联合应用厄贝沙坦和依达拉奉对大鼠边缘性体积供肝移植的供肝保护作用研究
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摘要
第一部分大鼠边缘性体积供肝肝移植模型的建立
目的
本部分实验通过离体减体积肝叶切除供肝―大鼠原位肝移植方式,探讨大鼠边缘性体积供肝肝移植模型建立的方法,为研究小肝综合症的发病机制及防治措施提供一个较为理想的小动物模型。
材料和方法
选用健康、9~12周龄、体重190~250g的雄性大鼠192只作为实验动物,取周龄相差1~3周,体重相差20~30克的大鼠,以小体重大鼠作为供体,采用离体减体积肝叶切除方式行不同体积供肝的大鼠原位肝移植。本部分实验设立4个实验组:A组,全肝移植组(n=24);B组,50%部分肝移植组(切除肝左叶,双乳突叶,保留肝中叶、右后叶和右前叶作为供肝,使供肝与受体肝比值控制在50%左右,n=24);C组,30%部分肝移植组,除保留大鼠肝中叶外,其余四叶均予以切除,使供肝重量与受体肝比值控制在30%～35%之间,n=24);D组:小于30%部分肝移植组(保留右前叶、右后叶和双乳突叶,切除肝中叶和左叶,使供肝与受体肝比值小于30%,n=24)。供、受体均采用乙醚持续开放式吸入麻醉,大鼠原位肝移植血管重建采用双袖套法,不做肝动脉血管重建。观察各组术后肝功能ALT和AST水平、门静脉压力和存活率,光镜下及电镜下表现,比较分析各组间ALT、门静脉压力及累积存活率之间的关系。
结果
1.全肝移植组(A组)7天累积存活率为100%(12/12),50%部分肝移植组(B组)7天累积存活率为83.3%(10/12),30%部分肝移植组(C组)7天累积存活率为16.7%(2/12),小于30%部分肝移植组(D组)均于术后48小时内死亡。各组间存活率经生存分析life-table方法比较,A组与B组累积存活率比较,组间差异无统计学意义,p=0.148; C组与A组累积存活率比较,组间差异有统计学意义,p<0.001;C组与B组两组存活率有显著性差异,p<0.001; C组与D组两组存活率有显著性差异,p<0.001;
2.受体在移植前基础门静脉压力各组间差异无统计学意义,p>0.05。A组术中开放门静脉后1小时内门静脉压力稳定,B组开放门静脉后门静脉压力虽有小幅上升,但门静脉压力仍保持相对稳定,而C组和D组开放门静脉后门静脉压力显著升高,15分钟达到峰值,两组门静脉压力峰值分别较基础门静脉压力升高65%和82%。两组门静脉压力30分钟开始回落,至45分钟到60分钟逐渐稳定,但仍维持于一高位。将供肝体积的大小与各时间点的门静脉压力进行Pearson相关分析后发现,供肝体积的大小与基础门静脉压力无相关性,相关系数r=0.249,p=0.241;而供肝体积大小与开放门静脉后5、15、30、45、60分钟门静脉压力呈负相关性,(相关系数分别为r=-0.926,r=-0.936, r=-0.904, r=-0.902, r=-0.867, p<0.05)。
3.肝移植术后24小时各组ALT和AST水平明显升高,四组中以D组水平最高,C组次之,B组和A组最低,各组间差异有统计学意义,p<0.001。将供肝体积大小与各组移植术后24小时ALT和AST水平进行Pearson相关分析后,结果显示供肝体积大小与移植术后24小时ALT和AST水平呈负相关性,相关系数r分别为-0.704和-0.815, p<0.05。
4.光镜下可见各组均出现不同程度的肝窦充血、局部肝窦扩张、血管内皮细胞完整性受损、肝板结构改变及肝细胞空泡变性等形态学异常的表现。与其他组相比较,C,D组在术后24小时形态学异常的表现均较为明显且程度严重。
5.电镜观察结果显示,C,D组在肝移植术后24小时出现严重的肝窦内皮细胞线性结构完整性破坏、线粒体肿胀等严重的形态学异常。A,B在相应的时间点肝细胞的超显微结构保持得相对完整
结论
1.再次证实直视下离体减体积肝叶切除供肝―大鼠原位肝移植模型是作为为小肝综合症基础性研究的较为理想的小动物模型,具有很好的可靠性和可重复性。
2.再次证实了大鼠减体积供肝肝移植模型供肝体积大小的安全界限为50%标准体积;体积介于35～30%标准体积之间的供肝应视为边缘性体积移植物,小于30%标准体积的供肝可视为超小体积肝移植。
3.大鼠边缘性体积供肝肝移植模型的建立,可选取周龄相差1～3周,体重相差20～30克的大鼠,以小体重的大鼠作为供体,除保留肝中叶外,其余四叶均予以切除,可以使供肝湿重与受体肝比值控制在30%～35%之间。
4.大鼠减体积供肝肝移植模型中,供肝体积大小与开放门静脉压力升高幅度及术后24小时ALT和AST水平呈负相关性,小体积供肝肝移植术中开放门静脉后急剧升高的门静脉压力对肝窦造成的应力性的损伤,是导致肝移植术后小体积移植物功能损害、受体存活率降低的主要原因。
第二部分联合应用厄贝沙坦和依达拉奉对大鼠边缘性体积肝移植的移植物保护作用的研究
目的
本部分实验拟对大鼠边缘性体积供肝肝移植术后小体积移植物早期损伤的机制进行初步研究,探讨在大鼠边缘性体积供肝肝移植术中联合使用厄贝沙坦和依达拉奉,降低再灌注期间门静脉压力,减轻缺血再灌注损伤对边缘性体积供肝早期损伤的保护作用机制。
材料和方法
选用健康、体重相差20~30克的雄性SD大鼠300只,以小体重大鼠为供体,按第一部分介绍的方法建立大鼠边缘性体积供肝肝移植模型,将供受体大鼠随机分为:A组,边缘性体积部分肝移植生理盐水对照组;B组,边缘性体积部分肝移植依达拉奉实验组;C组,边缘性体积部分肝移植厄贝沙坦实验组;D组,边缘性体积部分肝移植厄贝沙坦联合依达拉奉实验组;E组,假手术组。观察各组术后一般情况、门静脉压力和存活率,各组分别于术后6小时和24小时各取6只受体在无菌操作条件下采取下腔静脉血标本和肝组织标本。测定血清中ALT、AST水平、肝细胞匀浆内SOD活力和MDA含量、RT-PCR检测肝组织中Egr-1,ET-1,Bax mRNA表达情况,免疫组化检测肝组织中ET-1,Bax,TNF表达情况,TUNEL检测肝组织细胞凋亡情况以及光镜下观察肝组织形态学改变。
结果
1.光镜下可见各组均出现不同程度的肝窦充血、局部肝窦扩张、血管内皮细胞完整性受损、肝板结构改变及肝细胞空泡变性等形态学异常的表现。以术后6小时最为严重。与其他组相比较,A,B组在术后6小时和24小时形态学异常的表现均较为明显且程度严重。D组最轻。E组无明显变化。
2.A组7天累积存活率为8.33%(1/12),B组7天累积存活率为33.3%(4/12),C组7天累积存活率为58. 7%(7/12), D组7天累积存活率为83. 3%(10/12),E组7天累积存活率为100%(12/12),经SPSS生存分析life-table方法比较,各组累积存活率之间的差异有统计学意义。A组与B组累积存活率比较,组间差异有统计学意义,p=0.018; C组与A组累积存活率比较,组间差异有统计学意义,p<0.001;D组与A组两组存活率有显著性差异,p<0.001; E组与A组两组存活率有显著性差异,p<0.001;
3.C,D组受体移植前基础门静脉压力低于A,B组,各组间均数比较,差异有统计学意义(8.21,8.15 vs 10.28,10.55,p=0.019)。各组开放门静脉恢复血流灌注后门静脉压力的峰值均出现在开放门静脉后的15分钟处,但C,D组门静脉压力峰值要明显低于A,B组,各组间均数比较差异有显著统计学意义(15.76,15.80 vs 18.11,18.55 ,p<0.001)。开放门静脉30分钟之后两组门静脉逐渐回落,C,D组开放门静脉后门静脉压力维持相对稳定,波动于12.63～13.42cmH_2O之间,峰值门静脉压力较基础门静脉压力升高幅度达23.1%。而A,B组恢复门静脉灌注后门静脉压力显著升高,波动于15.47～16.52cmH_2O之间,峰值门静脉压力较基础门静脉压力升高幅度高达65.5%。C,D组在恢复门静脉灌注后的5、15、30和60分钟各时间点均明显低于A,B组,各组各时间点门静脉压力均数经单因素方差分析,LSD分析,p<0.001,差异有显著统计学意义。
