目的探讨乌司他丁对脂多糖(LPS)诱导的大鼠脓毒症急性肝损伤的治疗作用及相关机制,并与p38丝裂原活化蛋白激酶(MAPK)通路特异性阻断剂SB203580的疗效进行比较。方法通过尾静脉注射5 mg/kg的LPS制造LPS诱导的大鼠脓毒症急性肝损伤模型。将清洁级雄性Sprague-Dawley大鼠32只分为4组:空白组(尾静脉注射1 m L等渗Na Cl溶液),LPS组(尾静脉注射1 m L的LPS),LPS+乌司他丁(UTI)组(建模后立即腹腔注射1 m L乌司他丁),LPS+p38MAPK通道阻断剂(SB)组(建模后立即腹腔注射1 m L SB203580),每组8只。建模后24 h处死大鼠,取下腔静脉血测定大鼠血清中谷氨酸-丙酮酸转氨酶(ALT)、胆红素(BIL)和碱性磷酸酶(AKP)的浓度,利用酶联免疫吸附测定(ELISA)法检测大鼠肝组织肿瘤坏死因子α(TNF-α)水平,Western-blotting法测定大鼠肝组织磷酸化p38蛋白水平表达,以及通过肝组织病理切片和电镜下观察肝细胞微结构的变化。结果建模后24 h,LPS组有2只大鼠死亡。四组大鼠血清AKP水平无显著性差异(F=1.153,P=0.351);与空白组比较,LPS组大鼠血清ALT[(10.7±1.8)U/L vs.(46.3±5.0)U/L]、BIL[(0.63±0.12)μmol/L vs.(1.55±0.16)μmol/L]、肝组织TNF-α[(4 621±793)ng/L vs.(7 222±773)ng/L]、磷酸化p38蛋白水平[(12 073±172)ng/L vs.(15 515±630)ng/L]均显著升高(P均<0.05);病理切片提示LPS组肝细胞水样变性、炎症细胞浸润、肝细胞再生;电镜结果也提示肝细胞核固缩,线粒体嵴肿胀、断裂或者消失,内质网结构不清。而LPS+UTI组和LPS+SB组肝组织TNF-α、磷酸化p38蛋白表达均与空白组无显著差异(P均>0.05);病理切片提示两组肝细胞水样变性、炎症细胞浸润、肝细胞再生较LPS组轻,但较空白组仍严重;电镜结果显示肝细胞核、线粒体及内质网结构变化较LPS组减轻。与空白组相比,LPS+SB组血清ALT无显著差异(P>0.05),而LPS+UTI组血清ALT明显升高[(10.7±1.8)U/L vs.(29.5±2.5)U/L,P<0.05],提示SB203580对血清ALT作用更明显;而与空白组比较,LPS+UTI组血清BIL水平无显著差异(P>0.05),而LPS+SB组血清BIL明显升高[(0.63±0.12)μmol/L vs.(1.52±0.20)μmol/L,P<0.05],提示乌司他丁对血清BIL作用更明显。结论乌司他丁可减轻LPS引起的大鼠脓毒症急性肝损伤,是通过p38MAPK通路来发挥炎症抑制作用的。与p38MAPK通路特异性阻断剂比较,两者在减轻TNF-α、磷酸化p38蛋白等作用上相似,但是对血清学指标的影响有一定差别。 Objective To investigate the therapeutic effect of ulinastatin on lipopolysaccharide (LPS) -induced acute liver injury induced by sepsis in rats and its mechanism, and to investigate the effect of ulinastatin on pathophysiology of p21 mitogen-activated protein kinase (MAPK) pathway-specific blocker SB203580 Compare. Methods LPS-induced acute liver injury model of sepsis was induced by injecting 5 mg / kg LPS through tail vein. Thirty-two male Sprague-Dawley rats were divided into 4 groups: blank group (1 m L NaCl solution injected into caudal vein), LPS group (1 m L LPS injected into caudal vein), LPS + ulinastatin (UTI) group (intraperitoneal injection of ulinastatin 1 ml immediately after modeling) and LPS + p38MAPK channel blocker (SB) group (1 ml SB203580 immediately after modeling). Rats were sacrificed at 24 h after model establishment. The levels of glutamate-pyruvate aminotransferase (ALT), bilirubin (BIL) and alkaline phosphatase (AKP) The level of tumor necrosis factor-α (TNF-α) was detected by ELISA, the level of phosphorylated p38 protein in rat liver tissue was determined by Western-blotting, and the expression of p38 protein in liver tissue was detected by histological sections and electron microscopy Microstructure changes. Results 24 h after modeling, 2 rats died in LPS group. Compared with the blank group, the serum ALT level in the LPS group was significantly higher than that in the blank group ([(10.7 ± 1.8) U / L vs. (46.3 ± 5.0) U / L vs L and BIL in the liver tissue were significantly higher than those in the control group (P <0.05). The levels of TNF-α in the liver tissue [(4621 ± 793) ng / L vs. (7222 ± 773) ng / L] and phosphorylated p38 protein levels in the LPS group [(12 073 ± 172) ng / L vs. (15 515 ± 630) ng / L] were significantly higher than those in the LPS group Denaturation, inflammatory cell infiltration, hepatocyte regeneration; electron microscopy results also suggest that liver cell nuclear condensation, mitochondrial cristae swelling, rupture or disappearance, endoplasmic reticulum structure is unclear. However, the expression of TNF-α and phosphorylated p38 protein in liver tissue of LPS + UTI group and LPS + SB group were not significantly different from those of blank group (all P> 0.05). Pathological examination showed that hepatocytes degeneration, inflammatory cell infiltration, The regeneration of hepatocytes was lighter than that of LPS group, but was still more severe than that of blank group. Electron microscopy showed that the changes of the structure of nucleus, mitochondria and endoplasmic reticulum of hepatocytes were lighter than that of LPS group. Compared with the blank group, there was no significant difference in serum ALT between LPS + SB group and LPS + UTI group [(10.7 ± 1.8) U / L vs. (29.5 ± 2.5) U / L , P <0.05], suggesting that the effect of SB203580 on serum ALT was more obvious. Compared with the blank group, serum BIL level in LPS + UTI group was not significantly different (P> 0.05) ± 0.12) μmol / L vs. (1.52 ± 0.20) μmol / L respectively, P <0.05], suggesting that ulinastatin may have a more significant effect on serum BIL. Conclusion Ulinastatin can attenuate acute liver injury induced by LPS in rats with sepsis and exert its inhibitory effect through the p38MAPK pathway. Compared with the p38MAPK pathway-specific blocker, both of them are similar in reducing the effects of TNF-α and phosphorylated p38 protein, but have some differences on the serological indexes.