Prostaglandins.-猫眼课题宝

前列腺素。

DOI：

10.1152/ajpregu.00298.2003

发表时间：

2003

期刊：

American journal of physiology. Regulatory, integrative and comparative physiology

影响因子：

通讯作者：

中科院分区：

文献类型：

作者：

Holger C. Scholz

前列腺素属于一类脂质介质，称为类二十烷酸（来自希腊语eicosa，意思是二十;为20碳脂肪酸衍生物）。Bergström等人。（1）在他们的诺贝尔奖获奖作品中证明，野牡丹素是由必需脂肪酸花生四烯酸合成的。在通过磷脂酶A2（PLA 2）从细胞膜磷脂动员后，花生四烯酸被呈递给前列腺素H合酶，其也被称为考克斯。存在两种考克斯酶同工型（考克斯-1和考克斯-2），它们具有高度的序列同源性和相同的催化活性。最近发现了第三种酶（考克斯-3），代表考克斯-1的剪接变体（4）。尽管考克斯-1在大多数组织中组成型表达，但考克斯-2可由几种生理和促炎刺激物诱导，包括白细胞介素（IL）-I、肿瘤坏死因子（TNF）和表皮生长因子（EGF）。考克斯催化花生四烯酸转化为PGH 2，PGH 2是许多细胞特异性前列腺素和血栓烷脱氢酶的直接底物。PGH 2可以酶促转化为PGE 2、PGD 2、PGF 2和血栓烷A2（TXA 2），它们从细胞中释放并以自分泌或旁分泌方式起作用。本聚焦的目的是总结前列腺素和考克斯研究领域的一些最新进展，发表在美国生理学杂志-调节，整合和比较生理学。已充分确立了洋地黄素在对LPS的发热反应中的作用。分析大鼠在LPS致热过程中不同时期PGE 2合成酶的表达变化。研究结果显示，除了分泌型PLA 2-IIA的表达增强外，肝脏和肺部的微粒体PGE合酶也显着上调，使这些酶成为抗炎治疗的潜在靶点（10）。LPS诱导的发热在近期妊娠动物中减弱。两项独立的研究表明，近期发热的抑制与LPS对脑内皮细胞中考克斯-2的诱导减少有关，导致PGE 2减少（9，20）。正如在给编辑的一封信中所概述的，妊娠相关的解热作用也可能涉及PGE 2从大脑中流出，这是由于载体蛋白和15-羟基-前列腺素脱氢酶（主要的PGE 2失活酶）的上调（11）。值得注意的是，在某些条件下，如冬眠，没有观察到对细菌LPS的急性期反应。然而，通过脑室内注射PGE 2可以引起地松鼠从冬眠和发烧中觉醒（22）。由于介导发热反应的神经信号通路在冬眠期间明显起作用，因此有人提出周期性唤醒可能会激活休眠的免疫系统以对抗入侵的病原体（22）。肾脏是体内前列腺素形成和作用的主要部位。最近的研究结果表明，肾传入神经活动的调制肾盂压力的变化。增加的神经活动涉及通过激活cAMP-蛋白激酶A途径，PGE 2介导的P物质从肾机械感觉神经释放（17）。此外，在喂食高钠饮食的大鼠中，响应于PGE 2的P物质释放增强，局部应用ANG II减弱了这种作用（16）。这些观察结果提出了一种有趣的可能性，即PGE 2依赖性肾传入神经活动参与了对肾盂压力变化的钠和水稳态的调节。除了控制肾血管和肾小管功能外，胰高血糖素也是肾小球细胞分泌肾素的重要调节剂。与胰高血糖素在肾素调节中的作用一致，限盐导致大鼠肾脏肾小球体中的肾素和考克斯-2基因表达平行增加（13）。在低钠饮食条件下，血管紧张素转换酶（ACE）的抑制作用强烈增强了肾素、考克斯-2和神经元型一氧化氮合酶（nNOS）基因表达的上调（13）。总之，在盐限制期间这些基因的激活显然受到ANG II的直接负反馈效应的限制。由考克斯-1形成的前列腺素似乎对响应ACE抑制的肾素刺激不是关键的。最近发现，在野生型小鼠和考克斯-1基因同源破坏的小鼠中，用卡托普利抑制ACE可使血浆肾素活性和肾脏中的肾素mRNA增加相同程度，这一发现支持了这一点（5）。在同一项研究中，据报道，抑制考克斯-2活性可阻断ACE抑制引起的肾肾素浓度升高（5）。前列腺素也与食欲和食物摄入的控制有关。Lugarini及其同事（19）在他们的研究中证明，选择性抑制考克斯-2可减轻LPS诱导的大鼠厌食症，而阻断考克斯-1活性无效。促炎性细胞因子刺激体重减轻的机制是转载请求和其他信件的地址：H。Scholz，Johannes-Müller-Institut für Physiologie，Humboldt-Universität，Charité，Tucholskystrasse 2，10117柏林，德国（电子邮件：holger. charite.de）。Am J Physiol Regul Integr Comp Physiol 285：R512-R514，2003; 10.1152/ajpregu.00298.2003。

