)分，n t＝19.361，n P<0.05；(0.83±0.52)分比(2.50±0.55)分，n t＝5.423，n P<0.05]。检测结果提示MIF mRNA及蛋白表达均低于SAP组，两组差异有统计学意义(7.780±1.370比22.470±0.870，n t＝15.642，n P<0.05；22 958±5 926比42 750±1 488，n t＝7.935，n P<0.05)。n 结论:ISO-1可特异性抑制SAP大鼠肝内胆管细胞MIF的表达对SAP时肝内胆管细胞损伤有一定保护作用。“,”Objective:To explore the protection mechanism of (S, R)-3- (4-hydroxyphenyl)-4, 5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1) on severe acute pancreatitis (SAP)-associated intrahepatic bile duct (IBD) injury in rats.Methods:A total of 48 specific pathogen free (SPF) male Wistar rats (bought from Huafukang Biology Ltd. in Beijing, certificate NO. 11401300010796) were randomly divided into four groups (n n=12 in each group): sham operation (SO) group, SAP model (SAP) group, ISO-1 treatment (ISO-1) group and ISO-1 control (ISO-1con) group. All rats were killed after 12 h of modeling. Immunohistochemistry was used to detect the expression of macrophage migration inhibitory factor (MIF) and p38 in IBD cells. MIF mRNA expression in IBD cells was detected using real-time quantitative polymerase chain reaction (real-time PCR). In addition, Western blotting was used to detect the protein expression of p38, phosphorylated p38 (p-p38), nuclear factor-κB (NF-κB p65), and tumor necrosis factor alpha (TNF-α). Enzyme-linked immunosorbent assay was used to analyze the levels of TNF-α, IL-1β, and IL-6 in the IBD of rats.n Results:As compared with SAP group, the pathological injuries of pancreas and IBD cells in ISO-1 group were remarkably alleviated (5.00±0.84 vs. 12.50±0.45, n t=19.361, n P<0.05; 0.83±0.52 vs. 2.50±0.55,n t=5.423, n P<0.05). The expression of MIF mRNA and protein in the IBD cells was significantly downregulated in ISO-1 treatment group as compared with that i the SAP group (7.780±1.370 vs. 22.470±0.870,n t=15.642, n P<0.05; 22 958±5 926 vs. 42 750±1 488,n t=7.935, n P<0.05).n Conclusion:ISO-1 may protect the IBD cells, and alleviate pathological injuries and the inflammatory response in SAP rats.