PATHOPHYSIOLOGY OF ENDOTOXIN-MEDIATED FEVER

描述(改编自申请人的摘要)：一般认为 发烧不是由外源性引起的，而是由内源性热原引起的， 一系列称为细胞因子的多肽介质。这些都是详细说明和发布的 主要由系统性单核巨噬细胞激活进入循环 外源性药物，并运输到视前下丘脑前部 大脑的区域(POA)，它们在那里活动。前列腺素E2(PGE2)被认为是 在这些细胞因子的诱导下，成为POA中的发烧调节剂。尽管 静脉注射后视前区前列腺素E_2水平迅速升高 外源性(如脂多糖、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 对于PGE2的快速生产，因为它是在PGE2开始之前很久就开始的 它们刺激的合成酶(环氧合酶-2，环氧合酶-2)变得活跃。 此外，在静脉注射后的血液中也检测不到细胞因子。LP截止日期 在发烧反应已经开始后，没有证据表明 它们可以很容易地穿透大脑。因此，其他的，更快地被唤起 可以推定调解人参与了发烧反应的启动。 基于公认的内毒素作用机制，我们假设 LP几乎立即激活补体(C)级联，产生 过敏性毒素C3a和C5a，其功能是激活巨噬细胞并迅速 诱导一种能够刺激周围感觉神经的介质 然后将该信息传输到POA。我们有数据支持 系统C参与豚鼠对脂多糖的发热反应，但 当注射脂多糖时，情况更为关键。而不是静脉注射。我们 根据初步数据的假设，这种对C的不同依赖可能是 与腹膜不同的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PGE2，而可能是 也不是像人们想象的那样来自巨噬细胞。这样做的目的是 因此，拟议的研究是为了解决我们的发现提出的问题。 这一结果将有助于理解外周神经损伤的机制。 热原信号，特别是关于发烧的开始，以及 构成对传染性疾病的多变量宿主防御反应的过程 一般的刺激物。

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.