摘要
部分肝移植的广泛开展,一定程度上缓解了供肝短缺矛盾,使更多肝病患者得到及时有效的治疗,但由于供肝体积较小,特别是在小体积肝移植时,常常由于供肝功能不足导致术后出现不同程度的小肝综合征(SFSS)表现,影响受体存活,严重困扰部分肝移植的进一步发展。目前对SFSS的详细发生机制并不清楚,可能与供、受体双方多种因素有关,门静脉高灌注损伤、肝动脉低灌注、肝内微循环障碍以及异常的肝再生与SFSS的发生发展密切相关。理想的动物模型是进行基础和干预研究的前提,非静脉转流下的猪小体积肝移植模型与临床有着相似的手术操作过程和病理生理变化,不但进行了大鼠模型中不常采用而临床必需的肝动脉重建,保留了肝动脉灌注的动态变化对SFSS发生发展的作用,而且避免了传统猪移植模型中体外静脉转流带来的不必要的脾脏切除及其对术后早期门脉高灌注、供肝再生等的干扰,因此特别适合SFSS的系统研究。生长抑素(SST)是一种多效应激素,在降低门脉血流、调节肝窦收缩、抑制肝脏纤维增生、减轻肠道缺血再灌注损伤以及抑制肝细胞再生等多个方面具有重要作用,基于大鼠模型和临床个案的研究结果显示SST具有潜在的减轻小体积供肝损伤的作用,但是目前仍然缺少更多证据的支持。在本课题中,我们先建立非转流下猪30%体积供肝移植模型,并评价其安全性和临床贴合性；然后在稳定有效的小体积肝移植模型上,进行SST的干预研究,并初步探讨相关机制。
一、非转流下猪小体积肝移植物损伤模型的建立
目的：建立非转流下猪30%体积供肝移植模型,并评价其安全性和临床贴合性。
材料和方法：13对巴马小型猪,体重25-30kg,随机分为100%全肝移植组(n=5)和30%小体积肝移植组(n=8),均在非静脉转流条件下完成肝移植术。观察比较两组供肝特征及增重率,存活情况(非转流耐受率、手术存活率、供肝7d累积存活率),术中血流动力学及血气变化,术后2h及第1、2、3、5、7d的肝肾功能变化。
结果：两组除供肝大小外,在热缺血时间、冷缺血时间、温缺血时间、无肝期、肝下下腔静脉阻断时间、受体手术时间以及术中输血量方面差异均无统计学意义；两组非静脉转流耐受率分别为80%(4／5)和100%(8／8),手术存活率为80%(4／5)和75%(6／8)；30%供肝组的供肝7d累积存活率明显低于100%供肝组(33.3%vs.100%),但由于实验例数较少,尚无统计学差异(P=0.0521>0.05)；两组受体无肝期均出现相似的血流动力学改变,与无肝前期比较,MAP、CVP、PH以及BE值显著下降(P<0.01),而HR及血K+浓度显著升高(P<0.01),但两组间比较无统计学差异,门脉血流开放后,上述指标逐渐恢复,至关腹前除轻微酸中毒外已基本恢复至无肝前期水平；与100%供肝组比较,30%供肝组ALT、AST在术后5d内显著升高(P<0.05), TBIL在术后1至7d显著升高(P<0.01),PT同样在术后1、2、5和7d明显延长(P<0.05)。两组血清肌酐均于术后第1d达到高峰后快速恢复,组间比较没有显著性差异。30%供肝组的供肝平均增重率明显高于100%供肝组(152.8%vs.15.9%)。
结论：非转流下猪30%体积供肝移植模型稳定有效,可以用于小体积肝移植物损伤的研究。
二、生长抑素对猪小体积肝移植物损伤的保护作用及机制
目的：研究SST对术后早期猪小体积肝移植物损伤的保护,并初步从门脉压力梯度变化(PPG)、肝内微循环调节、肝再生及凋亡等方面探讨相关机制。
材料和方法：12对巴马小型猪,体重25-30kg,随机分为30%小体积肝移植+生理盐水对照组(小肝NS组,n=7)和30%小体积肝移植+SST干预组(小肝SST组,n=5),均在非静脉转流条件下完成肝移植术,另取前一部分中手术存活的100%供肝组(全肝对照组,n=4)作为模型对照。SST-14干预方案：受体门脉开放前3min团注125μg,然后以5μg/kg/h持续给药24h,B组以等量生理盐水作为对照。观察比较各组供肝特征及增重率,供肝7d累积存活率,术后2h及第1、2、3、5、7d的肝肾功能变化,术后2h、3d和7d的肝脏病理改变(光镜和电镜),盐水柱法监测术中及术后PPG的变化；免疫组化和TUNEL法分别检测术后2h、3d和7d的Ki-67增殖指数和凋亡指数;Real-time PCR和免疫组化法分别检测术后2h各组肝内ET-1转录和第3d的蛋白表达水平；ELISA法连续检测术后2h、1、2、3、5、7d外周血ET-1和NO的浓度,并计算两者比值。
结果：
1、供肝存活率：各组除供肝大小外,在热缺血时间、冷缺血时间、温缺血时间、无肝期、肝下下腔静脉阻断时间、受体手术时间以及术中输血量方面差异均无统计学意义；小肝SST组供肝7d累积存活率高于小肝NS组(80%vs.42.9%),但是差异仍缺少统计学意义,可能与实验例数较少有关(P=0.1283＞0.05, Log-rank test)。
2、肝肾功能变化：与小肝NS组比较,小肝SST组ALT、AST在术后1、2、3d显著下降(P<0.05), TBIL在术后1至7d显著下降(P<0.05),PT同样在术后1至5d显著下降(P<0.05)。术后肌酐水平各时间点两组比较均无显著性差异。
3、光镜下病理检查：小肝NS组与全肝对照组比较,术后2h肝细胞肿胀变性坏死、肝窦扩张淤血、门管区静脉内皮损伤、出血等均较严重,术后第3d大量肝细胞脂肪变,肝索增厚、坏死后纤维增生、汇管区扩大及炎症反应均较明显,术后第7d仍然存在肝小叶结构紊乱和肝细胞空泡样变性,可见肝细胞增殖反应；与小肝NS组比较,小肝SST组各时间点的损伤、增殖及纤维化反应均较轻,肝小叶结构无明显紊乱,炎症反应不明显。
4、电镜下超微结构检查：小肝NS组与全肝对照组比较,术后2h肝细胞线粒体明显肿胀,胞浆内可见大量脂肪滴,细胞核有固缩反应,肝窦淤血、窦内皮破坏严重,Disse间隙消失并可见间隙内出血；与小肝NS组比较,小肝SST组肝细胞变性轻微,线粒体轻度扩张,肝窦结构基本完整。
5、PPG的变化：与全肝对照组比较,小肝NS组术后5d内各时间点PPG显著升高(P<0.05),并于术后30min和ld达到峰值,至术后7d基本恢复,而小肝SST组较NS组显著降低(P<0.05),术后5min达到峰值后逐步下降,术后第3d基本恢复,与全肝组比较,术后各时间点及术后2d仍显著升高(P<0.05)。
6、肝再生情况：与全肝对照组比较,小肝NS组术后2h、3d、7d的Ki-67增殖指数均显著升高(P<0.05),第7d的供肝增重率明显升高(P<0.05)；与小肝NS组比较,小肝SST组术后2h和第3d的Ki-67增殖指数显著下降(P<0.05),但术后第7d两者无显著性差异,且两组供肝增重率比较亦无显著性差异。
7、凋亡指数：与全肝对照组比较,小肝NS组术后2h、3d、7d的凋亡指数均显著升高(P<0.05)；与小肝NS组比较,小肝SST组术后各时间点凋亡指数均显著下降(P<0.05)。
