Prostaglandins.

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.