4.实验中各组肝移植术后血清ALT和AST水平显著升高,均在再灌注6小时升至峰值,术后24小时虽有所下降,但仍处于高水平状态。说明移植后移植物的肝实质细胞的损伤以6小时最为严重,24小时内仍处于一个急性期阶段。与其他组相比较A,B组在术后6小时和24小时血清ALT和AST水平显著升高,均较为明显且程度严重。D组最轻。E组无明显变化。各组间ALT和AST均数经比较差异有统计学意义,p<0.05。说明再灌注期间降低门脉压力,抗氧化减轻缺血再灌注损伤可减轻小体积移植物肝实质细胞的损伤的程度。
5.本实验中各组肝移植术后MDA水平显著升高,均在再灌注6小时升至峰值,术后24小时虽有所下降,但仍处于高水平状态。说明移植后移植物的缺血再灌注损伤以6小时最为严重,24小时内仍处于一个急性期阶段。与其他组相比较,A,B组在术后6小时和24小时MDA水平显著升高。均较为明显且程度严重。D组最轻。E组无明显变化。各组间MDA均数经比较差异有统计学意义,p<0.05。本实验中各组肝移植术后SOD水平显著下降,说明移植后移植物的缺血再灌注损伤SOD不断耗竭,24小时内仍处于耗竭阶段。与其他组相比较,A,B组在术后6小时和24小时SOD水平显著降低。均较为明显且程度严重。D组最轻。E组无明显变化。各组各亚组间SOD均数经比较差异有统计学意义,p<0.05。说明各组大鼠受体均不同预处理后,缺血再灌注损伤有显著差别。D组缺血再灌注损伤较A,B,C组轻。E组无明显变化。说明联合使用厄贝沙坦和依达拉奉能明显减轻小体积移植物缺血再灌注损伤。
6.A组术后6小时和24小时Egr-1 mRNA ,ET-1mRNA ,BaxmRNA表达均高于其他组(p<0.05)。D组术后6小时和24小时Egr-1 mRNA ,ET-1mRNA ,BaxmRNA表达较A,B,C组表达低(p<0.05)。说明在厄贝沙坦和依达拉奉的联合作用下,Egr-1 mRNA ,ET-1mRNA ,BaxmRNA表达较低。而C组术后6小时和24小时Egr-1mRNA, ET-1mRNA , BaxmRNA表达均低于B组(p<0.05)。说明在小体积肝移植中,门静脉一过性增高对这些mRNA影响大于缺血再灌注因素。
7、免疫组化显示:A组术后6小时和24小时ET-1,Bax,TNF表达均高于其他组(p<0.05)。D组术后6小时和24小时ET-1 ,Bax,TNF表达较A,B,C组表达低(p<0.05)。说明在厄贝沙坦和依达拉奉的联合作用下,ET-1,Bax,TNF表达较低。而C组术后6小时和24小时ET-1 ,Bax,TNF表达均低于B组(p<0.05)。说明在小体积肝移植中,门静脉一过性增高对这些基因蛋白的影响大于缺血再灌注因素。
8、Tunel显示:A组术后6小时和24小时凋亡指数高于其他组(p<0.05)。D组术后6小时和24小时凋亡指数较A,B,C组表达低(p<0.05)。说明在厄贝沙坦和依达拉奉的联合作用下,肝细胞凋亡较少。而C组术后6小时和24小时凋亡指数表达均低于B组(p<0.05)。说明在小体积肝移植中,门静脉一过性增高对细胞凋亡的影响大于缺血再灌注因素。
结论
1.大鼠边缘性体积部分肝移植术后造成小体积移植物的灌注后损伤的特殊性就在于其面临的是早期门静脉过度灌注和缺血再灌注的双重损伤。
2.在大鼠边缘性体积供肝移植中,门静脉压力升高和缺血再灌注损伤两个因素中,门静脉压力升高对肝窦内皮细胞造成的应力性损伤,对供肝的损害最大。
3.针对以上两个损伤因素,联合使用厄贝沙坦和依达拉奉可通过降低门静脉压力,抗氧化减轻缺血再灌注损伤的双重保护作用可明显的减轻大鼠边缘性体积肝移植术后早期小体积移植物的损伤程度,较单纯使用一种药物效果好。
第三部分联合应用厄贝沙坦和依达拉奉对大鼠边缘性体积肝移植的移植物再生影响的研究
目的
本部分实验通过在大鼠边缘性体积供肝肝移植术中联合使用厄贝沙坦和依达拉奉,降低再灌注期间门静脉压力,抗氧化减轻缺血再灌注损伤,减轻小体积移植物早期损伤,初步探讨联合使用厄贝沙坦和依达拉奉对大鼠边缘性体积供肝肝移植术后小体积供肝再生的影响。
材料和方法
选用健康、体重相差20～30克的雄性SD大鼠72只,以小体重大鼠为供体,按第一部分介绍的方法建立大鼠边缘性体积肝脏移植模型。随机分为:A组,边缘性体积部分肝移植依达拉奉实验组和B组,边缘性体积部分肝移植厄贝沙坦实验组,C组,边缘性体积部分肝移植厄贝沙坦联合依达拉奉实验组。各组于术后2、7天各随机抽取6只存活受体在乙醚麻醉下取肝组织标本。分别测定供肝湿重、肝组织免疫组化Ki-67标记指数,了解大鼠边缘性体积供肝肝脏移植术后供肝再生的初步情况。
结果
1、C组移植术后供肝湿重(D1)、移植术后大鼠供肝湿重与受体原肝脏湿重之比(D1/R)和供肝再生率(D1/R -D0/R)在第2天和第7天明显高于A,B组,p<0.05,差异有统计学意义.B组移植术后供肝湿重(D1)、移植术后大鼠供肝湿重与受体原肝脏湿重之比(D1/R)和供肝再生率(D1/R -D0/R)在第2天和第7天明显高于A组,p<0.05,差异有统计学意义。
2、免疫组化Ki-67标记指数结果显示,各组中Ki-67标记指数的高峰均出现在术后第2天。C组术后第2天和第7天的Ki-67标记指数均高于A组,B组,各组间比较差异有统计学意义(p<0.05),B组术后第2天和第7天的Ki-67标记指数均高于A组,各组间比较差异有统计学意义(p<0.05),
结论
1.联合使用厄贝沙坦和依达拉奉组对肝细胞的再生没有直接的促进作用,供肝再生的影响是通过通过降低门静脉压力,抗氧化减轻缺血再灌注损伤的双重保护作用减轻了边缘性体积供肝的损伤程度,间接的维护供肝细胞再生的顺利进行。比单纯使用一种药物的效果好。
2.厄贝沙坦和依达拉奉对肝细胞的再生没有直接的促进作用,厄贝沙坦通过降低门静脉压力减轻了边缘性体积供肝的损伤程度,间接维护供肝细胞再生的作用较依达拉奉抗氧化减轻缺血再灌注损伤,间接的维护供肝细胞再生的作用效果好。
PART 1 ESTABLISHMENT OF A LIVER TRANSPLANTATION MODEL USING MARGINAL SIZE GRAFT IN RATS
Objective: Our aim in this part is to establish an animal model of marginal size graft-orthotopic liver transplantation using reduced size liver transplantation on rats, provides a stable animal model for the investigation of the mechanism of small-for-size syndrome after liver transplantation..