PROSTAGLANDINS BELONG to a class of lipid mediators known as eicosanoids (from the Greek eicosa, meaning twenty; for the 20 carbon fatty acid derivatives). Bergström et al. (1) demonstrated in their Nobel Prizewinning work that prostaglandins are synthesized from the essential fatty acid arachidonic acid. After mobilization from cell membrane phospholipids by phospholipase A2 (PLA2), arachidonic acid is presented to prostaglandin H synthase, which is also referred to as COX. Two isoforms of COX enzymes (COX-1 and COX-2) exist that share a high degree of sequence homology and identical catalytic activity. A third enzyme (COX-3) representing a splicing variant of COX-1 was discovered recently (4). Although COX-1 is constitutively expressed in most tissues, COX-2 can be induced by several physiological and proinflammatory stimuli, including interleukin (IL)-I, tumor necrosis factor (TNF), and epidermal growth factor (EGF). COX catalyzes the conversion of arachidonic acid to PGH2, which is the immediate substrate for a number of cell-specific prostaglandin and thromboxane synthases. PGH2 can be enzymatically converted to PGE2, PGD2, PGF2 , and thromboxane A2 (TXA2), which are released from the cells and act in an autocrine or paracrine fashion. The purpose of this In Focus is to summarize some of the recent advances in the field of prostaglandin and COX research published in the American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. A role for prostaglandins in the febrile response to LPS is well established. The expressional changes in PGE2-synthesizing enzymes during different phases of LPS-induced fever were analyzed in rats. The findings revealed a significant upregulation of microsomal PGE synthases in the liver and lungs in addition to enhanced expression of secretory PLA2-IIA, making these enzymes potential targets for anti-inflammatory therapy (10). LPS-induced fever is attenuated in pregnant animals at near term. It was shown in two independent studies that suppression of fever at near term is associated with reduced induction of COX-2 in brain endothelial cells by LPS, resulting in a decrease of PGE2 (9, 20). As outlined in a letter to the editor, pregnancyrelated antipyretic effects may also involve efflux of PGE2 from the brain due to upregulation of carrier proteins and 15-hydroxy-prostaglandin dehydrogenase, the major PGE2-inactivating enzyme (11). Remarkably, the acute-phase response to bacterial LPS is not observed under certain conditions such as hibernation. However, arousal from hibernation and fever could be provoked by intracerebroventricular injection of PGE2 in ground squirrels (22). As the neural signaling pathways that mediate febrile responses are obviously functional during hibernation, it was proposed that periodic arousals might activate a dormant immune system to combat invading pathogens (22). The kidney is a major site of prostaglandin formation and action in the body. Recent findings indicate that renal afferent nerve activity is modulated by changes in renal pelvic pressure. Increased neural activity involves a PGE2-mediated release of substance P from renal mechanosensory nerves through activation of a cAMP-protein kinase A pathway (17). Furthermore, substance P release in response to PGE2 was enhanced in rats fed a high-sodium diet and locally applied ANG II attenuated this effect (16). These observations raise the interesting possibility that PGE2-dependent renal afferent nerve activity is involved in the regulation of sodium and water homeostasis in response to changes in renal pelvic pressure. In addition to the control of renal vascular and tubular function, prostaglandins are also important regulators of renin secretion from the juxtaglomerular cells. Consistent with a role for prostaglandins in renin regulation, salt restriction led to parallel increases of renin and COX-2 gene expression in the juxtaglomerular apparatus of rat kidneys (13). Upregulation of renin, COX-2, and neuronal nitric oxide synthase (nNOS) gene expression at low sodium diet was strongly enhanced in response to inhibition of angiotensin converting enzyme (ACE) (13). In conclusion, activation of these genes during salt restriction is apparently limited by a direct negative feedback effect of ANG II. The formation of prostaglandin by COX-1 does not seem to be critical for renin stimulation in response to ACE inhibition. This is supported by the recent finding that ACE inhibition with captopril increased plasma renin activity and renin mRNA in the kidneys to the same extent in both wild-type mice and mice with homozygously disrupted COX-1 gene (5). In the same study, inhibition of COX-2 activity was reported to block the elevation in renal renin concentration in response to ACE inhibition (5). Prostaglandins have also been implicated in the control of appetite and food intake. Lugarini and coworkers (19) demonstrated in their study that LPS-induced anorexia in rats could be attenuated by selective inhibition of COX-2, whereas blockade of COX-1 activity was ineffective. The mechanism by which proinflammatory cytokines can stimulate loss of body weight are Address for reprint requests and other correspondence: H. Scholz, Johannes-Müller-Institut für Physiologie, Humboldt-Universität, Charité, Tucholskystrasse 2, 10117 Berlin, Germany (E-mail: holger.scholz@charite.de). Am J Physiol Regul Integr Comp Physiol 285: R512–R514, 2003; 10.1152/ajpregu.00298.2003.