PROJECT IV - MAST CELL/MAST CELL MEDIATORS IN ISCHEMIA REPERFUSION INJURY

在创伤、某些外科手术和各种病理条件下发生的缺血和再灌流，会导致局部组织损伤和远端肺损伤。先天免疫系统的三个组成部分与损伤有关，即天然IgM、补体系统和肥大细胞(MC)。这些研究最初将集中于确定MC及其介体在骨骼肌缺血后损伤(局部和远程)中的作用，并将其与肠缺血后发生的损伤进行比较。MC及其调解人的角色的定义将使用由于有针对性的干扰而缺乏关键调解人的动物来完成 编码两种不同分泌颗粒蛋白水解酶的基因，这是一种产生肝素的关键酶，是合成前列腺素D2和白三烯C4的末端酶，以及细胞因子肿瘤坏死因子α。MC和不同的介体的作用的确认将通过将MC缺陷的小鼠植入正常或突变的MC来完成。该项目接下来将定义MC与其他先天性免疫系统组件的相互作用，以便定义这些不同途径之间的相互作用。这些研究将利用本计划其他部分提供的知识和资源来确定三者之间的相互依存和独立方面 在这两种不同的组织中产生局部和远端缺血损伤的成分。缺乏各种补体成分和天然抗体的小鼠将提供机会来确定这些不同途径之间的相互作用。最后，利用在这些研究中获得的知识，将探索预适应的保护机制，以区分这种短暂的智力障碍是由于脱敏、关键介质(S)的耗尽还是通过某种其他机制而起保护作用。通过这些研究，将更好地了解不同先天免疫系统组成部分的作用和相互作用，从而能够更好地干预以防止这些伤害。

An episode of ischemia followed by reperfusion such as occurs in traumatic injury, certain surgical procedures and various pathological conditions, results in injury in the local tissue and remote injury in the lungs as well. Three components of the innate immune system have been implicated in the injury, natural IgM, the complement system and mast cells (MC). These studies will initially focus on defining the role of the MC and its mediators in injury (both local and remote) following ischemia in the skeletal muscle and contrast that with the injury that occurs following ischemia in the intestine. The definition of the role of the MC and its mediators will be accomplished using animals lacking critical mediators due to targeted disruptions of the genes coding for 2 different secretory granule proteases, an enzyme critical for the production of heparin, the terminal enzymes in the pathway to synthesize prostaglandin D2 and leukotriene C4 and the cytokine tumor necrosis factor alpha. Confirmation of the role of the MC and the different mediators will be accomplished by engraftment of MC-deficient mice with the normal or mutant MC. The project will next define the interaction of the MC with the other innate immune system components in order to define the interaction, if any between these different pathways. These studies will make use of the knowledge and resources provided by the other parts of this program to define the aspects of interdependence and independence among the three components in producing the local and remote injury following ischemia in these two different tissues. Mice lacking various complement component and the natural antibody will provide the opportunity to define the interactions between these different pathways. Lastly, using the knowledge gained in these studies, the mechanism of protective of preconditioning will be explored in order to distinguish whether this short period of sichemia is protective due to desensitization, exhaustion of a critical mediator(s) or via some other mechanism. From these studies, a better understanding of the role of and interaction between the different innate immune system components will be achieved which will allow better interventions to prevent these injuries.