硝基还原酶介导的级联靶向硫化氢供体对烧伤休克期脏器缺血再灌注损伤的治疗作用

严重烧伤后产生的脏器缺血再灌注损伤，可进一步导致多脏器功能不全和血液微循环障碍，严重影响患者预后，对此临床尚无理想的治疗方案。根据我们前期工作基础，本课题提出可利用硫化氢供体方案开展烧伤休克期缺血再灌注损伤的治疗。拟通过硫化氢供体的结构设计，使其靶向到再灌注损伤出现最早的心脏和最常见的肾脏部位，并在损伤后细胞线粒体特异性高表达的硝基还原酶调控下，释放硫化氢分子，发挥抗氧化损伤、抗炎、线粒体保护和促血管生长等作用，用于缺血再灌注损伤的治疗。同时避免了硫化氢分子由于无靶向和不可控的释放引起的毒副作用。此外，本课题拟以所设计的硫化氢供体为工具，探索硫化氢分子用于烧伤休克期缺血再灌注损伤治疗的量效关系及潜在的生物学新机制，为烧伤休克期脏器缺血再灌注损伤的治疗提供临床新方案。

Ischemia-reperfusion injury from severe burns can further lead to multiple organ dysfunction and blood microcirculation disorders, which seriously affects the prognosis of patients, and there is no ideal clinical treatment for this disease. Based on our previous work, this proposal aims to design a novel hydrogen sulfide donor to treat of ischemia reperfusion injury during burn shock phase. Proposed by the structural design of hydrogen sulfide donor, make its targeted to heart and kidney, which suffer from reperfusion damage earliest and the most common respectively, and regulated by specificity high expression of nitroreductase formed in the damage cell mitochondria, and then release hydrogen sulfide molecules. Hydrogen sulfide can play an important role for the treatment of ischemia-reperfusion injury, by antioxidant damage, anti-inflammatory, mitochondria protection and angiogenesis. At the same time, the toxic side effects caused by untargeted and uncontrolled release of hydrogen sulfide molecules are avoided. In addition, this proposal intends to use the designed hydrogen sulfide donor as a tool to explore the dose-effect relationship and potential new biological mechanism of hydrogen sulfide molecule for the treatment of ischemia-reperfusion injury during burn shock stage, and provide a new protocol for the treatment of ischemia reperfusion injury during burn shock phase.