脓毒症大鼠不同时点缺氧性肝损伤病理生理学特点及乌司他丁的保护作用

Pathophysiological characteristics of hypoxic liver injury in sepsis rats at different time points and the protective effect of ulinastatin on sepsis rats

目的构建大鼠盲肠结扎穿刺(CLP)脓毒症模型,研究其不同时点病理生理学特点,探讨乌司他丁(UTI)对CLP大鼠肝脏的保护作用。方法将SD大鼠随机分为4组,假手术组(Sham组)、CLP组、假手术+乌司他丁组(Sham+UTI组)及CLP+UTI组,每组根据实验持续时间(12、24、36、48及72 h)分为5个亚组,评估大鼠一般情况,测定不同时点各组的血气分析、Hif-1α、丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)、白细胞介素-6(IL-6)、肿瘤坏死因子α(TNF-α)。结果 CLP组及CLP+UTI组大鼠各项指标发生显著变化,平均动脉压(MAP)在CLP后36 h下降(P <0. 05),CLP组血乳酸(Lac)水平和大鼠脓毒症评分(MSS)明显升高(P <0. 05)。CLP 36 h后大鼠动脉氧分压(Pa O2)下降,72 h达到最低,大鼠动静脉分压差(APPD)亦有相似趋势(P <0. 05)。CLP组及CLP+UTI组所有时点IL-6、TNF-α水平均明显升高(P <0. 05),AST在CLP后72 h才比Sham组有所提高(P> 0. 05),CLP后ALT无显著改变。CLP+UTI组病理生理学指标有所改善,尤其是CLP后48及72 h改善明显。结论 CLP诱导的脓毒症大鼠在不同时段发生多重病理生理学改变,CLP早期大鼠脓毒症进展较慢,36 h后病情迅速恶化,系统性地缺氧和肝细胞氧摄取下降是脓毒症肝损伤的主要原因;UTI对于CLP脓毒症引起的缺氧性肝损伤有一定保护作用,但并不能逆转病情进展。

Objective To construct the cecal ligation puncture(CLP)sepsis rat models to study the pathophysiological changes in different time points and to investigate the protective effect of ulinastatin(UTI)on the liver of CLP rats.Methods SD rats were divided into 4 groups:the sham group,sham+UTI group,CLP group,and CLP+UTI group.Each group was divided into 5 subgroups based on CLP time(12,24,36,48,and 72 h).Murine sepsis score(MSS)was used to evaluate the general condition of rats.We performed the blood gas analysis on rats and measured the levels of hypoxia inducible factor-1α(Hif-1α),ALT,AST,interleukin-6(IL-6),tumor necrosis factor-α(TNF-α)in each group at different time points.Results The indexes of the CLP group and CLP+UTI group changed significantly.Mean arterial pressure(MAP)decreased at 36 h after CLP(P<0.05).Blood lactate(Lac)level and MSS of rats in the CLP group increased significantly(both P<0.05).The arterial oxygen pressure(PaO 2)decreased at 36 h after CLP and reached the lowest level at 72 h.The arteriovenous partial pressure difference(APPD)of rats also showed a similar trend(P<0.05).The levels of IL-6 and TNF-αincreased significantly in the CLP group and CLP+UTI group(both P<0.05),but AST increased only at 72 h after CLP as compared with that of the sham group(P >0.05),and no significant change was found in ALT after CLP.UTI could improve the pathophysiological changes of CLP rats,especially at 48 and 72 h after CLP.Conclusions Multiple pathophysiological changes occur in sepsis rats induced by CLP in different periods.The early stage of sepsis in CLP rats progresses slowly and the condition deteriorates rapidly after 36 h.Systematic hypoxia and decreased oxygen uptake of liver cells are the main causes of liver injury in sepsis.UTI can play an protective role in inhibit the late stages of CLP sepsis-induced hypoxic liver injury,but it can not reverse the progress of inflammation.