缺血后处理抗大鼠缺血—再灌注肝损伤作用及其机制研究
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摘要
[背景与目的]
肝脏缺血-再灌注(ischemia／reperfusion，I／R)损伤是临床常见的病理生理现象，也是许多肝缺血疾病预后不良的重要原因。因此，深入研究I／R肝损伤的病理生理机制及寻找各种抗I／R肝损伤策略一直是肝脏研究领域的重要方向。作为一种启动机体内源性保护机制的方法，缺血预处理(ischemic preconditioning，IpreC)对I／R肝的保护作用已得到普遍的认可。然而，由于IpreC必须在器官长久缺血前实施，这在一定程度上限制了其在临床的推广。最近，一种新的干预策略——缺血后处理(ischemic postconditioning，IpostC)因其能减轻I／R心脏损伤而引起了广泛的关注。IpostC是指通过在再灌注起始实施数个循环的短暂的血流灌注(on)／阻断(off)，能够削弱随后再灌注引起的损伤。IpostC实施方法与IpreC相似，但其简便易行、实施时机合理的优点将使其在临床应用具有诱人的前景。当前大多数IpostC研究集中在心脏方面，其对其他I／R器官是否具有保护作用尚不确定，因此本研究首先探讨IpostC对SD大鼠I／R肝脏是否具有保护作用，随后进一步研究联合应用IpreC和IpostC是否能够提供相加的保护作用。同时，在此基础上我们探讨了抗氧化机制在IpostC抗I／R肝损伤中的作用。
在肝I／R过程中，细胞的最终命运常常表现为细胞凋亡和坏死。长久以来这两种细胞死亡方式被认为具有截然不同的特征和发生过程，然而近年来研究认为两者的发生至少部分经过共同的信号传导途径，称之为necrapoptosis(死亡通路)。线粒体通透性转换(MPT)在细胞死亡发生过程中发挥关键作用。MPT一旦发生，细胞要么凋亡要么坏死。肝I／R损伤常被划分为两期，早期(再灌注＜3 h内)主要以氧化应激引发的组织损伤为特征，晚期以募集在肝实质内的PMN引发的炎性损伤等为特征。另外，肝I／R损伤常常伴随有许多蛋白酶的激活，其中Calpain家族在引发I／R肝细胞死亡中发挥重要的作用。由于IpostC是再灌注起始采取的干预手段，其抗I／R肝损伤机制很可能与影响再灌注早期的分子事件有关。因此，本研究进一步探讨了IpostC对再灌注早期大鼠肝组织中与细胞死亡通路相关分子及其对细胞早期死亡特征的影响。
细胞在遭受损伤刺激的作用下必然同时会启动自身的防御性机制，其中细胞周期的启动对于细胞自身结构修复和功能恢复尤为重要。与其他器官不同，肝脏是机体内具有极强再生能力的器官。通常，绝大多数肝细胞处于静息状态(G_0期)，在接受外来刺激后可很快被启动进入细胞周期，发生增殖。从细胞启动到肝细胞分裂增殖的过程中涉及到许多重要分子的参与，其中细胞周期促进分子cyclin D_1和CDK4以及抑制分子p21相互协调并发挥着关键的作用。IpostC能否通过影响这些细胞周期分子的表达对I／R肝脏发挥保护作用尚不清楚，因此本研究着重研究了这些细胞周期相关分子的表达，以探讨IpostC对细胞周期的影响，为其未来研究和应用提供一定的理论基础。
[方法]
1．复制SD大鼠70％肝缺血-再灌注模型。在此基础上实验分两步进行。
第一步实验实验动物分为6组：假手术(S)组、单纯60 min缺血组、缺血再灌注(I／R)组和3组采用不同方案的缺血后处理(IpostC)组，即再灌注起始采用3个循环30 s灌注／30 s阻断(30 s on／off)的IpostC 1组、3个循环1 minon／off的IpostC 2组和2 min on／off的IpostC 3组。采用全自动生化分析仪测定各组大鼠血清ALT和AST活性，同时观察各组大鼠肝组织的病理组织学改变，评价IpostC对I／R肝脏的抗损伤作用。
第二步实验实验动物分为5组，即S组、I／R组、IpreC组(长时间缺血前应用2个循环的缺血5 min／再灌注5 min)、IpostC组(3周期1 min on／off方案)和联合应用IpreC组和IpostC组(IpreC／IpostC)。除了观察第一步实验的各项指标外，第二步实验采用70％肝缺血后全缺血肝再灌注模型来评价各组的术后7天生存率，用以评价联合IpreC和IpostC对I／R肝脏的抗损伤作用。
2．采用分光光度比色法测定大鼠肝组织中MDA、GSH的含量和SOD、GSH-Px和MPO的活性，评价抗氧化机制在IpostC抗I／R肝损伤中的作用。
3．采用ELISA法测定S组、UR组和IpostC组大鼠在再灌注1h和3h时肝组织和血清中TNF-α的含量。采用Western blot法测定各组大鼠在再灌注1h和3h肝组织中μ-Calpain、Talin、Bid、Cyt C和Caspase-3蛋白的表达。透射电镜观察各组大鼠在再灌注1h时的超微结构。应用流式细胞术Annexin V／PI双染色法鉴定各组大鼠再灌注1h和3h肝脏组织中生存的、早期凋亡的以及晚期凋亡和坏死的肝细胞生存率。评价IpostC对再灌注早期大鼠肝组织中与细胞死亡通路相关分子及其对细胞早期死亡特征的影响，
4．分别采用quantitative real-time PCR和Western blot方法测定S组、I／R组和IpostC组大鼠在再灌注1h、3h和24h时肝组织中cyclin D_1、CDK4和p21 mRNA和蛋白的表达情况。应用流式细胞术PI染色法测定各组大鼠在再灌注1h、3h和24h时肝细胞细胞周期各时相的百分比。评价IpostC对细胞周期和细胞周期相关分子表达的影响。
[结果]
1．缺血后处理对缺血-再灌注损伤肝脏的保护作用研究
1．1第一步实验结果显示，ALT和AST活性分别在S组(68.30±11.12 U／L和211.65±95.63 U／L)、缺血30 min(78.33±32.12 U／L和260.33+45.12 U／L)和缺血60min(210.85±75.75 U／L和340.93±108.52 U／L)大鼠血清中逐渐增高(P＜0.05)，伴随再灌注时间的延长，其酶活性进一步增加(P＜0.05)。与I／R组相比，IpostC1和IpostC 2组在再灌注60 min和6h的ALT和AST活性明显降低，IpostC 2组降低更明显，差异非常显著(P＜0.05)；IpostC 3组ALT和AST活性无降低。同时，病理组织学显示IpostC 1和IpostC 2组损害明显减轻，而IpostC 3组病理学损害与I／R相当。结果提示IpostC 2组具有显著的抗I／R肝损伤作用。
1．2第二步实验结果显示，与I／R组相比，IpreC、IpostC和IpreC／IpostC组ALT、AST活性均明显降低，差异显著(P＜0.05)。与IpreC和IpostC相比，IpreC／IpostC组ALT和AST值无进一步降低，反而有增加趋势，但差异无显著性(P＞0.05)。同样，与单独应用IpreC和IpostC相比，也不能使组织病理损害进一步减轻，反而有加重迹象。结果提示联合应用IpreC和IpostC不能提供相加的抗I／R肝损伤作用。
2．缺血后处理抗氧化机制的研究
与I/R组相比，IpostC 1和IpostC 2组在再灌注6h时肝组织中MDA含量减少、GSH含量增加、SOD和GSH-Px活性增高而MPO活性降低(P＜0.05)，以IpostC 2组各项指标变化更明显；IpostC 3组各项指标无明显改善。与单独应用IpreC和IpostC相比，联合应用IpreC和IpostC也不能进一步改善I／R肝组织中MDA、SOD、GSH-PX、GSH和MPO的水平。结果提示IpostC具有抗氧化损伤作用。
3．缺血后处理对细胞死亡通路的干扰与调控
