PATHOPHYSIOLOGY OF ENDOTOXIN-MEDIATED FEVER

描述：（申请人摘要）发热是感染的标志。 它 一般认为，它不是由外源性的，而是由内源性的 热原，称为细胞因子的肽介质阵列的成员。 这些 主要是由系统性的 单核吞噬细胞被外源性试剂激活，并被转运到 大脑的视前下丘脑前部区域（POA），它们在那里起作用。 前列腺素E2（PGE 2）被认为是POA中的发热介质， 由这些细胞因子引起的。 虽然PGE 2水平升高， 静脉（iv）给予外源性（例如， 脂多糖，LPS）或内源性热原，最近的数据表明， 这些物质不能直接解释PGE 2的快速产生 因为它比它们刺激的合成酶早启动 （环氧合酶-2，考克斯-2）变得活跃。 此外，细胞因子也不是 在静脉注射LPS后血液中可检测到，直到发热反应后， 已经在进行中，没有证据表明他们可以轻易地渗透 大脑 因此，其他更快诱发的介质可能被假定为 参与引发发热反应。 基于公认的 LPS作用机制和关于PGE 2诱导的新数据 合成，我们假设1）静脉注射LPS几乎立即 激活补体级联，产生过敏毒素C3 a，C4 a， 和C5 a，其2）用于快速诱导各种介质，例如， 血小板活化因子（PAF）、缓激肽（BK），即3）具有 刺激一氧化氮（NO）的形成，这反过来又诱导 前列腺素E2，因此，发烧。 我们有初步证据支持 全身补体和一氧化氮在器官中的参与 终板血管膜（OVLT，脑与 循环热原）对iv LPS的发热反应。 的目的 这项研究的目的是为了证实补体的作用。 和NO在iv LPS致热原反应中的作用，并确定PAF是否 和/或BK是可能将两者联系起来的因素。 如果得到证实， 将允许制定一个新的，具体的概念的病理生理学， LPS介导的发热，特别是关于这种反应的开始。 的 结果将与本质上仍然未知的中枢神经系统相关。 多种宿主对感染性疾病防御反应的机制 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.