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.

尽管全身血管阻力低是一个一致的 人类败血症的血流动力学特征相对较少 了解所涉及的机制。 问题很重要， 然而，由于外周血管舒缩调节有缺陷 语气是促进语气发展的一个因素 全身性动脉低血压（即感染性休克）患者 压倒性的感染。 震惊仍然是最重要的 脓毒症患者死亡率的重要预测因子。 目的 这项研究的目的是检验血管舒缩功能下降的假设 脓毒症的张力（至少部分）是由血管舒张介导的 前列腺素（PGE2 和/或 PGI2）及其释放 物质是通过补体系统的激活而启动的。 这些研究将采用兔内毒素血症模型，即 其特点是全身血管阻力低， 心输出量；即，该模型令人满意地复制了 人类脓毒症的全身血流动力学特征。 心输出量 将通过热稀释法测量；局部血流量将 使用放射性微球进行评估；血浆水平 PGE2 和 PGI2 的代谢物将通过以下方式测定 放射免疫测定法。 将进行三个系列的实验 实施。 首先将检查效果 药理学上限制前列腺素的形成或 补体衍生肽对全身和局部的影响 内毒素患者的血流动力学和血浆前列腺素水平 兔子。 前列腺素的合成会受到抑制 甲氯芬那酯或布洛芬；补体衍生的形成 肽将被眼镜蛇预先去补体所抑制 毒液因子或补体抑制剂治疗 激活。 第二系列实验将调查 全身和局部血流动力学和血浆前列腺素 注射分级剂量的酵母聚糖的兔子体内的水平 活化血浆（补体衍生肽的来源）或 眼镜蛇毒液因子（启动这些肽的形成 体内）。 研究将在存在和缺席的情况下进行 PG合成抑制剂。 第三系列实验将 确定血管舒张剂量是否对血流动力学产生影响 内毒素或激活补体的作用取决于相互作用 与多形核白细胞。 这些研究应该提供 对潜在机制的重要新见解 败血症时血管舒缩张力紊乱，可能导致 改进的治疗策略。