与S组相比，再灌注1h和3h时大鼠肝组织和血清中TNF-α含量均明显增高，以3h时增高最明显(P＜0.05)；IpostC能够明显减轻再灌注1h和3h时大鼠肝组织和血清中TNF-α含量(P＜0.05)，但仍显著高于S组(P＜0.05)。与I／R组相比，IpostC能使再灌注1h和3h时大鼠肝组织中μ-Calpain、Bid、Cyt C和Caspase-3的表达降低，Talin表达增高，细胞超微结构损害减轻。IpostC能够明显增加再灌注1h、3h的细胞生存率，降低早期凋亡细胞比例。
4．缺血后处理对肝细胞周期调控机制的研究
与I／R组相比，IpostC能够增加细胞周期相关分子cyclin D_1、CDK4和p21mRNA和蛋白的表达，而以CDK4表达增加更明显。与S组相比，I／R组和IpostC组中G_0／G_1期细胞百分比明显降低，而S期细胞百分比则明显增高。与I／R组相比时，IpostC能使G_0／G_1期细胞百分比进一步降低，S期细胞百分比进一步增高(P＜0.05)。结果提示IpostC能够启动和促进细胞周期运转。
[结论]
1．缺血后处理能够保护肝功能、减轻肝组织病理损害和提高生存率，具有抗大鼠I／R肝损伤作用。
2．联合应用缺血预处理和缺血后处理不能提供相加的保护作用，反而削弱了各自单独应用的保护效应。
3．缺血后处理抗大鼠缺血-再灌注肝损伤作用与抗氧化作用机制有关，可能通过减轻I／R肝组织脂质过氧化作用，提高抗氧化物质SOD、GSH-PX和GSH水平，减少中性粒细胞浸润和聚集发挥作用。
4．缺血后处理能够减轻肝细胞超微结构损害，增加肝细胞生存率，其作用机制可能与干扰再灌注早期死亡通路细胞因子TNF-α的产生和相关分子μ-Calpain、Bid、Cyt C、Caspase-3和Talin的蛋白表达有关。
5．缺血后处理能够促进肝细胞周期运转，其作用机制可能与增加细胞周期相关分子cyclin D_1、CDK4和p21 mRNA和蛋白的表达有关。
6．本研究不仅能为缺血后处理在肝脏外科的临床应用提供理论和实践依据，而且为开发新的模拟缺血后处理作用机制药物提供参考，还可为防治I／R肝损伤提供新靶点，具有广阔的应用前景以及重要的应用价值和意义。
Background and Objectives
Hepatic ischemia and reperfusion (I/R) is a pathophysiological phenomenon that occurs very frequently in clinical practice. More importantly, I/R is also responsible for liver injuries that often lead to poor prognosis. Many efforts are being made to investigate the pathophysiological mechanism of I/R injury and to search for strategies that will protect liver against I/R induced damage. One of the approaches that have gained widespread recognition involves the use of ischemic preconditioning (IpreC), which has displayed significant protective effects in hepatic I/R injury through its abilities to stimulate endogenous protective mechanisms. However, since IpreC must be performed prior to the sustained ischemia, its usefulness is limited in clinical practices. Recently, a new and alternative strategy focusing on ischemic postconditioning (IpostC) has attracted extensive interest largely due to its remarkable success in protecting heart from I/R injuries. Unlike IpreC, the IpostC applies the brief episodes of ischemia at the onset of reperfusion following a prolonged ischemia. Since IpostC can be easily applied with precisely controlled timing, this approach appears to have greater potential for clinical application. However, most of the current studies are concentrated on the I/R of heart, and it remained to be determined whether IpostC can provide similar effective protection to other I/R organs. This study was therefore designed to first explore the protective activities of IpostC against hepatic I/R injury, followed by investigating whether combined IpreC and IpostC could provide additive or synergistic protections. At the same time, we are also endeavored to define the underlying antioxidative mechanisms with which IpostC protects liver from I/R injuries.
Apoptosis and necrosis are the final outcome for hepatocytes during hepatic I/R process. Although they have long been believed as two distinct death modes, recent studies have revealed that the two processes partly employ a common signaling pathway, namely necrapoptosis, in which the mitochondrial permeability transition (MPT) is established to play a critical role. Formation of MPT can lead to cell apoptosis or necrosis. There are two distinct phases of liver injury after warm I/R. The initial phase (<3 h after