Methods: we used male Spraue-Dawley rats, (190~250grams,±20~30 grams), 4 groups designated according to the ratios of donor and recipient liver weight: Group A, whole graft group(n=24); group B, 50% ratio liver transplantation ( the median lobe and right lobe of the liver was selected to be the graft,n=24); group C, 30% ratio liver transplantation (the median lobe of the liver were selected to be the graft, n=24); group D, less than 30% ratio liver transplantation (the median lobe and left lobe of the liver were resected, and remaining lobe was selected to be the graft, n=24). A rat model of nonarterialized orthotopic liver transplantation without veno-venous bypass was used. In the small-for-size graft group, the lobe ligation technique was used to reduce the graft size on the backtable. Operation parameters, portal pressure, liver function indices and survival rate were observed and analyzed for all groups. Liver specimens were morphologically examined under the light microscopy and electron microscopy.
Results:
1. One week survival rate of the group A, B, C and D was 100%(12/12), 83.3%(10/12), 16.7%(2/12) and 0, respectively. The differences were statistically significant, p<0.001.
2. The portal pressure of the whole graft group were relative stable after reperfusion.But there was a significant increase in portal pressure in the reduce size graft group at 5 and 15 minutes after reperfusion compared with that pre-transplantation. This increase in portal pressure reached a peak at 15 minutes (increased by 65%～82%, group C, 16.47cmH20 vs 9.97 cmH20, p<0.05;group D,18.25 cmH20 vs 10.05 cmH20, p<0.05) and gradually subsided after 30 minutes of reperfusion. The relations between the size of graft and the portal pressure at 5,15,30,45,60 minutes after reperfusion are negative, (r=-0.926, r=-0.936, r=-0.904, r=-0.902, r=-0.867, p<0.05).
3. In each group ALT and AST levels increased significantly at 24 hours after liver transplantation, the highest in group D , followed by group C, group B, and group A. The differences were statistically significant, p<0.001. The relations between the size of graft and ALT and AST levels are negative, (r=-0.704, r=-0.815, p<0.05).
4. H&E staining revealed that the hepatic lobular architecture was well preserved in group A and group B at 24 hours after reperfusion. The hepatocytes and portal tracts showed normal morphological features. On the contrary, Focal necrosis was found mainly around the portal tract in the group C and group D at 24 hours after reperfusion.
5. In group C and group D, electron microscopy showed severe mitochondria and endoplasmic reticulum swelling of hepatocytes accompanied by loss of microvilli; while in group A and group B, both the cell nucleus and cellular organelles had no significant breakdown.
Conclusions:
1. We confirmed again that the rat model of marginal size graft-orthotopic liver transplantation using reduced size liver transplantation was a suitable and stable animal model for the investigation of the mechanism of small- for-size syndrome after liver transplantation.
2. We confirmed again that the minimum safely graft volume ratio in rat liver transplantation is 50%, the marginal size graft volume ratio is between 30～35%, and the ratio less than 30% should be considered as extra-small-for-size liver transplantation in the rat.
3. To establish an animal model of orthotopic liver transplantation using marginal size graft in rat,we can use rats (190~250grams,±20~30 grams). The median lobe of the liver was selected to be the graft to get the graft ratio in a range between 30～35%.
4. In a rat liver transplantation model using marginal size graft, the portal pressure changes in marginal size grafts are transient. Progressive damage of the graft may result from microcirculatory failure due to irreversible endothelial injury after reperfusion.
