PATHOPHYSIOLOGY OF ENDOTOXIN-MEDIATED FEVER

描述：(申请人摘要)发烧是感染的标志。它 一般认为不是外源性的，而是内源性的 热原，一系列称为细胞因子的多肽介质的成员。这些 在很大程度上是由系统性的 单核巨噬细胞被外源因子激活，并被输送到 视前下丘脑前区(POA)，它们在那里活动。 前列腺素E2(PGE2)被认为是POA中的发热介质， 由这些细胞因子诱导。尽管视前前列腺素E_2水平升高 在静脉(IV)给药外源(例如， 脂多糖)或内源性热原，最近的数据表明 这些物质不能直接解释前列腺素E_2的快速产生 因为它早在它们刺激的合成酶之前就被启动了 (环氧合酶-2，COX-2)变得活跃。此外，细胞因子也不是 在静脉注射脂多糖后的血液中可检测到，直到发热反应之后 已经在进行中，没有证据表明他们可以轻易地穿透 大脑。因此，其他更快被唤醒的调解人可以被推定为 参与启动发热反应。基于公认的 内毒素的作用机制及前列腺素E_2诱导的新数据 综上所述，我们假设1)静脉注射内毒素几乎立即 激活补体级联，产生过敏毒素C3a，C4a， 和C5a，其2)功能是快速诱导各种介质，例如， 血小板活化因子(PAF)、缓激肽(BK)具有 刺激一氧化氮(NO)的形成，进而导致 前列腺素E_2，因此，发烧。我们有初步证据支持 全身性补体和器官中一氧化氮的参与 终板血管(OVLT)，大脑和大脑之间的接口 循环热原)在静脉注射脂多糖的发热反应中。目的 这项拟议的研究是为了证实补语的假定作用 和NO在静脉注射内毒素的热原反应中的作用，并确定PAF 和/或BK是可能将两者联系在一起的因素。如果得到证实，这一假设 将允许形成一种新的、特定的病理生理学概念 脂多糖介导的发热，特别是关于这种反应的开始。这个 结果将与本质上仍未知的中枢神经相关 多变量宿主对传染性疾病的防御反应机制 病原体。

DESCRIPTION: (Applicant's abstract) Fever is the hallmark of infection. It is generally believed that it is caused not by exogenous, but by endogenous pyrogens, members of an array of peptide mediators called cytokines. These are elaborated and released into the circulation largely by systemic mononuclear phagocytes activated by the exogenous agents, and transported to the preoptic anterior hypothalamic area (POA) of the brain, where they act. Prostaglandin E2 (PGE2) is thought to be a fever mediator in the POA, induced by these cytokines. Although the intrapreoptic level of PGE2 rises rapidly following the intravenous (iv) administration of exogenous (e.g., lipopolysaccharides, LPS) or endogenous pyrogens, recent data indicate that these substances cannot account directly for the rapid production of PGE2 because it is initiated well before the synthase that they stimulate (cyclooxygenase-2, COX-2) becomes active. Moreover, cytokines also are not detectable in blood following iv LPS until after the febrile response is already underway, and there is no evidence that they can readily penetrate the brain. Hence, other, more quickly evoked mediators may be presumed to be involved in initiating the febrile response. Based on well-recognized mechanisms of LPS action and on new data regarding the induction of PGE2 synthesis, we have hypothesized that 1) iv LPS virtually immediately activates the complement cascade, generating the anaphylatoxins C3a, C4a, and C5a, which 2) function to rapidly induce various mediators, e.g., platelet-activating factor (PAF), bradykinin (BK), that 3) have the capacity to stimulate the formation of nitric oxide (NO) which, in turn, 4) induces PGE2 and, consequently, fever. We have preliminary evidence supporting the involvement of systemic complement and of nitric oxide in the organum vasculosum laminae terminalis (OVLT, the interface between the brain and circulating pyrogens) in the febrile response to iv LPS. The purpose of this proposed research is to substantiate the putative roles of complement and NO in the pyrogenic response to iv LPS, and to determine whether PAF and/or BK are factors that may link the two. If confirmed, this hypothesis would allow formulating a novel, specific concept of the pathophysiology of LPS-mediated fever, particularly regarding the onset of this response. The results will be relevant to the still essentially unknown central nervous mechanisms underlying the multivariate host defense reactions to infectious pathogens.