PATHOPHYSIOLOGY OF ENDOTOXIN-MEDIATED FEVER

描述（改编自申请人的摘要）：一般认为， 发热不是由外源性，而是由内源性热原引起的， 称为细胞因子的一系列肽介质。这些都是阐述和发布的 进入循环，主要是由全身单核吞噬细胞激活， 外源性物质，并运输到视前下丘脑前部 大脑的POA区，它们在那里活动。前列腺素E2（PGE 2）被认为 是POA中的发热介质，由这些细胞因子诱导。虽然 PGE 2的视前区水平在静脉（iv） 施用外源性（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的快速生产，因为它是在 它们刺激的合酶（环氧化酶-2，考克斯-2）变得活跃。 此外，在静脉内LPS后，细胞因子在血液中也不可检测，直到 在发热反应已经开始之后，没有证据表明 很容易穿透大脑因此，其他，更迅速地唤起 介质可被假定参与引发发热反应。 基于公认的LPS作用机制，我们假设， LPS几乎立即激活补体（C）级联反应，产生 过敏毒素C3 a和C5 a，其作用是激活巨噬细胞并迅速 诱导具有刺激外周感觉神经的能力的介质 然后将这些信息发送给POA。我们有数据支持 全身C参与豚鼠对LPS的发热反应，但 当腹腔注射LPS时比当静脉内施用LPS时更关键。我们 根据初步数据假设，这种对C的差异依赖性可能是 与腹膜的不同功能和生化特征有关 和肝巨噬细胞。最后，最近的初步数据表明， 作用于神经传入的释放的介质可能不是PGE 2， 也不是像人们所认为的那样来自巨噬细胞。这样做的目的 因此，拟议的研究是解决我们的研究结果所提出的问题。 这一结果将有助于理解外周血淋巴细胞的机制 致热信号，特别是关于发热的发作，以及 过程的基础上的多元宿主防御反应，以传染性 一般的刺激。

DESCRIPTION (adapted from applicant's abstract): It is generally believed that fever 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., lipopolysaccharide, 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 i.v. 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, we have hypothesized that LPS virtually immediately activates the complement (C) cascade, generating the anaphylatoxins C3a and C5a, which function to activate macrophages and rapidly induce a mediator that has the capacity to stimulate peripheral sensory nerves that then transmit this information to the POA. We have data supporting the involvement of systemic C in the febrile response of guinea pigs to LPS, but more critical when LPS is injected i.p. than when it is administered iv. We hypothesize from preliminary data that this differential dependence on C may be related to distinct functional and biochemical characteristics of peritoneal and hepatic macrophages. Finally, recent preliminary data have suggested that the released mediator that acts on neural afferents may not be PGE2 and may also not be derived from macrophages, as had been supposed. The purpose of this proposed research, therefore, is to address the issues raised by our findings. The results will contribute to understanding the mechanisms of peripheral pyrogenic signaling, particularly regarding the onset of fever, as well as the processes that underlie the multivariate host defense reactions to infectious stimuli in general.