PART 2 PROTECTIVE EFFECT OF IRBESARTAN AND EDARAVONE ON MARGINAL SIZE LIVER TRANSPLANTATION IN RATS
Objective: The aim of this study is to investigate the protective effect of IRBESARTAN and EDARAVONE on decreasing portal pressure and reducing ischemia- reperfusion injury in the rat liver transplantation model using marginal size graft and to explore the mechanism of the marginal size graft injury during acute phase of reperfusion.
Methods: The previously described rat model of nonarterialized liver transplantation using marginal size graft was used. Survived recipients were divided into five groups: group A, control group; group B, EDARAVONE treatment group; group C, IRBESARTAN treatment group; group D, IRBESARTAN and EDARAVONE treatment group; group E, sham operation group. Six rats in each group were sacrificed randomly at 6 hour and 24 hour after reperfusion respectively. The survival rate of animals and portal pressure were investigated. The rats in every group were sacrificed and its blood sample were collected for liver function measurement. Liver specimens were morphologically examined under light microscopy. The content of SOD and MDA in liver tissues were measured. Fresh liver tissue was used to detect the expression of Egr-1mRNA, ET-1 mRNA and Bax mRNA by RT-PCR. Paraffin-embedded liver specimen were used to histological change(HE), apoptosis (TUNEL) and the protein expression of ET-1,TNF-α, Bax. Six rats at each time pointing in each group were studied.
Results:
1. One week survival rate of the group A,B,C,D and E were 8.33%(1/12),33.3%(4/12) , 58. 7%(7/12), 83. 3%(10/12),100%(12/12), respectively.The differences were statistically significant, p<0.05.
2. The portal pressure in group C and group D were lower than those in group A and group B before transplantation (8.21,8.15 vs. 10.28,10.55,p=0.019) . There was a significant increase of portal pressure in each groups at 5 and 15 minutes after reperfusion compared with the baseline. This increase in portal pressure reached a peak at 15 minutes (increased by 65.5% in group A and group B, 23.1% in group C and group D, 18.11, 18.55 vs. 15.76, 15.80 , p<0.05), gradually subsided after 30 minutes of reperfusion. The portal pressure of group C and group D were relative stable after reperfusion. The portal pressure in group C and group D were lower than those in group A and group B at 5, 15, 30, 45 and 60 minutes after reperfusion. p<0.05.
3. Biochemical data showed that the levels of hepatic enzymes(ALT and AST) reached the peak at 6 hours after reperfusion in each group. At 6 and 24 hours after reperfusion, the ALT and AST levels in group A were the highest in four groups, followed by group B, group C, group D and group E. P<0.05.
4. H&E staining revealed that the hepatic lobular Architecture was well preserved in group D and group C at 6 hours and 24 hours after reperfusion. The hepatocytes and portal tracts showed normal morphological features. On the contrary,detachment of vascular endothelial cells together with patchy necrosis was present in the group A and group B at 6 hours after reperfusion. Focal necrosis was found mainly around the portal tract in the group A and group B at 24 hours after reperfusion.
5. RT-PCR showed that the intragraft expression of Egr-1mRNA, ET-1 mRNA and Bax mRNA in group E were the lowest at each time point after reperfusion among the five groups, followed by group D, group C, group B and group A. p<0.05.
6. The content of MDA after reperfusion was increased by time, inversely; the level of SOD was decreasing by time. The content of MDA in group E were the lowest at each time point after reperfusion among the five groups, followed by group D, group C, group B,and group A. The level of SOD in group E were the highest at each time point after reperfusion among five groups, followed by group D , group C, group B,and group A . p<0.05.
7. Immunohistochemical results showed that the intragraft expression of ET-1, TNF-αand BAX in group E were the lowest at each time point after reperfusion among the five groups, followed by group D, group C, group B and group A. p<0.05.
8. TUNEL results showed that the apoptotic index of group E was the lowest at each time point after reperfusion among the fiver groups, followed by group D, group C, group B and group A.p<0.05.
Conclusion:
1. The transient significant increase portal hypertention and ischemia reperfusion injury at the early phase after reperfusion were two significant contributors to the hepatic injury of marginal size liver graft in the rat liver transplantation mole using marginal size graft.
2. In the two significant contributors to the hepatic injury of marginal size liver graft in the rat liver transplantation mole using marginal size graft, irreversible endothelial injury by transient significant increase portal hypertention at the early phase was more harmful to ischemia reperfusion injury .
3. For two contributors above, IRBESARTAN and EDARAVONE could diminish acute phase injury in marginal size liver graft after reperfusion by anenuating the acute phase shear stress that resulted from transient increase portal hypertention and reduced ischemia reperfusion injury.This two protective methods used together were more effective to one method only.
PART 3 EFFECT OF IRBESARTAN AND EDARAVONE ON LIVER REGENERATION ON MARGINAL SIZE LIVER TRANSPLANTATION IN RATS
Objective: The aim of this study is to evaluate the effects of IRBESARTAN and EDARAVONE on liver regeneration in marginal size liver transplantation in rat.
Methods: The previously described rat model of nonarterialized liver transplantation using marginal size graft was used. Survived recipients were divided into three group: group A, EDARAVONE treatment group; groupB, IRBESARTAN treatment group; group C, IRBESARTAN and EDARAVONE treatment group. Six rats in each group were sacrificed randomly at 2 and 7 days after reperfusion respectively. Each graft was removed and weighed. The regenerative response of liver graft was evaluated by the expression of Ki-67 antigen in hepatocyte that was measured by immunohistochemistry assay.
Results:
1. On 2 and 7 days after transplantation the wet weight of graft and liver regeneration rate in IRBESARTAN and EDARAVONE treatment group was the highest in three groups, followed by IRBESARTAN treatment group and EDARAVONE treatment group. p<0.05.
2. Ki-67 labeling index of the graft reach a peak at 2 days after transplantation in three groups. The Ki-67 labeling index of the graft in IRBESARTAN and EDARAVONE treatment group was the higheset in three groups on 2 days and 7days after transplantation, followed by IRBESARTAN treatment group and EDARAVONE treatment group. p<0.05.
Conclusions
1. IRBESARTAN and EDARAVONE have no directly effect on hepatocyte regeneration in rat liver transplantation model using marginal size graft. It might protect the marginal size graft by reducing portal pressure and ischemia reperfusion injury. This two protective methods used together were more effective to one method only on hepatocyte regeneration.
