HO-1过表达稳定肥大细胞膜形成的供肝前置状态在移植后减轻I/RI及阻断供肝源DC归巢减轻急性排斥的双重作用

Protection of donor liver remains a big problem after transplantation clinically. We have proved that up-regulation of heme oxygenase-1 (HO-1) in donor liver can play a dual protective effect: inhibition of recipient rejection and protection of donor liver, under the financial assistance of our previous National Nature Science Foundation of China (NSFC). These results indicated that regulation of donor liver before transplantation can affect the prognosis. As a result, we brought up a concept of preconditioning status of donor liver. Based on the previous results, we hypothesize that stabilization of mast cells (MC) in donor liver is the key point of this preconditioning status before transplantation. On the one hand, ischemia/reperfusion injury can be alleviated directly through over-expression of HO-1 in MC which can inhibit degranulation of mast cells and decrease prostaglandin E2 (PGE2) release through blockage of Fc ε receptor binding with its ligand in order to prevent Ca2+ influx. On the other hand, migration and homing of dendritic cells (DC) in donor liver can be effected through blockage of combination of CC chemokine receptor and CC chemokine ligand, resulting in alleviation of acute rejection. Therefore, donor liver function is maintained after transplantation. This research is an extension of our previous work. We hope that the cellular mechanisms of the preconditioning status of donor liver can be clarified by investigating MC degranulation, liver injury after transplantation, migration of donor DC and immunological reaction of the recipient. Finally, we can provide some new theories to improve the prognosis of liver transplantation.

移植后肝脏功能维护依然是困扰临床的重要问题。课题组在前期NSFC项目资助下，验证了供肝保护性基因HO-1上调，可以起到抑制宿主免疫、保护供肝的双重效应。该结果提示通过调控供肝植入前的状态可以影响到预后。于是我们提出供肝前置状态概念，并结合预初结果和理论，提出假设：供肝源肥大细胞（MC）膜稳定状态是前置状态的关键,供肝MC HO-1过表达,通过阻断Fcε受体/配体结合途径，阻止Ca2+内流，抑制MC脱颗粒，PGE2释放减少，直接减轻移植后缺血再灌注损伤，同时通过阻断CCR/CCL途径，使得供肝源DC迁移归巢发生障碍，影响其成熟，进而减轻移植后急性排斥反应，最终达到保护移植后肝功能的目的。本课题是对前一课题的延续深入，通过观察MC脱颗粒、移植后供肝损伤、供肝源DC迁移和受体免疫反应等指标，最终阐明供肝前置状态形成的细胞机制假说，为改善肝移植愈后提供新的理论依据。

供肝保护性基因 HO-1 上调,可以抑制宿主免疫,发挥保护供肝的双重效应。但机制不明确，我们结合预初实验提出肝源肥大细胞(MC)膜稳定状态是前置状态的关键。通过体内体外两部分实验观察 MC 脱颗粒、供肝源 DC 迁移、移植后供肝损伤、受体免疫反应等指标发现MC HO-1 过表达,阻止 Ca2+内流,抑制 MC 脱颗粒,抑制 DC 迁移影响其成熟,进而抑制同种异体淋巴细胞增殖。稳定肥大细胞膜阻断肥大细胞脱颗粒减轻移植后缺血再灌注损伤及急性免疫排斥反应。最终达到保护移植后肝功能的目的。阐明了供肝前置状态形成的细胞机制假说,为改善肝移植愈后提供新的理论依据。