15-keto-13-14-dihydroprostaglandin-f2alpha and Shock--Septic

Prostaglandin F2alpha (PGF2alpha), a foremost stable vasoactive cyclooxygenase (COX)-catalyzed prostaglandin, regulates a number of key physiological functions such as luteolysis, ovarian function, luteal maintenance of pregnancy, and parturition as a constitutive part of ongoing reproductive processes of the body. It has recently been implicated in the regulation of intricate pathophysiological processes, such as acute and chronic inflammation, cardiovascular and rheumatic diseases. Since the discovery of a second isoform of COXs, it has been shown that PGF2alpha can be formed in vivo from arachidonic acid through both isoforms of COXs, namely cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Being synthesized in various parts of the body, it metabolizes instantly to a number of rather inactive metabolites mainly in the lungs, liver, kidney, and efficiently excretes into the urine. 15-Keto-dihydro-PGF2alpha, a major stable metabolite of PGF2alpha that reflects in vivo PGF2alpha biosynthesis, is found in larger quantities than its parent compound in the circulation and urine in basal physiological conditions, with short-lived pulses during luteolysis, induced termination of pregnancy and parturition, and is increased in tissues and various body fluids during acute, sub-chronic, and severe chronic inflammation. Further, the close relationship of PGF2alpha with a number of risk factors for atherosclerosis indicates its major role in inflammation pathology. This review addresses multiple aspects of PGF2alpha in addition to its emerging role in physiology to inflammation.

Topics: Animals; Atherosclerosis; Body Fluids; Carbon Tetrachloride Poisoning; Carotid Arteries; Cyclooxygenase 1; Cyclooxygenase 2; Diabetes Complications; Dinoprost; Female; Humans; Inflammation; Linoleic Acids, Conjugated; Luteolysis; Myocardial Reperfusion Injury; Obesity; Pregnancy; Risk Factors; Shock, Septic; Smoking

The aim of this study was to determine the effects of enrofloxacin (ENR), flunixin meglumine (FM) and dexamethasone (DEX) on antioxidant status and organ damage markers in experimentally-induced endotoxemia. Rats were divided into three groups. To induce endotoxemia, lipopolysaccharide (LPS) was injected into all groups, including the positive control. The two other groups received the following drugs (simultaneously with LPS): ENR + FM + low-dose DEX and ENR + FM + high-dose DEX. After the treatments, blood samples were collected at 0, 1, 2, 4, 6, 8, 12, 24 and 48 h. Oxidative stress parameters were determined by ELISA, while serum organ damage markers were measured by autoanalyser. LSP increased (p < 0.05) malondialdehyde, 13,14-dihydro-15-keto-prostaglandin F(2 alpha) and nitric oxide, while LPS reduced vitamin C. These changes were especially inhibited (p < 0.05) by ENR + FM + high-dose DEX. LPS increased organ damages markers. Cardiac and hepatic damage was not completely inhibited by any treatment, whereas renal damage was inhibited by two treatments. This study suggested that ENR + FM + high-dose DEX is most effective in the LPS-caused oxidative stress and organ damages.

Topics: Animals; Ascorbic Acid; Autoanalysis; Biomarkers; Clonixin; Dexamethasone; Dinoprost; Disease Models, Animal; Drug Therapy, Combination; Enrofloxacin; Enzyme-Linked Immunosorbent Assay; Female; Fluoroquinolones; Heart Diseases; Kidney Diseases; Lipopolysaccharides; Liver Diseases; Male; Malondialdehyde; Multiple Organ Failure; Nitric Oxide; Oxidative Stress; Rats; Rats, Sprague-Dawley; Shock, Septic; Superoxide Dismutase; Time Factors

Prostaglandins are profoundly involved in endotoxaemic shock. Twenty pigs were given endotoxin at various doses (0.063-16 microg kg(-1) h(-1)). Three non-endotoxaemic pigs served as controls. Two eicosanoids were measured in plasma (8-iso-PGF(2alpha), a free radical-mediated lipid peroxidation product, and 15-keto-dihydro-PGF(2alpha) a major metabolite of COX activity) and evaluated against the pathophysiological responses that occur during endotoxaemic shock. Endotoxin mediates an increase in both 8-iso-PGF(2alpha) and 15-keto-dihydro-PGF(2alpha). An increase in the endotoxin dose induced significant log-linear responses in 8-iso-PGF(2alpha) and 15-keto-dihydro-PGF(2alpha). Oxidative injury correlated to the TNF-alpha, IL-6, reductions in cardiac performance and to oxygen delivery and utilisation. COX-mediated inflammatory responses correlated to TNF-alpha, IL-6 and to reductions in arterial oxygen tension. Thus, oxidative injury and COX-mediated inflammation play a central role in the manifestation of endotoxaemic shock. Furthermore, formation of these eicosanoids on endotoxin-mediated alterations in pulmonary hypertension, oxygen delivery and oxygen utilisation seems to be independent of the administered endotoxin dose.