2. On hepatocyte regeneration in rat liver transplantation model using marginal size graft, reducing portal pressure was more effective to reducing ischemia reperfusion injury.
目的
本部分实验通过离体减体积肝叶切除供肝―大鼠原位肝移植方式,探讨大鼠边缘性体积供肝肝移植模型建立的方法,为研究小肝综合症的发病机制及防治措施提供一个较为理想的小动物模型。
材料和方法
选用健康、9~12周龄、体重190~250g的雄性大鼠192只作为实验动物,取周龄相差1~3周,体重相差20~30克的大鼠,以小体重大鼠作为供体,采用离体减体积肝叶切除方式行不同体积供肝的大鼠原位肝移植。本部分实验设立4个实验组:A组,全肝移植组(n=24);B组,50%部分肝移植组(切除肝左叶,双乳突叶,保留肝中叶、右后叶和右前叶作为供肝,使供肝与受体肝比值控制在50%左右,n=24);C组,30%部分肝移植组,除保留大鼠肝中叶外,其余四叶均予以切除,使供肝重量与受体肝比值控制在30%～35%之间,n=24);D组:小于30%部分肝移植组(保留右前叶、右后叶和双乳突叶,切除肝中叶和左叶,使供肝与受体肝比值小于30%,n=24)。供、受体均采用乙醚持续开放式吸入麻醉,大鼠原位肝移植血管重建采用双袖套法,不做肝动脉血管重建。观察各组术后肝功能ALT和AST水平、门静脉压力和存活率,光镜下及电镜下表现,比较分析各组间ALT、门静脉压力及累积存活率之间的关系。
结果
1.全肝移植组(A组)7天累积存活率为100%(12/12),50%部分肝移植组(B组)7天累积存活率为83.3%(10/12),30%部分肝移植组(C组)7天累积存活率为16.7%(2/12),小于30%部分肝移植组(D组)均于术后48小时内死亡。各组间存活率经生存分析life-table方法比较,A组与B组累积存活率比较,组间差异无统计学意义,p=0.148; C组与A组累积存活率比较,组间差异有统计学意义,p<0.001;C组与B组两组存活率有显著性差异,p<0.001; C组与D组两组存活率有显著性差异,p<0.001;
2.受体在移植前基础门静脉压力各组间差异无统计学意义,p>0.05。A组术中开放门静脉后1小时内门静脉压力稳定,B组开放门静脉后门静脉压力虽有小幅上升,但门静脉压力仍保持相对稳定,而C组和D组开放门静脉后门静脉压力显著升高,15分钟达到峰值,两组门静脉压力峰值分别较基础门静脉压力升高65%和82%。两组门静脉压力30分钟开始回落,至45分钟到60分钟逐渐稳定,但仍维持于一高位。将供肝体积的大小与各时间点的门静脉压力进行Pearson相关分析后发现,供肝体积的大小与基础门静脉压力无相关性,相关系数r=0.249,p=0.241;而供肝体积大小与开放门静脉后5、15、30、45、60分钟门静脉压力呈负相关性,(相关系数分别为r=-0.926,r=-0.936, r=-0.904, r=-0.902, r=-0.867, p<0.05)。
3.肝移植术后24小时各组ALT和AST水平明显升高,四组中以D组水平最高,C组次之,B组和A组最低,各组间差异有统计学意义,p<0.001。将供肝体积大小与各组移植术后24小时ALT和AST水平进行Pearson相关分析后,结果显示供肝体积大小与移植术后24小时ALT和AST水平呈负相关性,相关系数r分别为-0.704和-0.815, p<0.05。
4.光镜下可见各组均出现不同程度的肝窦充血、局部肝窦扩张、血管内皮细胞完整性受损、肝板结构改变及肝细胞空泡变性等形态学异常的表现。与其他组相比较,C,D组在术后24小时形态学异常的表现均较为明显且程度严重。
5.电镜观察结果显示,C,D组在肝移植术后24小时出现严重的肝窦内皮细胞线性结构完整性破坏、线粒体肿胀等严重的形态学异常。A,B在相应的时间点肝细胞的超显微结构保持得相对完整
结论
1.再次证实直视下离体减体积肝叶切除供肝―大鼠原位肝移植模型是作为为小肝综合症基础性研究的较为理想的小动物模型,具有很好的可靠性和可重复性。
2.再次证实了大鼠减体积供肝肝移植模型供肝体积大小的安全界限为50%标准体积;体积介于35～30%标准体积之间的供肝应视为边缘性体积移植物,小于30%标准体积的供肝可视为超小体积肝移植。
3.大鼠边缘性体积供肝肝移植模型的建立,可选取周龄相差1～3周,体重相差20～30克的大鼠,以小体重的大鼠作为供体,除保留肝中叶外,其余四叶均予以切除,可以使供肝湿重与受体肝比值控制在30%～35%之间。
4.大鼠减体积供肝肝移植模型中,供肝体积大小与开放门静脉压力升高幅度及术后24小时ALT和AST水平呈负相关性,小体积供肝肝移植术中开放门静脉后急剧升高的门静脉压力对肝窦造成的应力性的损伤,是导致肝移植术后小体积移植物功能损害、受体存活率降低的主要原因。
第二部分联合应用厄贝沙坦和依达拉奉对大鼠边缘性体积肝移植的移植物保护作用的研究
目的
本部分实验拟对大鼠边缘性体积供肝肝移植术后小体积移植物早期损伤的机制进行初步研究,探讨在大鼠边缘性体积供肝肝移植术中联合使用厄贝沙坦和依达拉奉,降低再灌注期间门静脉压力,减轻缺血再灌注损伤对边缘性体积供肝早期损伤的保护作用机制。
材料和方法
选用健康、体重相差20~30克的雄性SD大鼠300只,以小体重大鼠为供体,按第一部分介绍的方法建立大鼠边缘性体积供肝肝移植模型,将供受体大鼠随机分为:A组,边缘性体积部分肝移植生理盐水对照组;B组,边缘性体积部分肝移植依达拉奉实验组;C组,边缘性体积部分肝移植厄贝沙坦实验组;D组,边缘性体积部分肝移植厄贝沙坦联合依达拉奉实验组;E组,假手术组。观察各组术后一般情况、门静脉压力和存活率,各组分别于术后6小时和24小时各取6只受体在无菌操作条件下采取下腔静脉血标本和肝组织标本。测定血清中ALT、AST水平、肝细胞匀浆内SOD活力和MDA含量、RT-PCR检测肝组织中Egr-1,ET-1,Bax mRNA表达情况,免疫组化检测肝组织中ET-1,Bax,TNF表达情况,TUNEL检测肝组织细胞凋亡情况以及光镜下观察肝组织形态学改变。
结果
1.光镜下可见各组均出现不同程度的肝窦充血、局部肝窦扩张、血管内皮细胞完整性受损、肝板结构改变及肝细胞空泡变性等形态学异常的表现。以术后6小时最为严重。与其他组相比较,A,B组在术后6小时和24小时形态学异常的表现均较为明显且程度严重。D组最轻。E组无明显变化。
2.A组7天累积存活率为8.33%(1/12),B组7天累积存活率为33.3%(4/12),C组7天累积存活率为58. 7%(7/12), D组7天累积存活率为83. 3%(10/12),E组7天累积存活率为100%(12/12),经SPSS生存分析life-table方法比较,各组累积存活率之间的差异有统计学意义。A组与B组累积存活率比较,组间差异有统计学意义,p=0.018; C组与A组累积存活率比较,组间差异有统计学意义,p<0.001;D组与A组两组存活率有显著性差异,p<0.001; E组与A组两组存活率有显著性差异,p<0.001;
3.C,D组受体移植前基础门静脉压力低于A,B组,各组间均数比较,差异有统计学意义(8.21,8.15 vs 10.28,10.55,p=0.019)。各组开放门静脉恢复血流灌注后门静脉压力的峰值均出现在开放门静脉后的15分钟处,但C,D组门静脉压力峰值要明显低于A,B组,各组间均数比较差异有显著统计学意义(15.76,15.80 vs 18.11,18.55 ,p<0.001)。开放门静脉30分钟之后两组门静脉逐渐回落,C,D组开放门静脉后门静脉压力维持相对稳定,波动于12.63～13.42cmH_2O之间,峰值门静脉压力较基础门静脉压力升高幅度达23.1%。而A,B组恢复门静脉灌注后门静脉压力显著升高,波动于15.47～16.52cmH_2O之间,峰值门静脉压力较基础门静脉压力升高幅度高达65.5%。C,D组在恢复门静脉灌注后的5、15、30和60分钟各时间点均明显低于A,B组,各组各时间点门静脉压力均数经单因素方差分析,LSD分析,p<0.001,差异有显著统计学意义。
