GUT ISCHEMIA & MOF SYNDROME--MICROVASCULAR TRANSDUCTION

手术、输血治疗、急诊和 重症监护产生了越来越多的患者， 最初从循环（低血容量和 心源性）休克，但后来死于多器官衰竭 共晶型（MOF）。 先前已经定义了血液动力学机制， 以及内脏器官（肠，结肠， 胃和肝）是缺血和再灌注损伤的靶 在休克期间，该项目现在寻求更好地了解机制， 这些受损的内脏器官通过其影响远距离损伤 图10示出了在MOF的猪模型中的（非内脏）器官的解剖图。 待评估的具体假设包括： 胰腺是重要的循环毒素的来源，其中一些 蛋白水解活性B）微血管内皮细胞是一种 这些介质的重要初始靶点; c）有毒氧代谢物 由黄嘌呤氧化酶（XO）产生，由这些循环毒素激活 从黄嘌呤脱氢酶（XD）的内皮细胞表面，是 微血管损伤的初始触发点 这个假设是基于 基于令人兴奋的新发现， 免疫反应性XO以高浓度存在于外表面上 EC细胞膜。d）在大气中的中子积累 微血管系统本身具有重要的毒性后果， 这种原发性内皮细胞损伤。 在猪原位、猪交叉循环和离体灌注 器官（猪肺和大鼠肝脏）和小鼠网状内皮细胞 功能制剂，并在培养的内皮细胞单层，这些 将通过蛋白酶（胰凝乳蛋白酶）探测来检验假设 抗蛋白酶（大豆胰蛋白酶抑制剂），特异性抗氧化剂 （超氧化物歧化酶和过氧化氢酶）和黄嘌呤氧化酶的抑制 与别嘌呤醇和一种新的单克隆抗体阻断XO 活动 内皮XO将与XD定量区分， 用一种新的组织化学方法，以及用区分XO的单克隆抗体， 来自XD 这些方法应该可以让我们评估中央 假设内皮细胞质膜表面黄嘌呤 氧化还原酶，通过翻译后XD到XO的转化， 循环毒性和炎症介质进入终末器官损伤 构成多器官衰竭

Improvements in surgery, transfusion therapy, emergency and intensive care have generated increasing numbers of patients who initially survive resuscitation from circulatory (hypovolemic and cardiogenic) shock, only to succumb later from the multiple organ failure synidrome (MOF). Having previously defined the hemodynamic mechanism, and a major toxic pathway by which splanchnic organs (intestine, colon, stomach, and liver) are targets for ischemia and reperfusion injury during shock, this project now seeks to better understand the mechanisms by which these injured splanchnic organs influence injury in distant (non-splanchnic) organs in a porcine model of MOF. Specific hypotheses to be evaluated include: a) The intestine and/or pancreas are sources of important circulating toxins, some of which have proteolytic activity. b) The microvascular endothelial cell is an important initial target of these mediators; c) Toxic oxygen metabolites generated by xanthine oxidase (XO), activated by these circulating toxins from xanthine dehydrogenase (XD) on the endothelial cell surface, are the initial trigger of this microvascular injury. This hypothesis is based upon the exciting new finding that enzymatically active and immunoreactive XO is present in high concentration on the outside surface of the EC plasma membrane. d) Neutrophil accumulation in the microvasculature, with its own important toxic consequences, is secondary to this primary endothelial cell injury. In porcine in situ, porcine cross circulation, and ex situ perfused organ (porcine lung and rat liver), and mouse reticuloendothelial function preparations, and in cultured endothelial monolayers, these hypotheses will be tested by probing with proteases (chymotrypsin) antiproteases (soybean trypsin inhibitor), specific antioxidants (superoxide dismutuse and catalase) and xanthine oxidase inhibition both with allopurinol and with a new monoclonal antibody that blocks XO activity. Endothelial XO will be quantitatively distinguished from XD in situ by a new histochemical method, and by MoAb's that distinguish XO from XD. These methods should allow us to evaluate the central hypothesis, that endothelial cell plasma membrane surface xanthine oxidoreductase, via post-translational XD to XO conversion, transduces circulating toxic and inflammatory mediators into the end organ injury that constitutes multiple organ failure.