8、肝内ET-1转录及表达水平：与全肝对照组比较,小肝NS组术后2h ET-1转录及第3d的蛋白表达水平均显著升高(P<0.05)；与小肝NS组比较,小肝SST组术后2h ET-1转录及第3d的蛋白表达水平均显著降低(P<0.05)。
9、外周血ET-1/NO比值的变化：与全肝对照组比较,小肝NS组术后l、2、3d的ET/NO比值显著升高(P<0.05)；而小肝SST组术后除第1d显著下降外,其余各时间点与全肝对照组无显著性差异；与小肝NS组比较,小肝SST组术后1、2、3d的ET/NO比值显著下降(P<0.05)。
结论：
1、小体积肝移植术后早期持续升高的PPG和微循环障碍与小体积供肝损伤密切相关。
2、小体积肝移植术后早期肝细胞的过度增殖对于小肝功能和体积的恢复并不是必需的,甚至可能存在负面效应。
3、SST-14可通过降低PPG、改善ET-1与NO介导的肝内微循环功能紊乱及减少肝细胞凋亡来保护小体积供肝功能,改善供肝7d累积存活率。
4、短期SST-14干预可降低小体积肝移植术后早期肝细胞增殖速度,但是并不影响供肝功能和体积的恢复。
Partial liver transplantation (PLT) is currently gaining wider acceptance, which definitely alleviates donor organ shortage, but also reveals the problem of small-for-size graft syndrome (SFSS). Currently, the precise mechanism behind it remains still unknown. Both clinic and animal studies have shown the portal hyperperfusion, hepatic arterial hypoperfusion, imbalance of hepatic microvesicular regulation, and the abnormal liver regeneration account much for the occurrence and development of SFSS. Rodent models as well as those large animal ones established under the help of veno-venous bypass (VVB) are away from clinical situation. Pigs transplanted with 30% liver grafts without VVB are more suitable for the study of SFSS because of their similarity to clinic procedures in PLT and the physiological status of humans. Somatostatin (SST) has been used for two decades to treat oesophageal variceal haemorrhage for its capacity to decrease portal venous pressure without major side effects. Additionally, SST can induce diverse physiological effects in different tissues and cells, mediated by five different reciptors of SST (SSTR). It was reported recently SST, but other analogues, has intrahepatic effects such as inhibition of ET-1-induced contraction of hepatic stellate cells (HSC), and the transcription and expression of ET-1. It has been indicated low-dose SST-14 can rescue small-for-size (SFS) grafts in rat models and also comfirmed by the individual clinical reports, but further investigations have to be conducted. In this study, we will try to establish a feasible and effective porcine model with 30% liver graft without VVB, and then SST-14 will be applied to the model to assess the effect on the SFS graft injury. Portal pressure gradient (PPG), Changes of microvesicular regulation, apoptosis and the liver regeneration will be addressed to search for the protective mechanism.
Part1. Establishing the model of small-for-size graft injury in pigs without veno-venous bypass
Objective:To establish a feasible and effective SFS graft injury models in miniature pigs. Materials and Methods:13 pairs of Ba-Ma miniature pigs were randomly assigned into two groups:100% liver graft group (n=5) and 30% liver graft group (n=8), both transplanted with no VVB. The profiles of intra-operative hemodynamics and metabolism were investigated. Animals were followed for 7 days with daily serum for biochemistry exam. The survival rate (non-VVB tolerance rate, operative survival rate, and 7-day accumulative graft survival rate) were respectively calculated as well as the graft weight increase rate at post operative day (POD) 7.