reperfusion) is characterized by oxidative stress, where production and release of ROS appears to directly result in hepatocellular injury. The late phase of liver injury, which occurs 6 to 48 h after hepatic reperfusion, is an inflammatory disorder mediated by recruited neutrophils. In addition, many proteases will also be activated during I/R, and one particulary family of these proteases, calpain, is often responsible for cell death. Since IpostC is designed to apply in the early phase of reperfusion, it may exert protective effects through modulating the molecular alterations in the first 3 h after reperfusion. Therefore, we further explored whether IpostC could activate the protective molecular pathoways against necrapoptosis and reverse the cell death process, especially those occur in the early reperfusion phase.
Cells can spontaneously respond to injury insults through activating its defensive mechanisms. Among them, cell cycle regulation plays a key role in cell structure and function recovery. Unlike many other organs, the liver possesses extreme ability of regeneration. Although the majority of hepatocytes stay in quiescent phase (GO phase), they can be quickly activated into cell cycle and start rapid proliferation upon proper stimulation. There are many critical molecules regulating the process from priming to proliferating. Amongst these molecules the cell cycle promoting factors, cyclin D_1 and CDK4, and suppressing factors, p21, play a critical role through dynamic coordination with each other. It is unclear whether the protection afforded by IpostC is related with any of these molecular alterations. This has prompted us to examine the expression of cyclin D_1, CDK4 and p21 so as to determine the impact of IpostC on cell cycle regulation and provide experimental evidences to guide future research and clinical application.
Methods
1. Establishment of 70% hepatic ischemia and reperfusion models in SD rats. This is accomplished through two phases of experiments. For phase one study, rats were divided into 6 experimental groups, i.e. (1) sham operation (S) group, (2) ischemia only (60 min) (I), (3) ischemia and reperfusion (I/R), and 3 IpostC groups that are subjected to 3 different cycles of reperfusion and occlusion at the onset of reperfusion, including (4) IpostC 1 (30 sec on/off), (5) IpostC 2 ( 1 min on/off) and (6) IpostC 3 group ( 2 min on/off). Changes of alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) activities were measured with automatic biochemistry analyzer, together with the pathological evaluation of liver damages with microscopy in all groups.
In the second phase of experiment we divided the rats into 5 groups, i.e. S group, I/R group, IpreC group, IpostC group (3 cycles of 1 min on/off) and combined IpreC and IpbstC (IpreC/IpostC ) group. In addition to the parameters detected in the first phase of experiment we have also evaluated the 7 days of survival rate in I/R、IpreC、IpostC and IpreC/IpostC groups by using the total hepatic ischemia/reperfusion after 70% liver ischemia.
2. To explore the role of antioxidative mechanisms in protection of IpostC against hepatic I/R injury, the tissue levels of MDA, GSH, SOD, GSH-P_X and MPO at 6 hour after reperfusion were analyzed by colorimetric method.
