白三烯C4（LTC4）是重要的前炎症因子。我们前期报道肝缺血再灌注(IR)早期LTC4异常增加与LTC4合酶（LTC4S）表达和酶活性增加有关；NO供体硝普钠能抑制LTC4S表达和酶活性，减少LTC4堆积，保护肝功能。本课题拟用在体肝IR早期损伤和离体肝切片缺氧/复氧模型，研究①LTC4异常增加与5-脂氧化酶（5-LO）基因和蛋白表达、分布和酶活性的相关性，肝IR是否经5-LO/LTC4S提高LTA4含量增加LTC4合成；②NO供体降低LTC4含量与其对5-LO表达、分布和酶活性的影响及5-LO和LTC4S酪氨酸残基硝化修饰的相关性，NO供体是否经5-LO/LTC4S减少LTA4含量抑制LTC4合成；③NO供体是否间接经激活sGC/cGK，抑制5-LO和/或LTC4S减少LTC4合成。阐释肝IR早期LTC4异常增加及NO供体调控的分子机制。为治疗肝移植和肝肿瘤切除等疾病提供新实验理论依据。

Hepatic ischemia reperfusion (IR) injury is an important clinical issue and its mechanism not fully clear. Nitric oxide (NO) has become the subject of both intense research as well as heated debate over its role in various biological and pathophysiological processes since its discovery. The role of NO during hepatic I/R still largely contradictory. Increasing evidences indicate that hepatic IR injury involve in leukotriene (LT). LTs are arachidonic acid-derived metabolites that are synthesized via the 5-lipoxygenase pathway. That the LTC4 synthase (LTC4S) catalyzes LTA4 and reduced glutathione to generate LTC4 is the first committed step in the synthesis of cysteinyl LTs, LTC4, LTD4 and LTE4. Our previous series of findings suggest: 1.abnormal LTC4 accumulation after hepatic IR can be caused partially by LTC4S expression up-regulation and the LTC4S activity augment. 2.that sodium nitroprusside(SNP), a NO donor decrease LTC4 production during hepatic IR could be partially resulted from SNP down-regulating the protein expression of LTC4S rather than mGST2 or mGST3 and its suppression of the LTC4S activity. 3.SNP downregulated LTC4S mRNA expression by inhibiting NF-kB activation independent of IkBa. However, there is no literature that studied the relationships among the abnormal increased LTC4 production and the changes in the mRNA and protein expression,distribution and activity of 5-lipoxygenase, as well as the direct and indirect effects of NO donor on them during hepatic IR injury in rats. Here using in vivo rat model of 70% hepatic IR injury and in vitro model of liver slice hypoxygen/reoxygenation, we will concentrate on the following topics: 1.How about the relationships between the abnormal increased LTC4 production and the changes in the expression,distribution and activity of 5-lipoxygenase? Did the abnormal increased LTC4 production come from the increased LTA4 synthesis via the 5-LO/LTC4S pathway or just from the up-regulated expression and activity of LTC4S？2. How about the relationship among NO donor induced decrease of LTC4 synthesis, the changes in the expression,distribution and activity of 5-lipoxygenase,as well as the 3-nitrotyrosine formation of 5-LO and LTC4S? Did the NO donor induced supression of LTC4 synthesis come from NO decreasing LTA4 synthesis via the 5-LO/LTC4S pathway or just from NO down-regulating the expression and activity of LTC4S during hepatic IR injury？3. In addition to the above direct effects of NO donor, whether NO donor induced suppression of LTC4 synthesis involved in NO inhibiting 5-LO and/or LTC4S indirectly through activation of the sGC and cGK pathways? All these works if completed will further elucidate the molecular mechanisms underlying the abnormal increased LTC4 production and NO donor inhibiting LTC4 systhesis in the early phase of hepatic IR injury in rats. It will provide some new experimental and theoretic evidence for the treatment of liver transplantation and liver resectional surgery.