Results:All the recipients survived the anhepatic period except one in 30% graft group died of irretrievable acidosis. non-VVB tolerance rate and operative survival rate were all above 75% in both groups.7-day accumulative survival rate in 30% graft group was lower than that in 100% graft group (33.3% vs.100%) but with no significant difference (P=0.0521>0.05). Pigs in 30% graft group showed significantly prolonged prothrombin time, elevated bilirubin and aminotransferase levels during almost the entire follow-up. Serum creatinine concentrations were similar in both groups, with a sharp increase in the first one day, and then settled at values of no significant difference to that before reperfusion. MAP, CVP and BE in both groups, particularly in 30% graft group, decreased significantly at anhepatic phase for the rapid impairment to the effective blood volume (P＜0.01), which inversely evoked a significant elevation of heart rate and K+. After reperfusion, MAP, CVP and K+ restored gradually and got almost complete recovery at the end of operation despite a mild acidosis.
Conclusions:Porcine model of 30% liver graft transplantation without VVB can be safely established and used for the study of SFS graft injury as its good clinical simulation on operative procedures and clinicopathological performance.
Part2. Protective effect of somatostatin on small-for-size liver grafts in pigs and the underlying mechanism
Objective:Investigate the protective effect of SST on the SFS graft injury and explore the preliminary underlying mechanisms.
Materials and Methods:12 pairs of Ba-Ma miniature pigs were assigned into two groups: SFS+NS group (n=7), transplanted with 30% liver graft with normal saline as control; SFS+SST group (n=5), transplanted with 30% liver graft with SST administered as following method:Bolus infusion via peripherial veins 3 minutes just before portal reperfusion followed by continous infusion at 5μg/kg/h for 24 hours. The whole liver group (n=4) transplanted with 100% liver graft established in our first part study was used as model control in this research; All animals were followed for 7 days with daily serum for biochemistry exam. The 7-day accumulate graft survival rate and the graft weight increase at POD 7 were respectively calculated.The kinesis of PPG during 7 days follow-up and pathological findings at 2 hours after reperfusion, POD3 and 7 were evaluated. Additional parts of liver tissues were harvested to detect the expression of Ki-67、ET-1 by imnunohistochemistry and the apoptosis by TUNEL. The transcription levels of ET-1 mRNA were examed by Real-Time PCR. ELISA kits were also used to detect the levels of ET-1 and NO in peripheral plasm at 2 hours post reperfusion and on POD1、2、3、5 and 7, and the ratio of ET-1 to NO was further calculated.
