N-乙酰半胱氨酸对多器官功能障碍综合征大鼠器官的保护作用及其机制

Organ protective effects of N-acetylcysteine on rats with multiple organ dysfunction syndrome and its possible mechanism

目的通过观察N-乙酰半胱氨酸(NAC)对多器官功能障碍综合征(MODS)大鼠的器官功能、核因子(NF)-κB、肿瘤坏死因子(TNF)-α、白细胞介素(IL)-6的影响,探讨NAC对MODS的器官保护作用及其机制。方法将35只Sprague-Dawley大鼠分为假手术对照(Sham)组(5只)、MODS组(15只)、MODS+NAC组(15只)。用肠缺血/再灌注结合酵母多糖腹腔注射制作成MODS大鼠动物模型,动脉夹夹闭肠系膜上动脉45 min,然后松夹恢复灌注,在恢复灌注12 h后,腹腔注射酵母多糖与0.9%氯化钠溶液混悬液(250 mg/kg)。MODS+NAC组在恢复再灌注时,注射NAC 150 mg/kg。于注射酵母多糖18 h后,测定大鼠的动脉血氧分压(PaO2)、丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)、总胆红素(TBIL)、尿素氮(BUN)、肌酐(Cr)、肌酸激酶(CK),取肝、肾组织,应用凝胶迁移率法检测NFκ-B的活性,酶联免疫吸附试验检测大鼠的血清TNF-α、IL-6含量,留肺、肝脏、肾、小肠标本行病理组织学检查。结果MODS组大鼠的PaO2较Sham组大鼠显著降低(P<0.01),而MODS+NAC组大鼠的PaO2较MODS组大鼠显著升高(P<0.01)。MODS组大鼠的ALT、AST、TBIL、BUN、Cr、CK均较Sham组显著升高(P值均<0.01),而MODS+NAC组大鼠上述指标较MODS组大鼠显著降低(P值均<0.01)。MODS组大鼠的血清TNF-α、IL-6含量较Sham组显著升高(P值均<0.01),而MODS+NAC组则较MODS组大鼠显著降低(P值均<0.01)。MODS组大鼠的肝脏、肾脏NFκ-B活性均较Sham组显著升高(P值均<0.01),而MODS+NAC组则较MODS组显著降低(P值均<0.01)。Sham组大鼠肺、肝脏、肾脏及小肠的病理表现基本正常,MODS组大鼠各器官存在明显的病理损伤,而MODS+NAC组的病理损伤程度较MODS组有所好转。结论应用NAC可以对MODS大鼠起到器官保护作用,其机制可能与抑制NFκ-B活性从而减少炎性因子合成有关。

Objective To observe the influence of N-αcetylcysteine （NAC） on nuclear factor-kappa B （NF-KB）, tumor necrosis factor-α （TNF-α） and interleukin-6 （IL-6） in rats with multiple organ dysfunction syndrome （MODS）, so as to discuss the protective effect of NAC against MOD$ and the related mechanism. Methods Thirty-five Sprague-Dawley rats were randomly divided into sham group （n = 5）, MODS group （ n = 15） and MODS＋ NAC group （n = 15）. The rat MODS model was established by intestinal ischemia-reperfusion （I/R） combined with intraperitoneal injection of zymosan. In the MODS and MODS ＋ NAC groups, the superior mesenteric arteries （SMA） of rats were occluded for 45 min and reperfused for 12 h, and then zymosan （250 mg/kg i. p. ） was administered. NAC （ 150 mg/kg i. v. ） was given immediately after reperfusion in the MODS＋ NAC group. Eighteen hours after the injection of zymosan, blood and tissue samples were collected from each group. Then the pathomorphological and functional changes of the lung, heart, liver and kidney tissues （including pressure of arterial oxygen E PaO2 ], alanine aminotransferase. [ALT], aspartate aminotransferase [AST], total bilirubin [TBIL], blood urea nitrogen [BUN], creatinine [Cr], and creatine kinase [CK] were observed. Serum TNF-α and IL-6 concentrations were detected by enzyme linked immunosorbent assay （ELISA）. The activities of NF-KB in the liver and kidney tissues were examined by electrophoretic mobility shift assay （EMSA）. Results The PaO2 in the MODS group was significantly lower than those in the sham operation group and the MODS＋ NAC group （both P〈0.01）. The serum levels of ALT, AST, TBIL, BUN, Cr, and OK in the MODS group were significantly higher than those in the sham group and the MODS＋ NAC group （all P〈O. 01 ）. The serum levels of IL-6 and TNF-c（ in the MODS group were significantly higher than those in the sham group and the MODS-I-NAC group （all P〈O. 01 ）. The activities of NF-KB in the liver and kidney in the MODS group were significantly higher than those in the sham group and the MODS-t-NAC group （all P〈O, 01）. The pathology of the lung, liver, and kidney was nearly normal in the sham group, and rats in the MODS group had obvious injuries of different organs. The pathologic lesions in the lung, kidney, liver, and intestine tissues in the MODS-I-NAC group were milder than those in the MODS group. Conclusion NAC has an organ protective effect on MODS rats, and the mechanism might be associated with the inhibition of NF-KB activity and the subsequent decrease of inflammatory responses. （Shanghai Med J, 2009, 32： 987-991）