PGE2 AND FEVER: INSIGHTS FROM TRANSGENIC MICE MODELS

PGE2 和发烧：来自转基因小鼠模型的见解

• 批准号: 6197592
• 负责人: CLARK M BLATTEIS
• 金额: $ 31.36万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-25 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6197592
• 关键词: blood brain barrier; body temperature regulation; brain regulatory center; endotoxins; enzyme induction /repression; genetically modified animals; hyperthermia; interleukin 1; isozymes; laboratory mouse; neural information processing; nitric oxide synthase; norepinephrine; prostaglandin E; prostaglandin endoperoxide synthase; pyrogens

Our knowledge of the mechanism(s) by which fever-producing agents, or pyrogens, act upon the thermoregulatory regions of the brain to raise body temperature is still incomplete. Previous studies have shown that prostaglandin E2 (PGE2), a member of a family of lipids present in most organs, functions as a fever mediator in the brain. The mechanism by which peripheral pyrogens signal the brain to induce the formation of PGE2, however, is still unknown. It is also unclear which cells in the brain synthesize this PGE2. But it is established that its generation requires the mediation of an enzyme, cyclooxygenase (COX), which exists in two isoforms, one constitutive, COX-1, present in most cells, and another slowly inducible, COX-2, elicited in certain cells, e.g., phagocytic and endothelial cells, by inflammatory (e.g., pyrogenic) stimuli. It has been suggested, therefore, that perivascular phagocytic cells and/or microvascular endothelial cells (collectively termed barrier cells) in the brain may be the targets of circulating pyrogens, inducing COX-2 and consequently, producing PGE2. A difficulty with this notion, however, is that fever is initiated following the intravenous (iv) injection of a pyrogen (e.g., endotoxin) significantly quicker that the synthesis of COX-2. Neurons, however, are special among brain cells in that they express constitutive COX-2. Based on previous data by our group and other data in the literature, we have hypothesized, therefore, that peripheral endotoxin may signal the brain initially via neural inputs that stimulate the release of norepinephrine (NE) in the region where fever is regulated, viz., the preoptic anterior hypothalamus. There, NE may rapidly activate another enzyme, nitric oxide synthase (NOS), constitutively also present in neurons, thereby causing the local formation of NO which, it is known, can activate COX. NO, in turn, can activate COX-2, yielding PGE2 and the first of the characteristically biphasic febrile response to iv endotoxin. We further speculate that the second febrile rise is due to a similar sequence, initiated, however, by a different, meanwhile synthesized brain-derived pyrogen, interleukin-1beta, which activates inducible NOS in the barrier cells. This study is designed to verify these putative pathways by analyzing the activities of the various isozymes and cells presumed to be involved. The results should help to advance our understanding of the central mechanism of fever production and may have relevance to its management in infectious disease.

我们对发热剂或热原作用于大脑的温度调节区域以提高体温的机制的了解仍然不完整。先前的研究表明，前列腺素E2 （PGE2）是存在于大多数器官中的脂类家族的一员，在大脑中起着发烧介质的作用。然而，外周热原向大脑发出信号诱导PGE2形成的机制尚不清楚。目前还不清楚大脑中哪些细胞合成这种PGE2。但已经确定，它的产生需要一种酶的介导，环氧合酶（COX），它存在于两种异构体中，一种是组成型的COX-1，存在于大多数细胞中，另一种是缓慢诱导型的COX-2，在某些细胞中，如吞噬细胞和内皮细胞中，通过炎症（如热原性）刺激引起。因此，有人认为，脑内的血管周围吞噬细胞和/或微血管内皮细胞（统称为屏障细胞）可能是循环热原的目标，诱导COX-2，从而产生PGE2。然而，这一观点的一个难点是，静脉注射热原（如内毒素）后开始发烧的速度明显快于COX-2的合成。然而，神经元在脑细胞中是特殊的，因为它们表达组成型COX-2。根据我们小组之前的数据和文献中的其他数据，我们假设，因此，外周内毒素可能最初通过神经输入向大脑发出信号，刺激在调节发烧的区域（即视前下丘脑）释放去甲肾上腺素（NE）。在那里，NE可以迅速激活另一种酶，一氧化氮合酶（NOS），这种酶也组成性地存在于神经元中，从而导致局部形成一氧化氮，已知一氧化氮可以激活COX。NO，反过来，可以激活COX-2，产生PGE2和第一个特征性的对静脉内毒素的双相发热反应。我们进一步推测，第二次发热升高是由于类似的序列，然而，由不同的，同时合成的脑源性热原，白细胞介素-1 β启动，它激活屏障细胞中可诱导的NOS。本研究旨在通过分析各种同工酶和被认为参与的细胞的活性来验证这些假定的途径。结果应该有助于推进我们对发热产生的核心机制的理解，并可能与传染病的管理有关。