参附注射液对大鼠移植肝脏缺血再灌注损伤保护作用的研究
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摘要
目的:本文旨在从组织和细胞水平,探讨参附注射液(Shenfu injection, SF)对大鼠移植肝脏在缺血再灌注损伤(Ischemic reperfusion injury,IRI)中的保护作用及其具体机制。
方法:采用72只健康雄性SD(Sprague Dawley)大鼠,重190～220g,将其随机分为对照组和SF组(SF组受体在供肝植入门静脉血流恢复后即经尾静脉一次性注射SF 1ml/100g,对照组以相同的方式注射等量的生理盐水),每组18对,采用二袖套法进行原位肝移植。其中每组按门静脉再灌注时间不同,又分为三组,分别于肝移植完成2h、4h和6h后收集受体的血清和肝组织,采用ELISA(酶联免疫吸附)法测定血清中肿瘤坏死因子α(tumor necrosis factor-α,TNF-α)的浓度,免疫组织化学法测定核因子κB(nuclear factor kappa B,NF-κB)的表达,原位杂交法测定细胞间粘附分子(intercellular adhesion molecule-1,ICAM-1)mRNA。另选用36只健康雄性SD大鼠,重180～210g,随机分为对照组和SF组(SF组每孔细胞悬液滴加0.5mlSF,对照组每孔给予同等量生理盐水),其中每组按再氧化时间不同,又分为三组,分别进行原位肝脏灌注,所得细胞悬液进入缺氧-复氧模型(模拟体外IRI)。分别于复氧2h、4h和6h后取细胞悬液进行检测。采用ELISA法测定ICAM-1的表达,免疫细胞化学法测定NF-κB的表达。
结果:用于血清和组织学检测的大鼠中,在肝移植完成后2h、4h和6h,SF组TNF-α浓度分别为(576±60pg/ml、518±52pg/ml和421±35pg/ml ),较对照组的浓度( 831±65pg/ml、715±69pg/ml和598±52pg/ml)明显低(P<0.05);同时,SF组组织的NF-κB和ICAM-1mRNA表达均明显弱于对照组。在复氧2h、4h和6h后,SF组SEC的ICAM-1浓度分别为(44±3.4 pg/ml、68±3.2 pg/ml和73±4.5 pg/ml),明显低于对照组的(59±4.3 pg/ml、98±6.5 pg/ml和111±5.7 pg/ml,P<0.05);SF组SEC的NF-κB表达明显弱于对照组。
结论:SF能减轻IRI对移植肝脏特别是窦状内皮细胞的损伤,其机制是通过抑制肝组织中NF-κB的活化,有效下调TNF-α的分泌,降低ICAM-1的生成,从而减少白细胞对SEC的粘附,显著改善微循环。本研究可为提高肝移植质量提供一条新的途径。
Objective: To investigate the protective role of Shenfu injection (SF) in ischemic reperfusion injury of rat liver graft and its mechanism.
Methods: Seventy-two male Sprague Dawley (SD) rats were randomly divided into SF group and control group, and used as donors and recipients of orthotopic liver transplantation. The operation was performed according to the two-cuff technique. 2 hours, 4 hours and 6 hours after liver transplantation, serum and hepatic tissue of recipients were taken for following assays: TNF-α(tumor necrosis factor), NF-κB (nuclear factor kappa B) and ICAM-1mRNA(intercellular adhesion molecule-1 mRNA).
The other thirty-six male SD rats were divided into three groups according to different reoxidation time, and accepted orthotopic liver reperfusion. All the cells got into hypoxia-reoxidation model. 2 hours, 4 hours and 6 hours after reperfusion, the cells were taken for following assays: NF-κB and ICAM-1.
Results: Serum TNF-αof rat liver graft in SF group were (576±60pg/ml,518±52pg/ml and 421±35pg/ml) respectively, lower than in control group: (831±65pg/ml,715±69pg/ml and 598±52pg/ml, P<0.05). Moreover, expressions of NF-κB and ICAM-1mRNA in hepatic tissue of SF group were obviously poorer than control group. 2 hours, 4 hours and 6 hours after reperfusion, ICAM-1 levels of SEC in SF group were (44±3.4 pg/ml, 68±3.2 pg/ml and 73±4.5 pg/ml), lower than in control group: (59±4.3 pg/ml, 98±6.5 pg/ml and 111±5.7 pg/ml, P<0.05). And the expressions of NF-κB in SEC of SF group were obviously poorer than control group.