Results:
1. Survival rate:No significant differences were found among the groups in warm ischemia time, cold ischemia time, portal to arterial reperfusion time, infra-hepatic inferior vena cava occlusion time, operating time for recipient, and blood transfusion.7-day accumulative graft survival rate in SFS+SST group was visibly higher than that in SFS+NS group but with no significant difference. (80% vs.42.9%,P=1283>0.05).
2. Liver and renal function:Compared to SFS+NS group, the ALT and AST in SFS+SST group on POD1,2 and 3 were significantly decreased as well as the TBIL on POD 1 to 7 and PT on POD 1 to 5 (P<0.05). There were no significant differences of serum creatinine concentrations among three groups.
3. Light microscopy examination:Severe sinusoidal congestion and disruption of architecture in the centrilobular region as well as focal endothelial denudation and hemorrhage into the connective tissue at interface zone were observed in SFS+NS group as early as 2 hours after reperfusion, whereas in the whole liver group, these changes were minimal. By POD3, there were more extensive hepatocyte microvesicular steatosis and fibrosis in SFS+NS group and By POD 7, the pathological changes became less severe with evidence of repair of disrupted hepatic architecture. Compared to SFS+NS group, SFS+SST group presented mild injury with almost normal lobules of liver.
4. Electronic microscopy examination:In SFS+NS group, the hepatocyte microvesicular steatosis, tremendous mitochondrial swelling, and sinusoidal disruption were observed, whereas in the whole liver group, almost normal hepatocytes with only mild swelling of mitochondria and intact sinusoidal endothelial were observed. The pathological injury in group SFS+SST was less severe with almost integrity of sinusoidal endothelial lining.
5. Kinesis of PPG after reperfusion:Over the postoperative period, the values of PPG in SFS+NS group were significantly higher than those in the whole liver group (P＜0.01) with two crest values at 2 hours after reperfusion and on POD 1 whereas in SFS+SST group the values were significantly decreased (P＜0.01) but still higher than the whole liver group with peak at 5 minutes post-reperfusion and thereafter downward to baseline on POD 3.
6. Liver regeneration:The Ki-67 proliferation index in SFS+NS group was significantly increased at 2 hours post reperfusion and on POD 3 and 7 (P<0.05). Compared to SFS+NS group, the Ki-67 proliferation index in SFS+SST group was significantly decreased at 2 hours after reperfusion and on POD 3 (P<0.05), but with no significant difference on POD 7. There was also no significant difference of graft weight increase rate on POD 7.
7. Apoptosis index:Compared to the whole liver group, the apoptosis index in SFS+NS group was significantly increased at 2 hours post reperfusion and on POD 3 and 7 (P<0.05). Compared to SFS+NS group, the apoptosis index in SFS+SST group was significantly decreased at each time checked (P<0.05).
8. Transcription and expression of intrahepatic ET-1:Compared to the whole liver group, the transcription of ET-1 at 2 hours post reperfusion as well as the expression on POD 3 in SFS+NS group was significantly increased (P<0.05), whereas in SFS+SST group they both were significantly decreased when compared to SFS+NS group (P<0.05).
9. The ratio of ET-1/NO:Compared to the whole liver group, the ratio of ET-1/NO on POD1,2,3 in SFS+NS group was significantly increased (P＜0.05), whereas in SFS+SST group, it significantly decreased when compared to SFS+NS group (P<0.05).
Conclusions:
1. Persistent higher PPG and hepatic microcirculation disturbance at the early period of SFS liver transplantation accounts much for the SFS graft injury.
2. The over-proliferation of the hepatocytes at the early period of SFS liver transplantation is not necessitous for the size-reduced liver grafts'recovery in volume and function, and instead may even do harm to this process.
3. SST-14 can improve the the function and survival of SFS graft in pigs by decreasing the PPG, attenuation of hepatic microcirculation disturbance and reduction of apoptosis.
4. Short-term intervention of SST-14 with routine dose decreases the proliferation rate of hepatocytes at the early period of SFS liver transplantation, but has no impairment to the graft recovery in volume and function.
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