4.实验中各组肝移植术后血清ALT和AST水平显著升高,均在再灌注6小时升至峰值,术后24小时虽有所下降,但仍处于高水平状态。说明移植后移植物的肝实质细胞的损伤以6小时最为严重,24小时内仍处于一个急性期阶段。与其他组相比较A,B组在术后6小时和24小时血清ALT和AST水平显著升高,均较为明显且程度严重。D组最轻。E组无明显变化。各组间ALT和AST均数经比较差异有统计学意义,p<0.05。说明再灌注期间降低门脉压力,抗氧化减轻缺血再灌注损伤可减轻小体积移植物肝实质细胞的损伤的程度。
5.本实验中各组肝移植术后MDA水平显著升高,均在再灌注6小时升至峰值,术后24小时虽有所下降,但仍处于高水平状态。说明移植后移植物的缺血再灌注损伤以6小时最为严重,24小时内仍处于一个急性期阶段。与其他组相比较,A,B组在术后6小时和24小时MDA水平显著升高。均较为明显且程度严重。D组最轻。E组无明显变化。各组间MDA均数经比较差异有统计学意义,p<0.05。本实验中各组肝移植术后SOD水平显著下降,说明移植后移植物的缺血再灌注损伤SOD不断耗竭,24小时内仍处于耗竭阶段。与其他组相比较,A,B组在术后6小时和24小时SOD水平显著降低。均较为明显且程度严重。D组最轻。E组无明显变化。各组各亚组间SOD均数经比较差异有统计学意义,p<0.05。说明各组大鼠受体均不同预处理后,缺血再灌注损伤有显著差别。D组缺血再灌注损伤较A,B,C组轻。E组无明显变化。说明联合使用厄贝沙坦和依达拉奉能明显减轻小体积移植物缺血再灌注损伤。
6.A组术后6小时和24小时Egr-1 mRNA ,ET-1mRNA ,BaxmRNA表达均高于其他组(p<0.05)。D组术后6小时和24小时Egr-1 mRNA ,ET-1mRNA ,BaxmRNA表达较A,B,C组表达低(p<0.05)。说明在厄贝沙坦和依达拉奉的联合作用下,Egr-1 mRNA ,ET-1mRNA ,BaxmRNA表达较低。而C组术后6小时和24小时Egr-1mRNA, ET-1mRNA , BaxmRNA表达均低于B组(p<0.05)。说明在小体积肝移植中,门静脉一过性增高对这些mRNA影响大于缺血再灌注因素。
7、免疫组化显示:A组术后6小时和24小时ET-1,Bax,TNF表达均高于其他组(p<0.05)。D组术后6小时和24小时ET-1 ,Bax,TNF表达较A,B,C组表达低(p<0.05)。说明在厄贝沙坦和依达拉奉的联合作用下,ET-1,Bax,TNF表达较低。而C组术后6小时和24小时ET-1 ,Bax,TNF表达均低于B组(p<0.05)。说明在小体积肝移植中,门静脉一过性增高对这些基因蛋白的影响大于缺血再灌注因素。
8、Tunel显示:A组术后6小时和24小时凋亡指数高于其他组(p<0.05)。D组术后6小时和24小时凋亡指数较A,B,C组表达低(p<0.05)。说明在厄贝沙坦和依达拉奉的联合作用下,肝细胞凋亡较少。而C组术后6小时和24小时凋亡指数表达均低于B组(p<0.05)。说明在小体积肝移植中,门静脉一过性增高对细胞凋亡的影响大于缺血再灌注因素。
结论
1.大鼠边缘性体积部分肝移植术后造成小体积移植物的灌注后损伤的特殊性就在于其面临的是早期门静脉过度灌注和缺血再灌注的双重损伤。
2.在大鼠边缘性体积供肝移植中,门静脉压力升高和缺血再灌注损伤两个因素中,门静脉压力升高对肝窦内皮细胞造成的应力性损伤,对供肝的损害最大。
3.针对以上两个损伤因素,联合使用厄贝沙坦和依达拉奉可通过降低门静脉压力,抗氧化减轻缺血再灌注损伤的双重保护作用可明显的减轻大鼠边缘性体积肝移植术后早期小体积移植物的损伤程度,较单纯使用一种药物效果好。
第三部分联合应用厄贝沙坦和依达拉奉对大鼠边缘性体积肝移植的移植物再生影响的研究
目的
本部分实验通过在大鼠边缘性体积供肝肝移植术中联合使用厄贝沙坦和依达拉奉,降低再灌注期间门静脉压力,抗氧化减轻缺血再灌注损伤,减轻小体积移植物早期损伤,初步探讨联合使用厄贝沙坦和依达拉奉对大鼠边缘性体积供肝肝移植术后小体积供肝再生的影响。
材料和方法
选用健康、体重相差20～30克的雄性SD大鼠72只,以小体重大鼠为供体,按第一部分介绍的方法建立大鼠边缘性体积肝脏移植模型。随机分为:A组,边缘性体积部分肝移植依达拉奉实验组和B组,边缘性体积部分肝移植厄贝沙坦实验组,C组,边缘性体积部分肝移植厄贝沙坦联合依达拉奉实验组。各组于术后2、7天各随机抽取6只存活受体在乙醚麻醉下取肝组织标本。分别测定供肝湿重、肝组织免疫组化Ki-67标记指数,了解大鼠边缘性体积供肝肝脏移植术后供肝再生的初步情况。
结果
1、C组移植术后供肝湿重(D1)、移植术后大鼠供肝湿重与受体原肝脏湿重之比(D1/R)和供肝再生率(D1/R -D0/R)在第2天和第7天明显高于A,B组,p<0.05,差异有统计学意义.B组移植术后供肝湿重(D1)、移植术后大鼠供肝湿重与受体原肝脏湿重之比(D1/R)和供肝再生率(D1/R -D0/R)在第2天和第7天明显高于A组,p<0.05,差异有统计学意义。
2、免疫组化Ki-67标记指数结果显示,各组中Ki-67标记指数的高峰均出现在术后第2天。C组术后第2天和第7天的Ki-67标记指数均高于A组,B组,各组间比较差异有统计学意义(p<0.05),B组术后第2天和第7天的Ki-67标记指数均高于A组,各组间比较差异有统计学意义(p<0.05),
结论
1.联合使用厄贝沙坦和依达拉奉组对肝细胞的再生没有直接的促进作用,供肝再生的影响是通过通过降低门静脉压力,抗氧化减轻缺血再灌注损伤的双重保护作用减轻了边缘性体积供肝的损伤程度,间接的维护供肝细胞再生的顺利进行。比单纯使用一种药物的效果好。
2.厄贝沙坦和依达拉奉对肝细胞的再生没有直接的促进作用,厄贝沙坦通过降低门静脉压力减轻了边缘性体积供肝的损伤程度,间接维护供肝细胞再生的作用较依达拉奉抗氧化减轻缺血再灌注损伤,间接的维护供肝细胞再生的作用效果好。
PART 1 ESTABLISHMENT OF A LIVER TRANSPLANTATION MODEL USING MARGINAL SIZE GRAFT IN RATS
Objective: Our aim in this part is to establish an animal model of marginal size graft-orthotopic liver transplantation using reduced size liver transplantation on rats, provides a stable animal model for the investigation of the mechanism of small-for-size syndrome after liver transplantation..
