大鼠肝脏缺血预处理对肝脏及肺脏保护作用
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摘要
肝脏缺血再灌注是临床实践中必须时常面对的基本命题，在严重感染、创
伤、休克、心肺功能不全、肝移植等疾患的病理演变过程中起重要作用。肝脏
缺血再灌注不仅可以引起肝脏的局部组织损害，而且可以导致肠内细菌和毒素
移位到体循环，引起网状内皮系统发生系列反应，进而导致大量相关介质和细
胞因子的释放，甚至发生多系统器官功能不全综合征，其中急性肺损伤为多系
统器官功能不全综合征中较常见和危重情况，探索肝脏缺血再灌注损伤机制将
为肝细胞保护及肝脏疾病治疗提供新的理论依据。
缺血预处理系指组织或器官在经过短暂的缺氧或缺血预处理后，能够增加
其对随后长时间的缺氧或缺血的耐受能力。缺血预处理具有生物学普遍性。本
质上，缺血预处理作为一种应急性刺激使细胞或组织器官产生一种适应性的改
变，提高细胞或组织器官对继发的长时间缺血再灌注耐受能力。
本文旨在研究肝脏缺血预处理对肝脏及肺脏的保护作用，研究肝脏缺血再
灌注以及缺血预处理对肿瘤坏死因子、肝细胞凋亡及多形核细胞的作用，为肝
脏疾患治疗提供实验及理论依据。
本研究的主要实验方法和研究结果如下：
1．利用肝内血液分流方法建立大鼠肝脏缺血再灌注模型，术中以小肠血液回流
状态作为监测肝内分流技术是否成功的标志，发现肝内分流可以使肠道血液
顺利地进入体循环系统，不会产生因静脉淤血而导致的肠道损伤。采用集束
第四军医大学博士学位论文
阻断入肝血流在达到实验目的的同时，可以减少肝门血管骨骼化所带来的血
管损伤，提高实验成功率。
2．用无创伤血管夹阻断左、中叶入肝血流，首次将肝脏缺血再灌注时间限制在
5－15min以内，然后，用相同方法再次阻断肝门血管完成大鼠肝脏缺血预处
理和缺血再灌注模型制作。
3．以能量物质ATP、ADP、AW及腺苦变化为依据，结合转氨酶的改变探讨产生
最佳肝脏保护作用的处理方法及时间。实验结果表明。与对照组相比，缺血
预处理可以减轻缺血再灌注对肝脏的损伤，具有肝脏保护作用，10而n缺血
继之10min再灌注能使肝组织内ATP及腺昔含量最高，血液中转氨酶水平最
低，表明该预处理模式可以产生最佳的肝脏保护作用。
4．采用DNA缺口末端标记技术（TUNEL）、扫描电镜技术及DNA琼脂凝胶电泳检
测肝脏缺血再灌注和缺血预处理对肝细胞凋亡的作用。肝脏缺血再灌注可以
导致肝细胞凋亡，凋亡细胞以肝脏实质细胞为主，电镜及DNA琼脂凝胶电泳
均证实肝脏内细胞凋亡的存在。TUNEL染色与光镜技术结合计数凋亡细胞发
现，缺血预处理减少缺血再灌注引发的的肝细胞凋亡数目。
5．用肿瘤坏死因子（TNF－u）mRNA斑点杂交法检测肝组织内的表达，正常大
鼠肝组织 TNF－a mRNA表达量少，缺血再灌注增加肝组织 TNF－a mRNA表达，
再灌注30min时，达到峰值。缺血预处理显著地抑制再灌注30min以后肝组
织 TNF－a mRNA表达（p＜0．05）。
6．夹心酶联免疫吸附分析法呸LISA椰定肝组织及血浆内 TNF－a，肝组织 TNF－
a含量再灌注45min时，达到峰值；血浆内TNF－口水平低于肝组织内TNF－
a含量，与肝组织内TNF－口含量呈现同向变化趋势，二者为正相关关系
km．05人缺血预处理明显地抑制再灌注45min后肝组织TNF－口及血浆内
TNF、a（p＜0．05）。
7．测定肺组织的干湿比（D，y to Wet Weight Ratio）及髓过氧化物酶（MPO），
监测肝脏缺血再灌注对肺脏损伤。随着肝脏缺血再灌注时间的延长，肺组织
干湿比值逐渐降低，而肺组织内惭 活性则持续增加，再灌注 60min和 90min
— —3一
第四军医大学博士学位论文
时间点，肺组织干湿比值急剧下降（P＜0．05），而肺组织内 MPO活性急速增
高（p＜0．05）。缺血预处理显著地提高再灌注 60min和 90min时间点上肺组
织干湿比值和降低肺组织内惭 活性（P＜0．05），提示缺血预处理通过抑制
肺组织水肿及棚 活性起到保护肺脏作用。
上述研究结果表明，缺血预处理对肝脏缺血再灌注导致的肝、肺损伤
具有保护作用，TNF－a在肝脏缺血再灌注中通过一定机制导致肝脏和肺脏
的损伤，为临床上预防和治疗肝脏缺血再灌注损伤提供了实验依据和材料。
Protection from ischemia-reperftisiofl is a basic theme faced with clinical
situation, plays an impotant role in infection, trauma, shock, pulmonary and cardic
dysfunction, liver transplantation and so on. Hepatic ischemia reperfusion not only
causes liver injury , but also promotes the translocation of bacteria and endotoxin
from the gut into portal vein, activate reticuloendothelial system, release mediators
and cytokines, which cause multiple organ failure, among them, the acute
pulmonary injury is common and severe. Study of protective effect shows
