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Obesity is often associated with dyslipidemia, insulin resistance, and hypertension. Together, these metabolic perturbations greatly increase the risk of developing cardiovascular disease and diabetes. Although fish oil is a well-established hypolipidemic agent, the mechanisms by which it mediates its lipid-lowering effects are not clear. In addition, it has not been established whether dietary fish oil has different effects in lean and obese mice. LDL receptor deficient (LDLR-/-) and leptin deficient mice on a LDLR-/- background (ob/ob; LDLR-/-) were fed a high fat diet (39% total fat) supplemented with 6% olive oil or fish oil for 6 wk. Fish oil supplementation resulted in lower concentrations of plasma total cholesterol (P < 0.01), triglycerides (P< 0.01), and free fatty acids (P< 0.001) in lean LDLR-/- mice, but not in ob/ob; LDLR-/- mice. In contrast, a fish oil diet did not modulate insulin sensitivity in lean LDLR-/- mice, but it improved insulin sensitivity in ob/ob; LDLR-/- mice (P < 0.05) compared with olive oil fed ob/ob; LDLR-/- mice. Interestingly, plasma adiponectin concentrations were significantly higher and hepatic steatosis was reduced in both mouse models upon fish oil feeding. Finally, fish oil fed LDLR-/- mice exhibited higher hepatic AMP activated protein kinase (AMPK) phosphorylation (P < 0.05), whereas AMPK phosphorylation was not elevated by fish oil feeding in ob/ob; LDLR-/- mice. Taken together, our data suggest that fish oil reduces hepatic steatosis in both lean and obese mice, has potent plasma lipid lowering effects in lean mice, and exerts insulin sensitizing effects in obese mice. J. Nutr. 139: 2380-2386, 2009. Manuscript received June 12, 2009. Initial review completed July 17, 2009. Revision accepted October 15, 2009. First published online October 28, 2009; doi: 10.3945/jn.109.111567.

Cytosolic phospholipase [A.sub.2[alpha]] ([cPLA.sub.2[alpha]]) hydrolyzes arachidonic acid from cellular membrane phospholipids, thereby providing enzymatic substrates for the synthesis of eicosanoids, such as prostaglandins and leukotrienes. Considerable understanding of [cPLA.sub.2[alpha]] function has been derived from investigations of the enzyme and from [cPLA.sub.2[alpha]]-null mice, but knowledge of discrete roles for this enzyme in humans is limited. We investigated a patient hypothesized to have an inherited prostanoid biosynthesis deficiency due to his multiple, complicated small intestinal ulcers despite no use of cyclooxygenase inhibitors. Levels of thromboxane [B.sub.2] and 12-hydroxyeicosatetraenoic acid produced by platelets and leukotriene [B.sub.4] released from calcium ionophore--activated blood were markedly reduced, indicating defective enzymatic release of the arachidonic acid substrate for the corresponding cyclooxygenase and lipoxygenases. Platelet aggregation and degranulation induced by adenosine diphosphate or collagen were diminished but were normal in response to arachidonic acid. Two heterozygous single base pair mutations and a known SNP were found in the coding regions of the patient&apos;s [cPLA.sub.2[alpha]] genes (p.[Ser111Pro]+[Arg485His; Lys651Arg]). The total [PLA.sub.2] activity in sonicated platelets was diminished, and the urinary metabolites of prostacyclin, prostaglandin [E.sub.2], prostaglandin [D.sub.2], and thromboxane [A.sub.2] were also reduced. These findings characterize what we believe is a novel inherited deficiency of [cPLA.sub.2]., Introduction These investigations addressed the problem of a patient with multiple small intestinal ulcers that were not associated with use of NSAIDs. The patient had chronic gastrointestinal blood loss from [...]

Although fish oil has hypolipidemic and antiatherosclerotic properties, the potential for white adipose tissue (WAT) to mediate these effects has not been studied. LDL-receptor deficient (LDLR-/-) mice were fed high fat, olive oil-containing diets supplemented with additional olive oil or with fish oil for 12 wk. Fish oil feeding significantly reduced plasma lipid levels. In contrast, lipid storage in WAT was increased in fish oil-fed mice as evidenced by increased total fat (P < 0.05) and perigonadal WAT mass (P < 0.05), increased cholesterol storage (P < 0.001), and adipocyte hypertrophy. Despite increased adipose tissue mass, WAT-specific inflammation and insulin sensitivity were improved (P < 0.05), concomitant with reduced macrophage infiltration. Furthermore, fish oil increased WAT and plasma levels of adiponectin. In addition, fish oil feeding decreased the formation of proinflammatory F2- isoprostanes, markers of oxidative stress (P < 0.05). The increased WAT lipid storage in fish oil-fed mice was associated with reduced lipid accumulation in liver (P < 0.05) and decreased atherosclerotic lesion area (P < 0.05). Taken together, these data highlight the specific role of WAT in regulating dietary fish oil-mediated improvement in systemic lipid homeostasis and atherosclerosis.