3. To examine the changes of apoptosis and genes involved in apoptosis, three experimental groups were set up, including S group, I/R group and IpostC group. Tissue and plasma levels of TNF-αat 1 h and 3 h after reperfusion were quantified using ELISA. Expressions ofμ-Calpain、Talin、Bid、Cyt C and Caspase-3 proteins were also detected using Western blot analysis. The hepatic ultrastructure at 1 h after reperfusion were observed using transmission electron microscope (TEM). The survival rate of hepatocytes at 1 h and 3 h after reperfusion were assessed by flow cytometry (FCM) using Annexin V/PI double-stained method.
4. To determine the role of cell cycle regulators, three groups were set up, including S group, I/R group and IpostC group. Expressions of cyclin D_1, CDK4 and p21 proteins and messenger RNA were detected using Western blot analysis and real-time PCR respectively. The cell cycle percentage of hepatocytes were detected by FCM using PI stained method.
Results
1. Protective effects of ischemic postconditioning against hepatic ischemia/reperfusion injury.
In the first phase of experiment, our results showed increased plasma activities of ALT and AST in S group (68.30±11.12 U/L vs. 211.65±95.63 U/L), 30 min of ischemia (78.33±32.12 U/L vs. 260.33±45.12 U/L) and 60 min of ischemia (210.85±75.75 U/L vs. 340.93±108.52 U/L). With prolonged reperfusion time the plasma activities of ALT and AST further increased (P<0.05) . Compared with I/R group, the plasma activities of ALT and AST at 60 min and 6 h after reperfusion were lowered in IpostC 1 and IpostC 2 groups, with the later being more significant. No significant changes of the plasma activities of ALT and AST was found in IpostC 3 group. Histopatholoical examination revealed evidences of descreased cellular injuries in rat livers of IpostC 1 and IpostC 2 group, while rats in IpostC 3 groups suffered damages similar to those in the I/R group.
In the second phase of experiment, significantly decreased activities of ALT and AST were detected in IpreC、IpostC and IpreC/IpostC groups as compared with I/R group. When IpreC and IpostC group were compared, no further decrease was observed in IpreC/IpostC group. Instead, there appears to be a slight increase in IpreC/IpostC group, although the differences was not significant. Similarly, combined IpreC and IpostC failed to minimize pathologic injuries compared with either IpreC or IpostC group.
2. The role of antioxidative mechanism in protection of IpostC against hepatic I/R injury
Contrast to I/R group, decreased tissue MDA content and MPO activities, increased tissue GSH content and SOD and GSH-P_X activities at 6 h after reperfusion were found in IpostC 1 and IpostC 2 groups. The degree of alteration in IpostC 2 group was more pronounced than that in IpostC 1 group. No significant alteration was found in IpostC 3 group with the level comparable to I/R group. Similarly, combined IpreC and IpostC failed to produce improvement in the hepatic levels of MDA、SOD、GSH- PX、GSH and MPO.
3. Effect of ischemic postconditioning on the necrapoptosis pathway against ischemia/reperfusion injury
Compared with S group the contents of tissue and plasma TNF-αat 1 h and 3 h after reperfusion were higher in both I/R and IpostC groups. After ischemic postconditioning, decreased level of TNF-α, albeit higher than that in S group, was produced. Compared with I/R group, IpostC inhibited the expression ofμ-Calpain, Bid, Cyt C and Caspase-3, enhanced Talin expression and lessened the injury on cellular ultrastructure. IpostC promoted cell survive and suppressed cell death at 1 h and 3 h after reperfusion.
4. Effect of ischemic postconditioning on cell cycle molecules cyclin D_1,CDK4 and p21
Compared with I/R group, IpostC increased the expression of cyclin D_1、CDK4 and p21 both at proteins and mRNA levels, with highest expression level in CDK4. Compared with S group, although a shift of cell population from G_0/G_1 phases to S phase was observed in both I/R, a more pronounced changes were produced in the IpostC group.
Conclusions
1. Ischemic postconditiomng is effective in protecting against hepatic ischemia and reperfusion injuries, resulting in preservation of liver function, decrease of tissue pathologic injuries and significant improvement of 7 days survival rate.
2. Combined ischemic preconditioning with ischemic postconditiomng can not offer additive protection, only produced a weakened protection that is less effective than those produced by them acting alone.
3. The protective role of ischemic postconditiomng against hepatic ischemia and reperfusion injury are related to its antioxidative mechanisms that include reducing the activities of lipid peroxidation, increaseing tissue GSH content and SOD and GSH-P_X activities and suppressing polymorphonuclear neutrophils infiltration.
4. Ischemic postconditiomng can decrease the cellular injuries and promote cell survival through suppressing cytokine production and disturbing the protein expressions ofμ-Calpain, Bid, Cyt C, Caspase-3 and talin.
5. Ischemic postconditiomng can prime and promote the cell cycle entry through increasing the mRNA and protein expressions of cyclin D_1, CDK4 and p21.
4. Our study provided experimental evidences to support further study of the protective mechanism of ischemic postconditiomng against ischemia and reperfusion injury, which should not only guide future development of novel drugs mimicking the mechanisms of ischemic postconditiomng, but also provide new therapeutic targets in hepatic anti-ischemia and reperfusion injury researches.
