GUT ISCHEMIA & MOF SYNDROME--MICROVASCULAR TRANSDUCTION

肠道缺血

• 批准号: 2138678
• 负责人: Gregory B. Bulkley
• 金额: $ 24.93万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-01-01 至 1995-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2138678
• 关键词: cardiogenic shock; cardiovascular disorder chemotherapy; cardiovascular disorder diagnosis; creatine kinase; disease /disorder model; endotoxins; enteritis; free radical oxygen; gastrointestinal circulation; gastrointestinal circulatory insufficiency; gastrointestinal disorder diagnosis; gastrointestinal imaging /visualization; human subject; intestine disorder; ischemia; laboratory rat; multiple organ failure; orphan disease /drug; pancreatitis; radionuclide imaging /scanning; radiotracer; renin angiotensin system; reperfusion; swine; vasopressins; xanthine oxidase

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.

改进手术、输血治疗、急救和 重症监护产生了越来越多的患者 最初从循环复苏中存活下来(低血容量和 心源性)休克，但后来因多器官衰竭而死亡 Synidrome(MOF)在先前定义了血流动力学机制之后， 内脏器官(肠道、结肠、 胃和肝脏)是缺血和再灌注损伤的目标 在休克期间，这个项目现在试图更好地了解这些机制 这些受损的内脏器官通过什么影响远方的损伤 多器官衰竭猪模型的(非内脏)器官。 需要评估的具体假设包括：a)肠道和/或 胰腺是重要循环毒素的来源，其中一些具有 蛋白水解性。B)微血管内皮细胞是一种 这些介体的重要初始目标；c)有毒的氧代谢物 由黄嘌呤氧化酶(XO)产生，由这些循环毒素激活 来自内皮细胞表面的黄嘌呤脱氢酶(XD)，是 微血管损伤的最初导火索。这一假设是有根据的 在令人兴奋的新发现的基础上，酶活性和 免疫反应阳性的XO在外表面呈高浓度分布 EC质膜。D)中性粒细胞在 微血管系统具有其重要的毒性后果，是次要的。 这种原发内皮细胞损伤。 在猪原位、猪交叉循环和异位灌流 器官(猪肺和大鼠肝脏)和小鼠网状内皮细胞 功能制剂，以及在培养的内皮单层中，这些 假说将通过用蛋白水解酶(胰凝乳酶)进行检测来检验。 抗蛋白水解酶(大豆胰蛋白酶抑制剂)，特殊抗氧化剂 (超氧化物歧化酶和过氧化氢酶)和黄嘌呤氧化酶均有抑制作用 使用别嘌醇和一种新的阻断XO的单抗 活动。内皮细胞XO与XD的定量区别 通过一种新的组织化学方法和区分XO的Moab‘s方法进行原位检测 来自XD。这些方法应该能让我们评估中央 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的转换，转导 毒性和炎症介质循环进入终末器官损伤 这就构成了多器官衰竭。