mechanisms and new theory for hepatic ischemia reperfusion injury.
A short period of ischemia and reperfusion, called ischemic preconditioning,
protects various tissues against subsequent sustained ischemic insults. Ischemic
preconditiofliflg have been ubiquitous. ActalLy, ischemic preconditioning confers a
state of adaption for various tissues and organs and changes mediators and cytokines
in tissues and organs, the mechanisms by which ischemic preconditioning promotes
adaptability of tissues and organs to sustained ischemic insults.
The purpose of this study is to investigate the protective effect of ischemic
preconditiofling on the hepatic ischemic-reperfusiofl and lung injury in rats, and
relationsip between ischemic preconditioning and tumor necrosis factor- a
hepatocyte apoptosis, neutrophils, so as to provide the experimental data and
?-?
academic foundations for hepatobiliary deseases.
The main research methods and results in the study as follows:
1. Partial hepatic ischemia model was utilized to produce severe ischemic liver
damage without intestinal congestion. Results showed that partial hepatic
ischemic model prevented mesenteric veinous congestion and intestinal injury
by permitting portal decompression through the right lobe. All structures in the
portal triad (hepatic artery, portal vein, and bile duct) to the left and median liver
lobes were occluded in bloc for the denifite time under study, so as to decrease
portal triad damage brought with the skeleton of portal triad.
2. A nontraumatic vascular clamp was applied to interupt liver pedicle to the left
and median liver lobes for 5-1 5mm ischemia-reperfusion., then the liver pedicle
was occluded for 60mm for the second time.
3. ATP, ADP, AMP, adeno sine aspartate and alanine aminotrasferase were
examined to detect the best method and time for ischemic preconditioning of
liver. Results showed that in conparison with control group, ischemic
preconditioning ameliorated hepatic ischemic-reperfusion injury in rats. A single
ischemia of 10mm and reperfusion period of 10mm before 60mm warm
ischemia maintained ATP and adenosine in hepatic tissure, decreased the
concentrations of aminotransferase in blood, suggested that a single ischemia of
1 0mm and reperfusion period of 1 0mm produced the best protective effect on
liver injury in the rats.
