肝移植胆道缺血再灌注损伤时血红素氧合酶-1介导的保护机制研究

After liver transplantation, liver cold ischemia-reperfusion injury can result in severe ischemic biliary tract lesions that seriously affect the life quality of patients and liver graft survival. There are no effective preventive and therapeutical measures. The severe case need liver retransplantation again. Our previous studies found a strong protective effect of HO-1 in liver cold ischemia reperfusion injury. Rat liver transplantation cold ischemia reperfusion injury models were established, moreover, heme oxygenase-1(HO-1) levels of donors and recipients were induced to high expression or gene silencing. The potential effects of HO-1 in transplanted liver bile secretion and transit capacity were observed. We will analyze the affection of HO-1 on biliary epithelial cells damage, cholangitis and the process of fibrosis surrounding bile duct epithelium, and clarify the pathways and mechanisms of HO-1 in liver transplantation biliary ischemia reperfusion injury. Angiogenesis protein content, activation of endothelial progenitor cells and migration to specific target organ were detected. We will explore the roles and ways of HO-1 on vascular plexus regeneration around the bile duct, and further reveal the internal relations of HO-1 on peribiliary vascular plexus regeneration and biliary ischemia reperfusion injury. We will attempt to provide new ideas and methods that alleviate biliary cold ischemia reperfusion injury and that improve ischemic biliary tract lesions after liver transplantation through change HO-1 expression of donors and (or) recipients.

肝脏冷缺血再灌注损伤可引起肝移植术后严重的缺血型胆道病变，目前尚无有效的预防措施且治疗困难，严重影响患者生活质量及移植肝的存活，严重者需行再次肝移植。我们前期的研究发现血红素氧合酶-1(HO-1)在肝脏冷缺血再灌注损伤中有强大保护效应，本项目通过建立大鼠肝移植冷缺血再灌注损伤模型，诱导和(或)沉默供、受体HO-1表达，观察HO-1对移植肝胆汁分泌、转运能力的影响，分析HO-1与胆管上皮细胞损害、胆管炎发生及胆管上皮周围纤维化进程的内在联系，阐明肝移植胆道缺血再灌注损伤中HO-1的作用途径及机制。检测血管再生相关蛋白含量及内皮祖细胞活化、并向特定的靶器官迁移，探讨HO-1对胆管周围血管丛再生的作用及方式，进一步揭示HO-1对胆管周围血管丛的再生与胆道缺血再灌注损伤的内在联系，通过改变供体和(或)受体HO-1表达来减轻胆道冷缺血再灌注损伤，为改善肝移植术后缺血型胆道病变提供新的思路和方法。

肝移植作为治疗终末期肝病的唯一有效手段，已被广泛接受，目前围手术期死亡率已下降到5%左右，10年生存率达到了80%以上，然而，尽管在手术技术、器官保存和免疫抑制方面已经取得较大进展，供肝离体后的缺血再灌注损伤（ischemia reperfusion injury，IRI）仍然是造成移植后肝脏原发性无功能的主要原因之一。HO-1又被称为“移植保护基因”，在肝脏缺血再灌注损伤时，HO-1表达上调可以抑制肝脏Kupffer细胞释放炎症介质和细胞毒物质，通过抗氧化、抗炎、抗凋亡等多重机制发挥组织器官保护作用。我们的研究证实上调供体HO-1的表达，可改善肝功能、减轻炎性细胞浸润、引起胆道转运蛋白如 Bsep, Ntcp and Mrp2的分泌增多，影响TBA、PL的分泌水平，降低TBA/PL比值，对抗疏水性胆盐的毒性作用，明显减轻移植后胆道缺血再灌注损伤。