肝脏缺血-再灌注(ischemia／reperfusion，I／R)损伤是临床常见的病理生理现象，也是许多肝缺血疾病预后不良的重要原因。因此，深入研究I／R肝损伤的病理生理机制及寻找各种抗I／R肝损伤策略一直是肝脏研究领域的重要方向。作为一种启动机体内源性保护机制的方法，缺血预处理(ischemic preconditioning，IpreC)对I／R肝的保护作用已得到普遍的认可。然而，由于IpreC必须在器官长久缺血前实施，这在一定程度上限制了其在临床的推广。最近，一种新的干预策略——缺血后处理(ischemic postconditioning，IpostC)因其能减轻I／R心脏损伤而引起了广泛的关注。IpostC是指通过在再灌注起始实施数个循环的短暂的血流灌注(on)／阻断(off)，能够削弱随后再灌注引起的损伤。IpostC实施方法与IpreC相似，但其简便易行、实施时机合理的优点将使其在临床应用具有诱人的前景。当前大多数IpostC研究集中在心脏方面，其对其他I／R器官是否具有保护作用尚不确定，因此本研究首先探讨IpostC对SD大鼠I／R肝脏是否具有保护作用，随后进一步研究联合应用IpreC和IpostC是否能够提供相加的保护作用。同时，在此基础上我们探讨了抗氧化机制在IpostC抗I／R肝损伤中的作用。
在肝I／R过程中，细胞的最终命运常常表现为细胞凋亡和坏死。长久以来这两种细胞死亡方式被认为具有截然不同的特征和发生过程，然而近年来研究认为两者的发生至少部分经过共同的信号传导途径，称之为necrapoptosis(死亡通路)。线粒体通透性转换(MPT)在细胞死亡发生过程中发挥关键作用。MPT一旦发生，细胞要么凋亡要么坏死。肝I／R损伤常被划分为两期，早期(再灌注＜3 h内)主要以氧化应激引发的组织损伤为特征，晚期以募集在肝实质内的PMN引发的炎性损伤等为特征。另外，肝I／R损伤常常伴随有许多蛋白酶的激活，其中Calpain家族在引发I／R肝细胞死亡中发挥重要的作用。由于IpostC是再灌注起始采取的干预手段，其抗I／R肝损伤机制很可能与影响再灌注早期的分子事件有关。因此，本研究进一步探讨了IpostC对再灌注早期大鼠肝组织中与细胞死亡通路相关分子及其对细胞早期死亡特征的影响。
细胞在遭受损伤刺激的作用下必然同时会启动自身的防御性机制，其中细胞周期的启动对于细胞自身结构修复和功能恢复尤为重要。与其他器官不同，肝脏是机体内具有极强再生能力的器官。通常，绝大多数肝细胞处于静息状态(G_0期)，在接受外来刺激后可很快被启动进入细胞周期，发生增殖。从细胞启动到肝细胞分裂增殖的过程中涉及到许多重要分子的参与，其中细胞周期促进分子cyclin D_1和CDK4以及抑制分子p21相互协调并发挥着关键的作用。IpostC能否通过影响这些细胞周期分子的表达对I／R肝脏发挥保护作用尚不清楚，因此本研究着重研究了这些细胞周期相关分子的表达，以探讨IpostC对细胞周期的影响，为其未来研究和应用提供一定的理论基础。
[方法]
1．复制SD大鼠70％肝缺血-再灌注模型。在此基础上实验分两步进行。
第一步实验实验动物分为6组：假手术(S)组、单纯60 min缺血组、缺血再灌注(I／R)组和3组采用不同方案的缺血后处理(IpostC)组，即再灌注起始采用3个循环30 s灌注／30 s阻断(30 s on／off)的IpostC 1组、3个循环1 minon／off的IpostC 2组和2 min on／off的IpostC 3组。采用全自动生化分析仪测定各组大鼠血清ALT和AST活性，同时观察各组大鼠肝组织的病理组织学改变，评价IpostC对I／R肝脏的抗损伤作用。
第二步实验实验动物分为5组，即S组、I／R组、IpreC组(长时间缺血前应用2个循环的缺血5 min／再灌注5 min)、IpostC组(3周期1 min on／off方案)和联合应用IpreC组和IpostC组(IpreC／IpostC)。除了观察第一步实验的各项指标外，第二步实验采用70％肝缺血后全缺血肝再灌注模型来评价各组的术后7天生存率，用以评价联合IpreC和IpostC对I／R肝脏的抗损伤作用。
2．采用分光光度比色法测定大鼠肝组织中MDA、GSH的含量和SOD、GSH-Px和MPO的活性，评价抗氧化机制在IpostC抗I／R肝损伤中的作用。
3．采用ELISA法测定S组、UR组和IpostC组大鼠在再灌注1h和3h时肝组织和血清中TNF-α的含量。采用Western blot法测定各组大鼠在再灌注1h和3h肝组织中μ-Calpain、Talin、Bid、Cyt C和Caspase-3蛋白的表达。透射电镜观察各组大鼠在再灌注1h时的超微结构。应用流式细胞术Annexin V／PI双染色法鉴定各组大鼠再灌注1h和3h肝脏组织中生存的、早期凋亡的以及晚期凋亡和坏死的肝细胞生存率。评价IpostC对再灌注早期大鼠肝组织中与细胞死亡通路相关分子及其对细胞早期死亡特征的影响，
4．分别采用quantitative real-time PCR和Western blot方法测定S组、I／R组和IpostC组大鼠在再灌注1h、3h和24h时肝组织中cyclin D_1、CDK4和p21 mRNA和蛋白的表达情况。应用流式细胞术PI染色法测定各组大鼠在再灌注1h、3h和24h时肝细胞细胞周期各时相的百分比。评价IpostC对细胞周期和细胞周期相关分子表达的影响。
[结果]
1．缺血后处理对缺血-再灌注损伤肝脏的保护作用研究
1．1第一步实验结果显示，ALT和AST活性分别在S组(68.30±11.12 U／L和211.65±95.63 U／L)、缺血30 min(78.33±32.12 U／L和260.33+45.12 U／L)和缺血60min(210.85±75.75 U／L和340.93±108.52 U／L)大鼠血清中逐渐增高(P＜0.05)，伴随再灌注时间的延长，其酶活性进一步增加(P＜0.05)。与I／R组相比，IpostC1和IpostC 2组在再灌注60 min和6h的ALT和AST活性明显降低，IpostC 2组降低更明显，差异非常显著(P＜0.05)；IpostC 3组ALT和AST活性无降低。同时，病理组织学显示IpostC 1和IpostC 2组损害明显减轻，而IpostC 3组病理学损害与I／R相当。结果提示IpostC 2组具有显著的抗I／R肝损伤作用。
1．2第二步实验结果显示，与I／R组相比，IpreC、IpostC和IpreC／IpostC组ALT、AST活性均明显降低，差异显著(P＜0.05)。与IpreC和IpostC相比，IpreC／IpostC组ALT和AST值无进一步降低，反而有增加趋势，但差异无显著性(P＞0.05)。同样，与单独应用IpreC和IpostC相比，也不能使组织病理损害进一步减轻，反而有加重迹象。结果提示联合应用IpreC和IpostC不能提供相加的抗I／R肝损伤作用。
2．缺血后处理抗氧化机制的研究
与I/R组相比，IpostC 1和IpostC 2组在再灌注6h时肝组织中MDA含量减少、GSH含量增加、SOD和GSH-Px活性增高而MPO活性降低(P＜0.05)，以IpostC 2组各项指标变化更明显；IpostC 3组各项指标无明显改善。与单独应用IpreC和IpostC相比，联合应用IpreC和IpostC也不能进一步改善I／R肝组织中MDA、SOD、GSH-PX、GSH和MPO的水平。结果提示IpostC具有抗氧化损伤作用。
3．缺血后处理对细胞死亡通路的干扰与调控