Methods: we used male Spraue-Dawley rats, (190~250grams,±20~30 grams), 4 groups designated according to the ratios of donor and recipient liver weight: Group A, whole graft group(n=24); group B, 50% ratio liver transplantation ( the median lobe and right lobe of the liver was selected to be the graft,n=24); group C, 30% ratio liver transplantation (the median lobe of the liver were selected to be the graft, n=24); group D, less than 30% ratio liver transplantation (the median lobe and left lobe of the liver were resected, and remaining lobe was selected to be the graft, n=24). A rat model of nonarterialized orthotopic liver transplantation without veno-venous bypass was used. In the small-for-size graft group, the lobe ligation technique was used to reduce the graft size on the backtable. Operation parameters, portal pressure, liver function indices and survival rate were observed and analyzed for all groups. Liver specimens were morphologically examined under the light microscopy and electron microscopy.
Results:
1. One week survival rate of the group A, B, C and D was 100%(12/12), 83.3%(10/12), 16.7%(2/12) and 0, respectively. The differences were statistically significant, p<0.001.
2. The portal pressure of the whole graft group were relative stable after reperfusion.But there was a significant increase in portal pressure in the reduce size graft group at 5 and 15 minutes after reperfusion compared with that pre-transplantation. This increase in portal pressure reached a peak at 15 minutes (increased by 65%～82%, group C, 16.47cmH20 vs 9.97 cmH20, p<0.05;group D,18.25 cmH20 vs 10.05 cmH20, p<0.05) and gradually subsided after 30 minutes of reperfusion. The relations between the size of graft and the portal pressure at 5,15,30,45,60 minutes after reperfusion are negative, (r=-0.926, r=-0.936, r=-0.904, r=-0.902, r=-0.867, p<0.05).
3. In each group ALT and AST levels increased significantly at 24 hours after liver transplantation, the highest in group D , followed by group C, group B, and group A. The differences were statistically significant, p<0.001. The relations between the size of graft and ALT and AST levels are negative, (r=-0.704, r=-0.815, p<0.05).
4. H&E staining revealed that the hepatic lobular architecture was well preserved in group A and group B at 24 hours after reperfusion. The hepatocytes and portal tracts showed normal morphological features. On the contrary, Focal necrosis was found mainly around the portal tract in the group C and group D at 24 hours after reperfusion.
5. In group C and group D, electron microscopy showed severe mitochondria and endoplasmic reticulum swelling of hepatocytes accompanied by loss of microvilli; while in group A and group B, both the cell nucleus and cellular organelles had no significant breakdown.
Conclusions:
1. We confirmed again that the rat model of marginal size graft-orthotopic liver transplantation using reduced size liver transplantation was a suitable and stable animal model for the investigation of the mechanism of small- for-size syndrome after liver transplantation.
2. We confirmed again that the minimum safely graft volume ratio in rat liver transplantation is 50%, the marginal size graft volume ratio is between 30～35%, and the ratio less than 30% should be considered as extra-small-for-size liver transplantation in the rat.
3. To establish an animal model of orthotopic liver transplantation using marginal size graft in rat,we can use rats (190~250grams,±20~30 grams). The median lobe of the liver was selected to be the graft to get the graft ratio in a range between 30～35%.
4. In a rat liver transplantation model using marginal size graft, the portal pressure changes in marginal size grafts are transient. Progressive damage of the graft may result from microcirculatory failure due to irreversible endothelial injury after reperfusion.
