COMPLEMENT-DEPENDENT PROSTAGLANDIN SYNTHESIS IN SEPSIS

尽管低的全身血管阻力是一致的 脓毒症的血液动力学特征在人类中相对较少 了解其中涉及的机制。这个问题很重要， 然而，由于外周血管运动调节的缺陷 语气是导致发展的一个促成因素 慢性阻塞性肺疾病患者的全身动脉低血压(即感染性休克) 压倒性的感染。最令人震惊的仍然是 败血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这样一种假设，即血管运动减少 脓毒症的紧张感(至少部分)是通过血管扩张来调节的。 前列腺素(PGE2和/或PGI2)及其释放 物质是通过激活补体系统来启动的。 这项研究将使用内毒素血症的兔模型 以低血管阻力和高血管阻力为特征 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 将通过热稀释来测量；局部血流量将 使用放射性微球进行评估；血浆中 前列腺素E_2和前列环素的代谢物将通过 放射免疫分析。三个系列的实验将是 指挥。首先，我们将考察 从药理上限制前列腺素或 补体衍生多肽对全身和局部的影响 内毒素血症患者血流动力学及血浆前列腺素水平的变化 兔子。前列腺素的合成将被抑制 甲氯芬酯或布洛芬；补体衍生的形成 多肽将被预先用眼镜蛇分解而被抑制 毒液因子或补体抑制剂治疗 激活。第二系列实验将研究 全身和局部血流动力学与血浆前列腺素 注射不同剂量酵母多糖的兔体内水平 激活的血浆(补体衍生多肽的来源)或 眼镜蛇毒液因子(启动这些多肽的形成 Vivo)。研究将在在场和不在场的情况下进行 PG合成抑制剂。第三系列实验将 确定血管扩张剂量对血流动力学的影响 内毒素或激活的补体取决于相互作用 有多形核白细胞。这些研究应该提供 对潜在机制的重要新见解 脓毒症患者血管舒缩张力紊乱并可能导致 改进治疗策略。

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.