Prostaglandins
2003; American Physiological Society; Volume: 285; Issue: 3 Linguagem: Inglês
10.1152/ajpregu.00298.2003
ISSN1522-1490
Autores Tópico(s)Estrogen and related hormone effects
ResumoIN FOCUSProstaglandinsHolger ScholzHolger ScholzJohannes-Müller-Institut für Physiologie, Medizinische Fakultät Charité, Humboldt-Universität Berlin, 10117 Berlin, GermanyPublished Online:01 Sep 2003https://doi.org/10.1152/ajpregu.00298.2003MoreSectionsPDF (46 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations 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)-α, 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, PGF2α, 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, pregnancy-related 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 beginning to emerge. For example, anti-inflammatory agents prevented TNF-α-induced leptin secretion from adipocytes both in vitro and in vivo (7). On the other hand, the release of prostaglandins and proinflammatory mediators appears to depend on nutritional behavior. Thus hypercholesterolemia is characterized by increased levels of circulating 8-epi-prostaglandin-F2α (isoprostane), a vasoconstrictor and mediator of enhanced oxidative stress (18). Furthermore, feeding of conjugated linoleic acid significantly lowered antigen-induced histamine and PGE2 release in a rat model of type I (immediate) hypersensitivity (25, 26). In addition to the control of food intake, eicosanoids may also participate in the regulation of thirst and water ingestion. Consistently, pharmacological inhibition of central TXA2-prostaglandin H2 receptors in the brain (reviewed in Ref. 27) decreased water intake in response to ANG II (15).Important novel insights were obtained from studies aimed at exploring the role of prostaglandins in the control of vascular tone. The effect of incremental hypoxia was analyzed in rat gracilis muscle resistance arteries. Although inhibition of NOS abolished vascular responses to mild hypoxia, blockade of COX impaired the vasodilator response to more severe hypoxia (8). These observations suggest that vascular reactivity to progressive hypoxia represents an integration of several vasoactive mediators. Hypoxic vasodilation caused by prostaglandins can also have negative effects in certain situations. For example, permanent closure of the newborn ductus arteriosus (DA) occurs only if hypoxia develops locally within the vessel wall during luminal obliteration (12). The excessive inhibitory effects of endogenous prostaglandins (and NO) together with a weaker intrinsic DA vascular tone reduce the tension of the preterm DA. As a consequence, anatomic remodeling of the DA can be delayed in preterm newborns (12). Alterations in the release of vasodilator substances including prostacyclin (PGI2) and other endothelial autacoids may also play a role in the pathophysiology of preeclampsia, which is characterized by a severe increase in vascular resistance and arterial blood pressure (14).Inhibitory effects appear to exist between prostaglandins and NO in their relative contribution to the control of cerebral circulation. Thus piglets that were chronically treated with indomethacin to inhibit prostaglandin synthesis showed enhanced NOS activity and augmented response of the cerebral vasculature to the vasodilator effect of NO (28). In vivo experiments with anesthetized rats demonstrated a vasodilator effect of arachidonic acid that was mediated by activation of calcium-dependent potassium channels and hyperpolarization of the membrane potential of smooth muscle cells in basilar arteries (6).Prostaglandins may act as downstream mediators of a variety of vasoactive substances in certain vascular beds. For example, adenosine-dependent dilation of microperfused outer medullary descending vasa recta from rat kidney could be reversed with indomethacin (24). In contrast, COX inhibition had no significant effect on the vasodilator action of adenosine in the hindquarter vascular bed of the cat (2). Surprisingly, neuropeptide Y, which normally increases vascular resistance in mammals, produced vasorelaxation in teleost fish by both a direct action on smooth muscle and the release of prostaglandins (23). Finally, there is some good news for smokers who need to receive anti-inflammatory therapy. As demonstrated by Black and collaborators (3) in