与S组相比，再灌注1h和3h时大鼠肝组织和血清中TNF-α含量均明显增高，以3h时增高最明显(P＜0.05)；IpostC能够明显减轻再灌注1h和3h时大鼠肝组织和血清中TNF-α含量(P＜0.05)，但仍显著高于S组(P＜0.05)。与I／R组相比，IpostC能使再灌注1h和3h时大鼠肝组织中μ-Calpain、Bid、Cyt C和Caspase-3的表达降低，Talin表达增高，细胞超微结构损害减轻。IpostC能够明显增加再灌注1h、3h的细胞生存率，降低早期凋亡细胞比例。
4．缺血后处理对肝细胞周期调控机制的研究
与I／R组相比，IpostC能够增加细胞周期相关分子cyclin D_1、CDK4和p21mRNA和蛋白的表达，而以CDK4表达增加更明显。与S组相比，I／R组和IpostC组中G_0／G_1期细胞百分比明显降低，而S期细胞百分比则明显增高。与I／R组相比时，IpostC能使G_0／G_1期细胞百分比进一步降低，S期细胞百分比进一步增高(P＜0.05)。结果提示IpostC能够启动和促进细胞周期运转。
[结论]
1．缺血后处理能够保护肝功能、减轻肝组织病理损害和提高生存率，具有抗大鼠I／R肝损伤作用。
2．联合应用缺血预处理和缺血后处理不能提供相加的保护作用，反而削弱了各自单独应用的保护效应。
3．缺血后处理抗大鼠缺血-再灌注肝损伤作用与抗氧化作用机制有关，可能通过减轻I／R肝组织脂质过氧化作用，提高抗氧化物质SOD、GSH-PX和GSH水平，减少中性粒细胞浸润和聚集发挥作用。
4．缺血后处理能够减轻肝细胞超微结构损害，增加肝细胞生存率，其作用机制可能与干扰再灌注早期死亡通路细胞因子TNF-α的产生和相关分子μ-Calpain、Bid、Cyt C、Caspase-3和Talin的蛋白表达有关。
5．缺血后处理能够促进肝细胞周期运转，其作用机制可能与增加细胞周期相关分子cyclin D_1、CDK4和p21 mRNA和蛋白的表达有关。
6．本研究不仅能为缺血后处理在肝脏外科的临床应用提供理论和实践依据，而且为开发新的模拟缺血后处理作用机制药物提供参考，还可为防治I／R肝损伤提供新靶点，具有广阔的应用前景以及重要的应用价值和意义。
Background and Objectives
Hepatic ischemia and reperfusion (I/R) is a pathophysiological phenomenon that occurs very frequently in clinical practice. More importantly, I/R is also responsible for liver injuries that often lead to poor prognosis. Many efforts are being made to investigate the pathophysiological mechanism of I/R injury and to search for strategies that will protect liver against I/R induced damage. One of the approaches that have gained widespread recognition involves the use of ischemic preconditioning (IpreC), which has displayed significant protective effects in hepatic I/R injury through its abilities to stimulate endogenous protective mechanisms. However, since IpreC must be performed prior to the sustained ischemia, its usefulness is limited in clinical practices. Recently, a new and alternative strategy focusing on ischemic postconditioning (IpostC) has attracted extensive interest largely due to its remarkable success in protecting heart from I/R injuries. Unlike IpreC, the IpostC applies the brief episodes of ischemia at the onset of reperfusion following a prolonged ischemia. Since IpostC can be easily applied with precisely controlled timing, this approach appears to have greater potential for clinical application. However, most of the current studies are concentrated on the I/R of heart, and it remained to be determined whether IpostC can provide similar effective protection to other I/R organs. This study was therefore designed to first explore the protective activities of IpostC against hepatic I/R injury, followed by investigating whether combined IpreC and IpostC could provide additive or synergistic protections. At the same time, we are also endeavored to define the underlying antioxidative mechanisms with which IpostC protects liver from I/R injuries.
Apoptosis and necrosis are the final outcome for hepatocytes during hepatic I/R process. Although they have long been believed as two distinct death modes, recent studies have revealed that the two processes partly employ a common signaling pathway, namely necrapoptosis, in which the mitochondrial permeability transition (MPT) is established to play a critical role. Formation of MPT can lead to cell apoptosis or necrosis. There are two distinct phases of liver injury after warm I/R. The initial phase (<3 h after reperfusion) is characterized by