PGE2 AND FEVER: INSIGHTS FROM TRANSGENIC MICE MODELS

我们对发热剂或致热原作用于大脑体温调节区域以升高体温的机制的认识仍然不完全。 先前的研究表明，前列腺素E2（PGE 2）是大多数器官中存在的脂质家族的成员，在大脑中起发热介质的作用。 然而，外周热原向大脑发出信号以诱导PGE 2形成的机制仍然未知。 目前还不清楚大脑中的哪些细胞合成这种PGE 2。 但是已经确定，其产生需要酶，环氧合酶（考克斯）的介导，其以两种同种型存在，一种是组成型，考克斯-1，存在于大多数细胞中，另一种是缓慢诱导型，考克斯-2，在某些细胞中引起，例如，吞噬细胞和内皮细胞，通过炎症（例如，致热）刺激。 因此，已经提出，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点，诱导考克斯-2并因此产生PGE 2。 然而，这一概念的困难在于，发热是在静脉内（iv）注射热原（例如，内毒素）显著快于考克斯-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考克斯-2。 基于我们小组以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，神经输入刺激发热调节区域中去甲肾上腺素（NE）的释放，即，视前区下丘脑前部 在那里，NE可以快速激活另一种酶，一氧化氮合酶（NOS），其也组成性地存在于神经元中，从而引起NO的局部形成，已知NO可以激活考克斯。 NO反过来又能激活考克斯-2，产生PGE 2和对静脉内毒素的第一个特征性双相发热反应。 我们进一步推测，第二次发热是由于类似的序列，然而，由不同的，同时合成的脑源性热原，白细胞介素-1 β，激活屏障细胞中的诱导型NOS。 本研究旨在通过分析各种同工酶和假定参与的细胞的活性来验证这些假定的途径。 这些结果将有助于我们进一步了解发热产生的中心机制，并可能与感染性疾病的管理有关。

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.