isolated perfused human skin flaps, the amplification effect of nicotine on norepinephrine-induced vasoconstriction does not involve COX products. Similarly, COX inhibition with indomethacin did not affect the amplifying effect of endothelin-1 on TXA2-dependent skin vasoconstriction (21).In summary, the chapter on prostaglandins is far from closed, and exciting novel discoveries in this area of research are waiting to be made during the coming years. References 1 Bergström S, Danielsson H, and Samuelsson B. The enzymatic formation of prostaglandin E2 from arachidonic acid. Biochim Biophys Acta 90: 207-210, 1964.Crossref | PubMed | ISI | Google Scholar2 Bivalacqua TJ, Champion HC, Lambert DG, and Kadowitz PJ. Vasodilator responses to adenosine and hyperemia are mediated by A1 and A2 receptors in the cat vascular bed. Am J Physiol Regul Integr Comp Physiol 282: R1696-R1709, 2002.Link | ISI | Google Scholar3 Black CE, Huang N, Neligan PC, Levine RH, Lipa JE, Lintlop S, Forrest CR, and Pang CY. Effect of nicotine on vasoconstrictor and vasodilator responses in human skin vasculature. Am J Physiol Regul Integr Comp Physiol 281: R1097-R1104, 2001.Link | ISI | Google Scholar4 Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Tomsik J, Elton TS, and Simmons DL. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc Natl Acad Sci USA 99: 13926-13931, 2002.Crossref | PubMed | ISI | Google Scholar5 Cheng HF, Wang SW, Zhang MZ, McKanna JA, Breyer R, and Harris RC. Prostaglandins that increase renin production in response to ACE inhibition are not derived from cyclooxygenase-1. Am J Physiol Regul Integr Comp Physiol 283: R638-R646, 2002.Link | ISI | Google Scholar6 Faraci FM, Sobey CG, Chrissobolis S, Lund DD, Heistad DD, and Weintraub NL. Arachidonate dilates basilar artery by lipoxygenase-dependent mechanism and activation of K+ channels. Am J Physiol Regul Integr Comp Physiol 281: R246-R253, 2001.Link | ISI | Google Scholar7 Finck BN and Johnson RW. Anti-inflammatory agents inhibit the induction of leptin by tumor necrosis factor-α. Am J Physiol Regul Integr Comp Physiol 282: R1429-R1435, 2002.Link | ISI | Google Scholar8 Frisbee JC, Maier KG, Falck JR, Roman RJ, and Lombard JH. Integration of hypoxic dilation signaling pathways for skeletal muscle resistance arteries. Am J Physiol Regul Integr Comp Physiol 283: R309-R319, 2002.Link | ISI | Google Scholar9 Imai-Matsumura K, Matsumura K, Terao A, and Watanabe Y. Attenuated fever in pregnant rats is associated with blunted synthesis of brain cyclooxygenase-2 and PGE2. Am J Physiol Regul Integr Comp Physiol 283: R1346-R1353, 2002.Link | ISI | Google Scholar10 Ivanov AI, Pero RS, Scheck AC, and Romanovsky AA. Prostaglandin E2-synthesizing enzymes in fever: differential transcriptional regulation. Am J Physiol Regul Integr Comp Physiol 283: R1104-R1117, 2002.Link | ISI | Google Scholar11 Ivanov AI and Romanovsky AA. Near-term suppression of fever: inhibited synthesis or accelerated catabolism of prostaglandin E2? Am J Physiol Regul Integr Comp Physiol 284: R860-R865, 2003.Link | ISI | Google Scholar12 Kajino H, Chen YQ, Seidner SR, Waleh N, Mauray F, Roman C, Chemtob S, Koch CJ, and Clyman RI. Factors that increase the contractile tone of the ductus arteriosus also regulate its anatomic remodeling. Am J Physiol Regul Integr Comp Physiol 281: R291-R301, 2001.Link | ISI | Google Scholar13 Kammerl MC, Richthammer W, Kurtz A, and Kramer BK. Angiotensin II feedback is a regulator of renocortical renin, COX-2, and nNOS expression. Am J Physiol Regul Integr Comp Physiol 282: R1613-R1617, 2002.Link | ISI | Google Scholar14 Khalil RA and Granger JP. Vascular mechanisms of increased arterial pressure in preeclampsia: lessons from animal models. Am J Physiol Regul Integr Comp Physiol 283: R29-R45, 2002.Link | ISI | Google Scholar15 Kitiyakara C, Welch WJ, Verbalis JG, and Wilcox CS. Role of thromboxane receptors in the dipsogenic response to central angiotensin II. Am J Physiol Regul Integr Comp Physiol 282: R865-R869, 2002.Link | ISI | Google Scholar16 Kopp UC, Cicha MZ, and Smith LA. Endogenous angiotensin modulates PGE2-mediated release of substance P from renal mechanosensory nerve fibers. Am J Physiol Regul Integr Comp Physiol 282: R19-R30, 2002.Link | ISI | Google Scholar17 Kopp UC, Cicha MZ, and Smith LA. PGE2 increases release of substance