Conclusion: SF could be benefit for hepatic tissue and SEC during ischemic reperfusion injury in the liver transplantation, and improve long-term outcome.
方法:采用72只健康雄性SD(Sprague Dawley)大鼠,重190～220g,将其随机分为对照组和SF组(SF组受体在供肝植入门静脉血流恢复后即经尾静脉一次性注射SF 1ml/100g,对照组以相同的方式注射等量的生理盐水),每组18对,采用二袖套法进行原位肝移植。其中每组按门静脉再灌注时间不同,又分为三组,分别于肝移植完成2h、4h和6h后收集受体的血清和肝组织,采用ELISA(酶联免疫吸附)法测定血清中肿瘤坏死因子α(tumor necrosis factor-α,TNF-α)的浓度,免疫组织化学法测定核因子κB(nuclear factor kappa B,NF-κB)的表达,原位杂交法测定细胞间粘附分子(intercellular adhesion molecule-1,ICAM-1)mRNA。另选用36只健康雄性SD大鼠,重180～210g,随机分为对照组和SF组(SF组每孔细胞悬液滴加0.5mlSF,对照组每孔给予同等量生理盐水),其中每组按再氧化时间不同,又分为三组,分别进行原位肝脏灌注,所得细胞悬液进入缺氧-复氧模型(模拟体外IRI)。分别于复氧2h、4h和6h后取细胞悬液进行检测。采用ELISA法测定ICAM-1的表达,免疫细胞化学法测定NF-κB的表达。
结果:用于血清和组织学检测的大鼠中,在肝移植完成后2h、4h和6h,SF组TNF-α浓度分别为(576±60pg/ml、518±52pg/ml和421±35pg/ml ),较对照组的浓度( 831±65pg/ml、715±69pg/ml和598±52pg/ml)明显低(P<0.05);同时,SF组组织的NF-κB和ICAM-1mRNA表达均明显弱于对照组。在复氧2h、4h和6h后,SF组SEC的ICAM-1浓度分别为(44±3.4 pg/ml、68±3.2 pg/ml和73±4.5 pg/ml),明显低于对照组的(59±4.3 pg/ml、98±6.5 pg/ml和111±5.7 pg/ml,P<0.05);SF组SEC的NF-κB表达明显弱于对照组。
结论:SF能减轻IRI对移植肝脏特别是窦状内皮细胞的损伤,其机制是通过抑制肝组织中NF-κB的活化,有效下调TNF-α的分泌,降低ICAM-1的生成,从而减少白细胞对SEC的粘附,显著改善微循环。本研究可为提高肝移植质量提供一条新的途径。
Objective: To investigate the protective role of Shenfu injection (SF) in ischemic reperfusion injury of rat liver graft and its mechanism.
Methods: Seventy-two male Sprague Dawley (SD) rats were randomly divided into SF group and control group, and used as donors and recipients of orthotopic liver transplantation. The operation was performed according to the two-cuff technique. 2 hours, 4 hours and 6 hours after liver transplantation, serum and hepatic tissue of recipients were taken for following assays: TNF-α(tumor necrosis factor), NF-κB (nuclear factor kappa B) and ICAM-1mRNA(intercellular adhesion molecule-1 mRNA).
The other thirty-six male SD rats were divided into three groups according to different reoxidation time, and accepted orthotopic liver reperfusion. All the cells got into hypoxia-reoxidation model. 2 hours, 4 hours and 6 hours after reperfusion, the cells were taken for following assays: NF-κB and ICAM-1.
Results: Serum TNF-αof rat liver graft in SF group were (576±60pg/ml,518±52pg/ml and 421±35pg/ml) respectively, lower than in control group: (831±65pg/ml,715±69pg/ml and 598±52pg/ml, P<0.05). Moreover, expressions of NF-κB and ICAM-1mRNA in hepatic tissue of SF group were obviously poorer than control group. 2 hours, 4 hours and 6 hours after reperfusion, ICAM-1 levels of SEC in SF group were (44±3.4 pg/ml, 68±3.2 pg/ml and 73±4.5 pg/ml), lower than in control group: (59±4.3 pg/ml, 98±6.5 pg/ml and 111±5.7 pg/ml, P<0.05). And the expressions of NF-κB in SEC of SF group were obviously poorer than control group.
Conclusion: SF could be benefit for hepatic tissue and SEC during ischemic reperfusion injury in the liver transplantation, and improve long-term outcome.
引文
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