| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
IN FOCUS
Johannes-Müller-Institut für Physiologie, Medizinische Fakultät Charité, Humboldt-Universität Berlin, 10117 Berlin, Germany
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, 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--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-F2
(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.
FOOTNOTES
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{at}charite.de).
REFERENCES
. Am J Physiol Regul Integr Comp
Physiol 282:
R1429-R1435, 2002. in normal and
hypercholesterolemic pigs. Am J Physiol Regul Integr Comp
Physiol 283:
R303-R308, 2002.This article has been cited by other articles:
|
|
 |
|
  G. Elberg, D. Elberg, T. V. Lewis, S. Guruswamy, L. Chen, C. J. Logan, M. D. Chan, and M. A. Turman EP2 receptor mediates PGE2-induced cystogenesis of human renal epithelial cells Am J Physiol Renal Physiol, November 1, 2007; 293(5): F1622 - F1632. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. D. Bradford, J. D. Cotter, M. S. Thorburn, R. J. Walker, and D. F. Gerrard Exercise can be pyrogenic in humans Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2007; 292(1): R143 - R149. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