oxidative stress, where production and release of ROS appears to directly result in hepatocellular injury. The late phase of liver injury, which occurs 6 to 48 h after hepatic reperfusion, is an inflammatory disorder mediated by recruited neutrophils. In addition, many proteases will also be activated during I/R, and one particulary family of these proteases, calpain, is often responsible for cell death. Since IpostC is designed to apply in the early phase of reperfusion, it may exert protective effects through modulating the molecular alterations in the first 3 h after reperfusion. Therefore, we further explored whether IpostC could activate the protective molecular pathoways against necrapoptosis and reverse the cell death process, especially those occur in the early reperfusion phase.
Cells can spontaneously respond to injury insults through activating its defensive mechanisms. Among them, cell cycle regulation plays a key role in cell structure and function recovery. Unlike many other organs, the liver possesses extreme ability of regeneration. Although the majority of hepatocytes stay in quiescent phase (GO phase), they can be quickly activated into cell cycle and start rapid proliferation upon proper stimulation. There are many critical molecules regulating the process from priming to proliferating. Amongst these molecules the cell cycle promoting factors, cyclin D_1 and CDK4, and suppressing factors, p21, play a critical role through dynamic coordination with each other. It is unclear whether the protection afforded by IpostC is related with any of these molecular alterations. This has prompted us to examine the expression of cyclin D_1, CDK4 and p21 so as to determine the impact of IpostC on cell cycle regulation and provide experimental evidences to guide future research and clinical application.
Methods
1. Establishment of 70% hepatic ischemia and reperfusion models in SD rats. This is accomplished through two phases of experiments. For phase one study, rats were divided into 6 experimental groups, i.e. (1) sham operation (S) group, (2) ischemia only (60 min) (I), (3) ischemia and reperfusion (I/R), and 3 IpostC groups that are subjected to 3 different cycles of reperfusion and occlusion at the onset of reperfusion, including (4) IpostC 1 (30 sec on/off), (5) IpostC 2 ( 1 min on/off) and (6) IpostC 3 group ( 2 min on/off). Changes of alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) activities were measured with automatic biochemistry analyzer, together with the pathological evaluation of liver damages with microscopy in all groups.
In the second phase of experiment we divided the rats into 5 groups, i.e. S group, I/R group, IpreC group, IpostC group (3 cycles of 1 min on/off) and combined IpreC and IpbstC (IpreC/IpostC ) group. In addition to the parameters detected in the first phase of experiment we have also evaluated the 7 days of survival rate in I/R、IpreC、IpostC and IpreC/IpostC groups by using the total hepatic ischemia/reperfusion after 70% liver ischemia.
2. To explore the role of antioxidative mechanisms in protection of IpostC against hepatic I/R injury, the tissue levels of MDA, GSH, SOD, GSH-P_X and MPO at 6 hour after reperfusion were analyzed by colorimetric method.