PART 2 PROTECTIVE EFFECT OF IRBESARTAN AND EDARAVONE ON MARGINAL SIZE LIVER TRANSPLANTATION IN RATS
Objective: The aim of this study is to investigate the protective effect of IRBESARTAN and EDARAVONE on decreasing portal pressure and reducing ischemia- reperfusion injury in the rat liver transplantation model using marginal size graft and to explore the mechanism of the marginal size graft injury during acute phase of reperfusion.
Methods: The previously described rat model of nonarterialized liver transplantation using marginal size graft was used. Survived recipients were divided into five groups: group A, control group; group B, EDARAVONE treatment group; group C, IRBESARTAN treatment group; group D, IRBESARTAN and EDARAVONE treatment group; group E, sham operation group. Six rats in each group were sacrificed randomly at 6 hour and 24 hour after reperfusion respectively. The survival rate of animals and portal pressure were investigated. The rats in every group were sacrificed and its blood sample were collected for liver function measurement. Liver specimens were morphologically examined under light microscopy. The content of SOD and MDA in liver tissues were measured. Fresh liver tissue was used to detect the expression of Egr-1mRNA, ET-1 mRNA and Bax mRNA by RT-PCR. Paraffin-embedded liver specimen were used to histological change(HE), apoptosis (TUNEL) and the protein expression of ET-1,TNF-α, Bax. Six rats at each time pointing in each group were studied.
Results:
1. One week survival rate of the group A,B,C,D and E were 8.33%(1/12),33.3%(4/12) , 58. 7%(7/12), 83. 3%(10/12),100%(12/12), respectively.The differences were statistically significant, p<0.05.
2. The portal pressure in group C and group D were lower than those in group A and group B before transplantation (8.21,8.15 vs. 10.28,10.55,p=0.019) . There was a significant increase of portal pressure in each groups at 5 and 15 minutes after reperfusion compared with the baseline. This increase in portal pressure reached a peak at 15 minutes (increased by 65.5% in group A and group B, 23.1% in group C and group D, 18.11, 18.55 vs. 15.76, 15.80 , p<0.05), gradually subsided after 30 minutes of reperfusion. The portal pressure of group C and group D were relative stable after reperfusion. The portal pressure in group C and group D were lower than those in group A and group B at 5, 15, 30, 45 and 60 minutes after reperfusion. p<0.05.
3. Biochemical data showed that the levels of hepatic enzymes(ALT and AST) reached the peak at 6 hours after reperfusion in each group. At 6 and 24 hours after reperfusion, the ALT and AST levels in group A were the highest in four groups, followed by group B, group C, group D and group E. P<0.05.
4. H&E staining revealed that the hepatic lobular Architecture was well preserved in group D and group C at 6 hours and 24 hours after reperfusion. The hepatocytes and portal tracts showed normal morphological features. On the contrary,detachment of vascular endothelial cells together with patchy necrosis was present in the group A and group B at 6 hours after reperfusion. Focal necrosis was found mainly around the portal tract in the group A and group B at 24 hours after reperfusion.
5. RT-PCR showed that the intragraft expression of Egr-1mRNA, ET-1 mRNA and Bax mRNA in group E were the lowest at each time point after reperfusion among the five groups, followed by group D, group C, group B and group A. p<0.05.
6. The content of MDA after reperfusion was increased by time, inversely; the level of SOD was decreasing by time. The content of MDA in group E were the lowest at each time point after reperfusion among the five groups, followed by group D, group C, group B,and group A. The level of SOD in group E were the highest at each time point after reperfusion among five groups, followed by group D , group C, group B,and group A . p<0.05.
7. Immunohistochemical results showed that the intragraft expression of ET-1, TNF-αand BAX in group E were the lowest at each time point after reperfusion among the five groups, followed by group D, group C, group B and group A. p<0.05.
8. TUNEL results showed that the apoptotic index of group E was the lowest at each time point after reperfusion among the fiver groups, followed by group D, group C, group B and group A.p<0.05.
Conclusion:
1. The transient significant increase portal hypertention and ischemia reperfusion injury at the early phase after reperfusion were two significant contributors to the hepatic injury of marginal size liver graft in the rat liver transplantation mole using marginal size graft.
2. In the two significant contributors to the hepatic injury of marginal size liver graft in the rat liver transplantation mole using marginal size graft, irreversible endothelial injury by transient significant increase portal hypertention at the early phase was more harmful to ischemia reperfusion injury .
3. For two contributors above, IRBESARTAN and EDARAVONE could diminish acute phase injury in marginal size liver graft after reperfusion by anenuating the acute phase shear stress that resulted from transient increase portal hypertention and reduced ischemia reperfusion injury.This two protective methods used together were more effective to one method only.
PART 3 EFFECT OF IRBESARTAN AND EDARAVONE ON LIVER REGENERATION ON MARGINAL SIZE LIVER TRANSPLANTATION IN RATS
Objective: The aim of this study is to evaluate the effects of IRBESARTAN and EDARAVONE on liver regeneration in marginal size liver transplantation in rat.
Methods: The previously described rat model of nonarterialized liver transplantation using marginal size graft was used. Survived recipients were divided into three group: group A, EDARAVONE treatment group; groupB, IRBESARTAN treatment group; group C, IRBESARTAN and EDARAVONE treatment group. Six rats in each group were sacrificed randomly at 2 and 7 days after reperfusion respectively. Each graft was removed and weighed. The regenerative response of liver graft was evaluated by the expression of Ki-67 antigen in hepatocyte that was measured by immunohistochemistry assay.
Results:
1. On 2 and 7 days after transplantation the wet weight of graft and liver regeneration rate in IRBESARTAN and EDARAVONE treatment group was the highest in three groups, followed by IRBESARTAN treatment group and EDARAVONE treatment group. p<0.05.
2. Ki-67 labeling index of the graft reach a peak at 2 days after transplantation in three groups. The Ki-67 labeling index of the graft in IRBESARTAN and EDARAVONE treatment group was the higheset in three groups on 2 days and 7days after transplantation, followed by IRBESARTAN treatment group and EDARAVONE treatment group. p<0.05.
Conclusions
1. IRBESARTAN and EDARAVONE have no directly effect on hepatocyte regeneration in rat liver transplantation model using marginal size graft. It might protect the marginal size graft by reducing portal pressure and ischemia reperfusion injury. This two protective methods used together were more effective to one method only on hepatocyte regeneration.
2. On hepatocyte regeneration in rat liver transplantation model using marginal size graft, reducing portal pressure was more effective to reducing ischemia reperfusion injury.
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