脂联素对胰岛移植物缺血再灌注损伤的保护作用及其机制研究

Hypoxia- reoxygenation is the leading cause of β-cell death during islet preparation, implantation, and revascularization, with the highest percentage of islet graft loss and dysfunction occurring just days after transplantation, is an important factor restricting the development of clinical islet transplantation. A number of reports suggest that the beneficial vascular and anti-inflammatory activity of adiponectin might contribute to its therapeutic potential during ischemia–reperfusion injury. Our preliminary findings demonstrate that adiponectin protects islet cells against ischemia–reperfusion injury, dependent on COX-2—TNFα—NF-κB pathway. . In this study, to examine the effects and mechanisms of adiponectin on the resistance of islet ischemia–reperfusion injury, evaluate the possibility of adiponectin reducing islet graft loss occurring just days after transplantation and promoting the long-term functional islet survival, we used the islet vitro culture systems and performed kidney subcapsular syngeneic islet transplants to assess the islets, vitality and function, hypoxia and inflammatory injury, apoptosis status, and the vascular endothelial cell growth and microvascular reconstruction situations in addition. The success of our study will provide an effective non-immunotherapy beneficial to the clinical efficacy of islet transplantation.

移植后早期胰岛大量丢失是制约临床胰岛移植发展的重要因素，胰岛制备、移植和血运重建过程中的缺血再灌注损伤在其中发挥着首要作用。已有的研究表明脂联素可以降低炎性反应，保护血管内皮细胞，进而降低多种组织细胞的缺血再灌注损伤。我们的前期研究也已证实脂联素对胰岛缺氧再给氧损伤起到良好的保护作用，其作用机理与COX-2—TNFα—NF-κB信号通路密切相关。. 本项目拟利用胰岛体外培养体系和糖尿病小鼠胰岛移植模型，给予脂联素干预措施，观察胰岛的功能变化、缺氧和炎性损伤以及凋亡情况，血管内皮细胞生长和微血管重建情况，研究脂联素对胰岛缺血再灌注损伤的保护作用及其机制，评价脂联素降低移植后早期胰岛丢失，促进胰岛长期功能发挥的可能性。若获成功，将为提高临床胰岛移植疗效提供有效的非免疫治疗新思路

目的：胰岛移植目前被广泛认为是有效治疗 1 型糖尿病最具有潜力的一种手段，移植后早期胰岛大量丢失是制约临床胰岛移植成功的首要因素，其中移植后缺血导致移植物的大量的死亡。外源性脂联素可以有效防止因缺血缺氧所导致的细胞损伤或死亡。因此我们检测转染脂联素基因对胰岛的保护作用。.方法：体内实验分三组。移植组：移植胰岛细胞并尾静脉注射生理盐水；脂联素治疗组：移植胰岛细胞后通过尾静脉注射脂联素进行治疗；转基因移植组：分离小鼠胰岛细胞并通过体外转染脂联素基因移植到同基因糖尿病小鼠肾包膜下。移植后检测移植物功能及血管生成情况。体外通过缺氧再给氧模型、炎症模型和氧化应激模型检测脂联素对胰岛的保护作用及对其功能的影响。.结果：脂联素能够显著降低移植受着血糖，提高移植物的生存率，改善移植物功能，促进移植物血管化，而且转染基因后其功能发挥更持久；脂联素能够保护缺氧再给氧、炎症和氧化应激对胰岛细胞进行的损伤。.结论：脂联素能够通过降低移植后的炎症反应、对缺氧进行保护、促进移植物的血管化从而促进移植物的存活