3. To examine the changes of apoptosis and genes involved in apoptosis, three experimental groups were set up, including S group, I/R group and IpostC group. Tissue and plasma levels of TNF-αat 1 h and 3 h after reperfusion were quantified using ELISA. Expressions ofμ-Calpain、Talin、Bid、Cyt C and Caspase-3 proteins were also detected using Western blot analysis. The hepatic ultrastructure at 1 h after reperfusion were observed using transmission electron microscope (TEM). The survival rate of hepatocytes at 1 h and 3 h after reperfusion were assessed by flow cytometry (FCM) using Annexin V/PI double-stained method.
4. To determine the role of cell cycle regulators, three groups were set up, including S group, I/R group and IpostC group. Expressions of cyclin D_1, CDK4 and p21 proteins and messenger RNA were detected using Western blot analysis and real-time PCR respectively. The cell cycle percentage of hepatocytes were detected by FCM using PI stained method.
Results
1. Protective effects of ischemic postconditioning against hepatic ischemia/reperfusion injury.
In the first phase of experiment, our results showed increased plasma activities of ALT and AST in S group (68.30±11.12 U/L vs. 211.65±95.63 U/L), 30 min of ischemia (78.33±32.12 U/L vs. 260.33±45.12 U/L) and 60 min of ischemia (210.85±75.75 U/L vs. 340.93±108.52 U/L). With prolonged reperfusion time the plasma activities of ALT and AST further increased (P<0.05) . Compared with I/R group, the plasma activities of ALT and AST at 60 min and 6 h after reperfusion were lowered in IpostC 1 and IpostC 2 groups, with the later being more significant. No significant changes of the plasma activities of ALT and AST was found in IpostC 3 group. Histopatholoical examination revealed evidences of descreased cellular injuries in rat livers of IpostC 1 and IpostC 2 group, while rats in IpostC 3 groups suffered damages similar to those in the I/R group.
In the second phase of experiment, significantly decreased activities of ALT and AST were detected in IpreC、IpostC and IpreC/IpostC groups as compared with I/R group. When IpreC and IpostC group were compared, no further decrease was observed in IpreC/IpostC group. Instead, there appears to be a slight increase in IpreC/IpostC group, although the differences was not significant. Similarly, combined IpreC and IpostC failed to minimize pathologic injuries compared with either IpreC or IpostC group.
2. The role of antioxidative mechanism in protection of IpostC against hepatic I/R injury
Contrast to I/R group, decreased tissue MDA content and MPO activities, increased tissue GSH content and SOD and GSH-P_X activities at 6 h after reperfusion were found in IpostC 1 and IpostC 2 groups. The degree of alteration in IpostC 2 group was more pronounced than that in IpostC 1 group. No significant alteration was found in IpostC 3 group with the level comparable to I/R group. Similarly, combined IpreC and IpostC failed to produce improvement in the hepatic levels of MDA、SOD、GSH- PX、GSH and MPO.
3. Effect of ischemic postconditioning on the necrapoptosis pathway against ischemia/reperfusion injury
Compared with S group the contents of tissue and plasma TNF-αat 1 h and 3 h after reperfusion were higher in both I/R and IpostC groups. After ischemic postconditioning, decreased level of TNF-α, albeit higher than that in S group, was produced. Compared with I/R group, IpostC inhibited the expression ofμ-Calpain, Bid, Cyt C and Caspase-3, enhanced Talin expression and lessened the injury on cellular ultrastructure. IpostC promoted cell survive and suppressed cell death at 1 h and 3 h after reperfusion.
4. Effect of ischemic postconditioning on cell cycle molecules cyclin D_1,CDK4 and p21
Compared with I/R group, IpostC increased the expression of cyclin D_1、CDK4 and p21 both at proteins and mRNA levels, with highest expression level in CDK4. Compared with S group, although a shift of cell population from G_0/G_1 phases to S phase was observed in both I/R, a more pronounced changes were produced in the IpostC group.
Conclusions
1. Ischemic postconditiomng is effective in protecting against hepatic ischemia and reperfusion injuries, resulting in preservation of liver function, decrease of tissue pathologic injuries and significant improvement of 7 days survival rate.
2. Combined ischemic preconditioning with ischemic postconditiomng can not offer additive protection, only produced a weakened protection that is less effective than those produced by them acting alone.
3. The protective role of ischemic postconditiomng against hepatic ischemia and reperfusion injury are related to its antioxidative mechanisms that include reducing the activities of lipid peroxidation, increaseing tissue GSH content and SOD and GSH-P_X activities and suppressing polymorphonuclear neutrophils infiltration.
4. Ischemic postconditiomng can decrease the cellular injuries and promote cell survival through suppressing cytokine production and disturbing the protein expressions ofμ-Calpain, Bid, Cyt C, Caspase-3 and talin.
5. Ischemic postconditiomng can prime and promote the cell cycle entry through increasing the mRNA and protein expressions of cyclin D_1, CDK4 and p21.
4. Our study provided experimental evidences to support further study of the protective mechanism of ischemic postconditiomng against ischemia and reperfusion injury, which should not only guide future development of novel drugs mimicking the mechanisms of ischemic postconditiomng, but also provide new therapeutic targets in hepatic anti-ischemia and reperfusion injury researches.
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