4. Terminal deoxynucleotidy I transferase- mediated dUTP nick end labeling
deoxynucleotidyl transferase(TU7NEL), electron microscope, and DNA
fragmentation gel electrophoresis Were utilized to monitor hepatocytes in hepatic
ischemic preconditioning and ischemia-reperfusion. In this study , we have
demastrated that apoptosis of hepatocytes occurs after reperfusion following
warm ischemia. EM and DNA fragmentation gel electrophoresis
伤、休克、心肺功能不全、肝移植等疾患的病理演变过程中起重要作用。肝脏
缺血再灌注不仅可以引起肝脏的局部组织损害，而且可以导致肠内细菌和毒素
移位到体循环，引起网状内皮系统发生系列反应，进而导致大量相关介质和细
胞因子的释放，甚至发生多系统器官功能不全综合征，其中急性肺损伤为多系
统器官功能不全综合征中较常见和危重情况，探索肝脏缺血再灌注损伤机制将
为肝细胞保护及肝脏疾病治疗提供新的理论依据。
缺血预处理系指组织或器官在经过短暂的缺氧或缺血预处理后，能够增加
其对随后长时间的缺氧或缺血的耐受能力。缺血预处理具有生物学普遍性。本
质上，缺血预处理作为一种应急性刺激使细胞或组织器官产生一种适应性的改
变，提高细胞或组织器官对继发的长时间缺血再灌注耐受能力。
本文旨在研究肝脏缺血预处理对肝脏及肺脏的保护作用，研究肝脏缺血再
灌注以及缺血预处理对肿瘤坏死因子、肝细胞凋亡及多形核细胞的作用，为肝
脏疾患治疗提供实验及理论依据。
本研究的主要实验方法和研究结果如下：
1．利用肝内血液分流方法建立大鼠肝脏缺血再灌注模型，术中以小肠血液回流
状态作为监测肝内分流技术是否成功的标志，发现肝内分流可以使肠道血液
顺利地进入体循环系统，不会产生因静脉淤血而导致的肠道损伤。采用集束
第四军医大学博士学位论文
阻断入肝血流在达到实验目的的同时，可以减少肝门血管骨骼化所带来的血
管损伤，提高实验成功率。
2．用无创伤血管夹阻断左、中叶入肝血流，首次将肝脏缺血再灌注时间限制在
5－15min以内，然后，用相同方法再次阻断肝门血管完成大鼠肝脏缺血预处
理和缺血再灌注模型制作。
3．以能量物质ATP、ADP、AW及腺苦变化为依据，结合转氨酶的改变探讨产生
最佳肝脏保护作用的处理方法及时间。实验结果表明。与对照组相比，缺血
预处理可以减轻缺血再灌注对肝脏的损伤，具有肝脏保护作用，10而n缺血
继之10min再灌注能使肝组织内ATP及腺昔含量最高，血液中转氨酶水平最
低，表明该预处理模式可以产生最佳的肝脏保护作用。
4．采用DNA缺口末端标记技术（TUNEL）、扫描电镜技术及DNA琼脂凝胶电泳检
测肝脏缺血再灌注和缺血预处理对肝细胞凋亡的作用。肝脏缺血再灌注可以
导致肝细胞凋亡，凋亡细胞以肝脏实质细胞为主，电镜及DNA琼脂凝胶电泳
均证实肝脏内细胞凋亡的存在。TUNEL染色与光镜技术结合计数凋亡细胞发
现，缺血预处理减少缺血再灌注引发的的肝细胞凋亡数目。
5．用肿瘤坏死因子（TNF－u）mRNA斑点杂交法检测肝组织内的表达，正常大
鼠肝组织 TNF－a mRNA表达量少，缺血再灌注增加肝组织 TNF－a mRNA表达，
再灌注30min时，达到峰值。缺血预处理显著地抑制再灌注30min以后肝组
织 TNF－a mRNA表达（p＜0．05）。
6．夹心酶联免疫吸附分析法呸LISA椰定肝组织及血浆内 TNF－a，肝组织 TNF－
a含量再灌注45min时，达到峰值；血浆内TNF－口水平低于肝组织内TNF－
a含量，与肝组织内TNF－口含量呈现同向变化趋势，二者为正相关关系
km．05人缺血预处理明显地抑制再灌注45min后肝组织TNF－口及血浆内
TNF、a（p＜0．05）。
7．测定肺组织的干湿比（D，y to Wet Weight Ratio）及髓过氧化物酶（MPO），
监测肝脏缺血再灌注对肺脏损伤。随着肝脏缺血再灌注时间的延长，肺组织
干湿比值逐渐降低，而肺组织内惭 活性则持续增加，再灌注 60min和 90min
— —3一
第四军医大学博士学位论文
时间点，肺组织干湿比值急剧下降（P＜0．05），而肺组织内 MPO活性急速增
高（p＜0．05）。缺血预处理显著地提高再灌注 60min和 90min时间点上肺组
织干湿比值和降低肺组织内惭 活性（P＜0．05），提示缺血预处理通过抑制
肺组织水肿及棚 活性起到保护肺脏作用。
上述研究结果表明，缺血预处理对肝脏缺血再灌注导致的肝、肺损伤
具有保护作用，TNF－a在肝脏缺血再灌注中通过一定机制导致肝脏和肺脏
的损伤，为临床上预防和治疗肝脏缺血再灌注损伤提供了实验依据和材料。
Protection from ischemia-reperftisiofl is a basic theme faced with clinical
situation, plays an impotant role in infection, trauma, shock, pulmonary and cardic
dysfunction, liver transplantation and so on. Hepatic ischemia reperfusion not only
causes liver injury , but also promotes the translocation of bacteria and endotoxin
from the gut into portal vein, activate reticuloendothelial system, release mediators
and cytokines, which cause multiple organ failure, among them, the acute
pulmonary injury is common and severe. Study of protective effect shows
mechanisms and new theory for hepatic ischemia reperfusion injury.
