PGE2 AND FEVER: INSIGHTS FROM TRANSGENIC MICE MODELS

我们对发热剂或热原作用于大脑体温调节区以提高体温的机制(S)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一种脂质家族的成员，在大脑中起着发烧媒介的作用。然而，外周热原向大脑发出信号以诱导PGE2形成的机制仍不清楚。目前也不清楚大脑中的哪些细胞合成这种PGE2。但它的产生需要环氧合酶(COX)的调节，环氧合酶(COX)以两种亚型存在，一种是组成环氧合酶-1，存在于大多数细胞中，另一种是缓慢诱导的环氧合酶-2，在某些细胞中，如吞噬细胞和内皮细胞，由炎症(如热源)刺激引起。因此，有人认为，脑中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)可能是循环热原的靶标，诱导COX-2，从而产生PGE2。然而，这一概念的一个困难是，静脉注射热原(例如内毒素)后开始发热的速度明显快于COX-2的合成。然而，神经元在脑细胞中的特殊之处在于它们表达结构性的COX-2。因此，根据我们小组以前的数据和文献中的其他数据，我们假设外周内毒素最初可能通过神经输入刺激发热调节区域的去甲肾上腺素(NE)释放，即下丘脑的视前前部。在那里，NE可以迅速激活另一种酶，一氧化氮合酶(NOS)，该酶也存在于神经元中，从而导致局部NO的形成，众所周知，这可以激活COX。反过来，NO可以激活COX-2，产生PGE2，并对静脉注射内毒素产生第一种典型的双相发热反应。我们进一步推测，第二次发热上升是由于类似的序列，然而，启动的不同的，同时合成的脑源性热原，白介素1β，激活屏障细胞中的诱导型一氧化氮合酶。这项研究旨在通过分析各种可能参与的同工酶和细胞的活性来验证这些假定的途径。这一结果将有助于我们加深对发热产生的中枢机制的理解，并可能与其在传染病中的管理有关。

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.