Topics: Animals; Dinoprost; Heart; Inflammation; Oxidative Stress; Shock, Septic; Sus scrofa; Swine

Lipid peroxidation and antioxidant balance in the body is a crucial factor in the pathophysiology of various diseases. This study investigates the circulatory alpha-tocopherol levels and its relationship with 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha), a non-enzymatic and, 15-keto-13,14-dihydro-PGF2alpha (15-K-DH-PGF2alpha), a cyclooxygenase catalysed oxidation product of arachidonic acid in experimental septic shock in pigs. A steady decrease in alpha-tocopherol levels in plasma was observed in both survivor and non-survivor animals. A simultaneous increase of oxidative injury indicator, plasma 8-iso-PGF2alpha was seen in both groups but with a different fashion. 8-Iso-PGF2alpha levels increased steadily in the animals that died during the experiment. An early and rapid increase of plasma 15-K-DH-PGF2alpha, an inflammatory response indicator, was also observed in all animals. There was a significant difference in the kinetics of decrement of alpha-tocopherol levels and a concomitant increase in 15-K-DH-PGF2alpha levels among the non-survivors. Thus, a successive disappearance of circulatory vitamin E in conjunction with the surge of plasma isoprostanes and prostaglandins impairs the oxidant-antioxidant balance in favour of the former and may possibly have an effect on the survivality during experimental porcine septicaemia.

Topics: Animals; Arachidonic Acid; Dinoprost; Endotoxemia; F2-Isoprostanes; Female; Lipid Peroxidation; Male; Oxidative Stress; Prostaglandin-Endoperoxide Synthases; Shock, Septic; Swine; Vasoconstrictor Agents; Vitamin E

This study investigates the plasma levels of 8-iso-PGF2alpha, a non-enzymatic, and 15-K-DH-PGF2alpha, a cyclooxygenase catalyzed oxidation product of arachidonic acid in an experimental porcine endotoxemic shock model. A significant (P < 0.001) and rapid appearance and disappearance of PGF2alpha metabolite after endotoxin infusion was very similar in both non-survival and survival groups indicating an acute progression and recession of inflammation. When oxidative injury was assessed by measuring free 8-iso-PGF2alpha the levels in plasma increased significantly up to 2 h and remained at this level until death among the non-survivors. This was apparently different from the survivors where the 8-iso-PGF2alpha levels increased to its height at 1 h, then decreased to the basal levels after 5 h. Thus, free radical and cyclooxygenase catalyzed oxidation of arachidonic acid occurs during endotoxemia. Free radical dependent oxidative injury following endotoxin induced inflammation may be the major cause of organ failure and increased mortality.

Topics: Animals; Arachidonic Acid; Biomarkers; Dinoprost; Endotoxemia; Escherichia coli Infections; F2-Isoprostanes; Female; Inflammation; Male; Oxidative Stress; Radioimmunoassay; Shock, Septic; Survival Analysis; Swine; Time Factors

Nine surgical patients underwent haemodynamic and respiratory monitoring during the course of severe sepsis. Endogenous PGF2 alpha levels in mixed venous and arterial plasma were measured. Results indicate pulmonary net release of PGF2 alpha, since arterial levels (1252 +/- 119 pg/ml) are significantly higher than mixed venous ones (824 +/- 89 pg/ml) in full-pronounced hyperdynamic septic shock. By contrast, the inactive metabolite KH2PGF2 alpha was found in lowest concentrations during shock (368 +/- 72 pg/ml) which suggests impaired pulmonary degradation. It is concluded that circulating PGF2 alpha is a marker of stimulated prostaglandin production in severe human sepsis.

Topics: Adolescent; Adult; Dinoprost; Female; Hemodynamics; Humans; Male; Middle Aged; Platelet Count; Prostaglandins F; Respiratory Function Tests; Shock, Septic