A short period of ischemia and reperfusion, called ischemic preconditioning,
protects various tissues against subsequent sustained ischemic insults. Ischemic
preconditiofliflg have been ubiquitous. ActalLy, ischemic preconditioning confers a
state of adaption for various tissues and organs and changes mediators and cytokines
in tissues and organs, the mechanisms by which ischemic preconditioning promotes
adaptability of tissues and organs to sustained ischemic insults.
The purpose of this study is to investigate the protective effect of ischemic
preconditiofling on the hepatic ischemic-reperfusiofl and lung injury in rats, and
relationsip between ischemic preconditioning and tumor necrosis factor- a
hepatocyte apoptosis, neutrophils, so as to provide the experimental data and
?-?
academic foundations for hepatobiliary deseases.
The main research methods and results in the study as follows:
1. Partial hepatic ischemia model was utilized to produce severe ischemic liver
damage without intestinal congestion. Results showed that partial hepatic
ischemic model prevented mesenteric veinous congestion and intestinal injury
by permitting portal decompression through the right lobe. All structures in the
portal triad (hepatic artery, portal vein, and bile duct) to the left and median liver
lobes were occluded in bloc for the denifite time under study, so as to decrease
portal triad damage brought with the skeleton of portal triad.
2. A nontraumatic vascular clamp was applied to interupt liver pedicle to the left
and median liver lobes for 5-1 5mm ischemia-reperfusion., then the liver pedicle
was occluded for 60mm for the second time.
3. ATP, ADP, AMP, adeno sine aspartate and alanine aminotrasferase were
examined to detect the best method and time for ischemic preconditioning of
liver. Results showed that in conparison with control group, ischemic
preconditioning ameliorated hepatic ischemic-reperfusion injury in rats. A single
ischemia of 10mm and reperfusion period of 10mm before 60mm warm
ischemia maintained ATP and adenosine in hepatic tissure, decreased the
concentrations of aminotransferase in blood, suggested that a single ischemia of
1 0mm and reperfusion period of 1 0mm produced the best protective effect on
liver injury in the rats.
4. Terminal deoxynucleotidy I transferase- mediated dUTP nick end labeling
deoxynucleotidyl transferase(TU7NEL), electron microscope, and DNA
fragmentation gel electrophoresis Were utilized to monitor hepatocytes in hepatic
ischemic preconditioning and ischemia-reperfusion. In this study , we have
demastrated that apoptosis of hepatocytes occurs after reperfusion following
warm ischemia. EM and DNA fragmentation gel electrophoresis
引文
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