P from renal sensory nerves by activating the cAMP-PKA transduction cascade. Am J Physiol Regul Integr Comp Physiol 282: R1618-R1627, 2002.Link | ISI | Google Scholar18 Krier JD, Rodriguez-Porcel M, Best PJ, Romero JC, Lerman A, and Lerman LO. Vascular responses in vivo to 8-epi-PGF2α in normal and hypercholesterolemic pigs. Am J Physiol Regul Integr Comp Physiol 283: R303-R308, 2002.Link | ISI | Google Scholar19 Lugarini F, Hrupka BJ, Schwartz GJ, Plata-Salaman CR, and Langhans W. A role for cyclooxygenase-2 in lipopolysaccharide-induced anorexia in rats. Am J Physiol Regul Integr Comp Physiol 283: R862-R868, 2002.Link | ISI | Google Scholar20 Mouihate A, Clerget-Froidevaux MS, Nakamura K, Negishi M, Wallace JL, and Pittman QJ. Suppression of fever at near term is associated with reduced COX-2 protein expression in rat hypothalamus. Am J Physiol Regul Integr Comp Physiol 283: R800-R805, 2002.Link | ISI | Google Scholar21 Pang CY, Xu H, Huang N, Forrest CR, Perreault TM, and Neligan PC. Amplification effect and mechanism of action of ET-1 in U-46619-induced vasoconstriction in pig skin. Am J Physiol Regul Integr Comp Physiol 280: R713-R720, 2001.Link | ISI | Google Scholar22 Prendergast BJ, Freeman DA, Zucker I, and Nelson RJ. Periodic arousal from hibernation is necessary for initiation of immune responses in ground squirrels. Am J Physiol Regul Integr Comp Physiol 282: R1054-R1062, 2002.Link | ISI | Google Scholar23 Shahbazi F, Holmgren S, Larhammar D, and Jensen J. Neuropeptide Y effects on vasorelaxation and intestinal contraction in the Atlantic cod Gadus morhua. Am J Physiol Regul Integr Comp Physiol 282: R1414-R1421, 2002.Link | ISI | Google Scholar24 Silldorff EP and Pallone TL. Adenosine signaling in outer medullary descending vasa recta. Am J Physiol Regul Integr Comp Physiol 280: R854-R861, 2001.Link | ISI | Google Scholar25 Whigham LD, Cook EB, Stahl JL, Saban R, Bjorling DE, Pariza MW, and Cook ME. CLA reduces antigen-induced histamine and PGE2 release from sensitized guinea pig tracheae. Am J Physiol Regul Integr Comp Physiol 280: R908-R912, 2001.Link | ISI | Google Scholar26 Whigham LD, Higbee A, Bjorling DE, Park Y, Pariza MW, and Cook ME. Decreased antigen-induced eicosanoid release in conjugated linolenic acid-fed guinea pigs. Am J Physiol Regul Integr Comp Physiol 282: R1104-R1112, 2002.Link | ISI | Google Scholar27 Wright DH, Abran D, Bhattacharya M, Hou X, Bernier SG, Bouayad A, Fouron JC, Vazquez-Tello A, Beauchamp MH, Clyman RI, Peri K, Varma DR, and Chemtob S. Prostanoid receptors: ontogeny and implications in vascular physiology. Am J Physiol Regul Integr Comp Physiol 281: R1343-R1360, 2001.Link | ISI | Google Scholar28 Zhang Y and Leffler CW. Compensatory role of NO in cerebral circulation of piglets chronically treated with indomethacin. Am J Physiol Regul Integr Comp Physiol 282: R400-R410, 2002.Link | ISI | Google ScholarAUTHOR NOTES Address for reprint requests and other correspondence: H. Scholz, Johannes-Müller-Institut für Physiologie, Humboldt-Universität, Charité, Tucholskystrasse 2, 10117 Berlin, Germany (E-mail: [email protected]). Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Cited ByProstacyclin (PGI2) scaffolds in medicinal chemistry: current and emerging drugs30 May 2022 | Medicinal Chemistry Research, Vol. 31, No. 8Fluid flow shear stress upregulates prostanoid receptor EP2 but not EP4 in murine podocytesProstaglandins & Other Lipid Mediators, Vol. 104-105EP2 receptor mediates PGE2-induced cystogenesis of human renal epithelial cellsGerard Elberg, Dorit Elberg, Teresa V. Lewis, Suresh Guruswamy, Lijuan Chen, Charlotte J. Logan, Michael D. Chan, and Martin A. Turman1 November 2007 | American Journal of Physiology-Renal Physiology, Vol. 293, No. 5Exercise can be pyrogenic in humansCarl D. Bradford, James D. Cotter, Megan S. Thorburn, Robert J. Walker, and David F. Gerrard1 January 2007 | American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Vol. 292, No. 1Nutritional Management of Cachexia of Chronic Illness4 December 2009 More from this issue > Volume 285Issue 3September 2003Pages R512-R514 Copyright & PermissionsCopyright © 2003 the American Physiological Societyhttps://doi.org/10.1152/ajpregu.00298.2003PubMed12909575History Published online 1 September 2003 Published in print 1 September 2003 Metrics
Referência(s)