COMPLEMENT-DEPENDENT PROSTAGLANDIN SYNTHESIS IN SEPSIS

脓毒症中补体依赖性前列腺素合成

• 批准号: 3466034
• 负责人: Mitchell P. Fink
• 金额: $ 9.39万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-04-01 至 1992-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3466034
• 关键词: cardiovascular pharmacology; complement inhibitors; complement pathway; disease /disorder model; endotoxins; fatty acid biosynthesis; neutrophil; particle; prostaglandin inhibitors; prostaglandins; radioimmunoassay; radiotracer; thermal blood flow measurement; vasodilatation; vasomotion

Although low systemic vascular resistance is a consistent hemodynamic feature of sepsis in humans, relatively little is known about the mechanisms involved. The problem is important, however, because defective regulation of peripheral vasomotor tone is a contributing factor leading to the development of systemic arterial hypotension (i.e., septic shock) in patients with overwhelming infections. Shock remains the single most important predictor of mortality in septic patients. The purpose of this study is to test the hypothesis that decreased vasomotor tone in sepsis is mediated (at least in part) by vasodilating prostaglandins (PGE2 and/or PGI2) and that release of these substances is initiated by activation of the complement system. The studies will employ a rabbit model of endotoxemia that is characterized by low systemic vascular resistance and high cardiac output; i.e., the model satisfactorily replicates the systemic hemodynamic profile of human sepsis. Cardiac output will be measured by thermodilution; regional blood flow will be assessed using radioactive microspheres; plasma levels of metabolites of PGE2 and PGI2 will be determined by radioimmunoassay. Three series of experiments will be conducted. The first will examine the effect of pharmacologically limiting the formation of prostaglandins or complement-derived peptides on systemic and regional hemodynamics and plasma prostaglandin levels in endotoxic rabbits. Prostaglandin synthesis will be inhibited by administering meclofenamate or ibuprofen; formation of complement-derived peptides will be inhibited by prior decomplementation with cobra venom factor or treatment with inhibitors of complement activation. The second series of experiments will investigate systemic and regional hemodynamics and plasma prostaglandin levels in rabbits infused with graded doses of either zymosan- activated plasma (a source of complement-derived peptides) or cobra venom factor (to initiate the formation of these peptides in vivo). The studies will be performed in the presence and absence of PG synthesis inhibitors. The third series of experiments will ascertain whether the hemodynamic effects of vasodilating doses of endotoxin or activated complement depend upon interaction with polymorphonuclear leukocytes. These studies should provide important new insights into the mechanisms underlying the derangements in vasomotor tone in sepsis and possibly lead to improved therapeutic strategies.

虽然低的全身血管阻力是一致的 在人类脓毒症血流动力学特征中， 了解相关机制。 这个问题很重要， 然而，由于外周血管扩张调节缺陷， 音调是导致发展的一个因素， 全身性动脉低血压（即，脓毒性休克）的患者 严重的感染。 休克仍然是最单一的 脓毒症患者死亡率的重要预测因素。 目的 这项研究的目的是检验血管扩张减少的假设， 脓毒症中的紧张性（至少部分）是由血管舒张 前列腺素（PGE 2和/或PGI 2）及其释放 这些物质是通过激活补体系统而启动的。 这些研究将采用内毒素血症的兔模型， 其特征在于低的全身血管阻力和高的 心输出量;即，该模型令人满意地复制了 人脓毒症全身血流动力学特征。 心输出量 将通过热稀释法进行测量;局部血流量将 使用放射性微球进行评估; PGE 2和PGI 2的代谢产物将通过以下方法测定： 放射免疫法 三个系列的实验将是 进行。 第一部分将研究 限制类胡萝卜素形成的酶，或 补体衍生肽对全身和局部 内毒素血症患者血流动力学和血浆前列腺素水平 家兔 前列腺素的合成将被抑制， 甲氨蝶呤或布洛芬;补体衍生的形成 肽将被cobra预先去补体化抑制 毒因子或补体抑制剂治疗 activation. 第二组实验将研究 全身和局部血流动力学和血浆前列腺素 在输注了分级剂量的酵母聚糖- 活化血浆（补体衍生肽的来源）或 眼镜蛇毒因子（以启动这些肽在 体内）。 研究将在存在和不存在 PG合成抑制剂。 第三组实验将 确定血管舒张剂量的血液动力学效应 内毒素或活化补体的相互作用 多形核白细胞 这些研究将提供 重要的新见解的机制， 败血症中血管紧张性紊乱，可能导致 改善治疗策略。