The effect of lipid composition on the distribution of free radical oxidation products derived from arachidonic acid (20:4) esters is studied in vitro and in vivo. The results have described that dietary [omega]-3 polyunsaturated fatty acids (PUFAs) might influence the formation of bioactive peroxidation products derived from [omega]-6 PUFAs by channeling the free radical pathway away from the pro-inflammatory prostaglandin (PG) [F.sub.2]-like compounds, termed as [F.sub.2]-isoprostanes ([F.sub.2]IsoPs).

Tight regulation of COX-2 expression is a key feature controlling eicosanoid production in atherosclerosis and other inflammatory syndromes. Adhesive interactions between platelets and monocytes occur in these conditions and deliver [...]

The relationships between oxidant stress and nucleoside reverse transcriptase inhibitor (NRTI)-induced peripheral neuropathy were explored by quantifying plasma [F.sub.2]-Isoprostanes among AIDs Clinical Trials Group (ACTG) 384 participants. The findings suggest that symptomatic NRTI-associated peripheral neuropathy was not associated with increased plasma [F.sub.2]-Isoprostanes among ACTG 384 participants.

Electrophilic lipids, such as 4-hydroxynonenal (HNE), and the cyclopentenones 15-deoxy-[[DELTA].sup.12,14]-prostaglandin [J.sub.2] (15d-[PGJ.sub.2]) and 15-[J.sub.2]-isoprostane induce both reactive oxygen species (ROS) formation and cellular antioxidant defenses, such as heme oxygenase-1 (HO-1) and glutathione (GSH). When we compared the ability of these distinct electrophiles to stimulate GSH and HO-1 production, the cyclopentenone electrophiles were somewhat more potent than HNE. Over the concentration range required to observe equivalent induction of GSH, dichlorofluorescein fluorescence was used to determine both the location and amounts of electrophilic lipid-dependent ROS formation in endothelial cells. The origin of the ROS on exposure to these compounds was largely mitochondrial. To investigate the possibility that the increased ROS formation was due to mitochondrial localization of the lipids, we prepared a novel fluorescently labeled form of the electrophilic lipid 15d-[PGJ.sub.2]. The lipid demonstrated strong colocalization with the mitochondria, an effect which was not observed by using a fluorescently labeled nonelectrophilic lipid. The role of mitochondria was confirmed by using cells deficient in functional mitochondria. On the basis of these data, we propose that ROS formation in endothelial cells is due to the direct interaction of these lipids with the organelle. 15-deoxy-[[DELTA].sup.12,14]-prostaglandin [J.sub.2]; isoprostane; cyclopentenone; 4-hydroxynonenal; atherosclerosis; rho0

Numerous studies demonstrate links between chronic stress and indices of poor health, including risk factors for cardiovascular disease and poorer immune function. Nevertheless, the exact mechanisms of how stress gets 'under the skin' remain elusive. We investigated the hypothesis that stress impacts health by modulating the rate of cellular aging. Here we provide evidence that psychological stress--both perceived stress and chronicity of stress--is significantly associated with higher oxidative stress, lower telomerase activity, and shorter telomere length, which are known determinants of cell senescence and longevity, in peripheral blood mononuclear cells from healthy premenopausal women. Women with the highest levels of perceived stress have telomeres shorter on average by the equivalent of at least one decade of additional aging compared to low stress women. These findings have implications for understanding how, at the cellular level, stress may promote earlier onset of age-related diseases. psychological stress | telomere length | telomerase | oxidative stress

Glyceryl prostaglandins (PG-Gs) are generated by the oxygenation of the endocannabinoid, 2-arachidonylglycerol, by cyclooxygenase 2. The biological consequences of this selective oxygenation are uncertain because the cellular activities of PG-Gs have yet to be defined. We report that the glyceryl ester of [PGE.sub.2], PG[E.sub.2]-G, triggers rapid, concentration-dependent [Ca.sup.2+] accumulation in a murine macrophage-like cell line, RAW264.7. [Ca.sup.2+] mobilization is not observed after addition of [PGE.sub.2], [PGD.sub.2]-G, or [PGF.sub.2[alpha]]-G but is observed after addition of [PGF.sub.2[alpha]]. Moreover, PG[E.sub.2]-G, but not [PGE.sub.2], stimulates a rapid but transient increase in the levels of inositol 1,4,5-trisphosphate ([IP.sub.3]) as well as the membrane association and activation of PKC. [PGE.sub.2]-G induces a concentration-dependent increase in the levels of phospborylated extracellular signal regulated kinases 1 and 2 through a pathway that requires the activities of PKC, [IP.sub.3] receptor, and phospholipase C [beta]. The results indicate that [PGE.sub.2]-G triggers [Ca.sup.2+] mobilization, [IP.sub.3] synthesis, and activation of PKC in RAW264.7 macrophage cells at low concentrations. These responses are independent of the hydrolysis of [PGE.sub.2]-G to [PGE.sub.2].

Ionspray mass spectrometry and gas chromatography-mass spectrometry methods enable detection of the bicyclic endoperoxides formed during the oxidation of cholesterol arachidonate. Results show that arachidonate in the low-density lipoprotein is estrified to phospholipids and cholesterol esters, the latter leading to the formation of bicyclic endoperoxides.

Researchers have discovered D(sub 4)/E(sub 4)-neuroprostanes in brain tissue. These D/E-ring isoprostane-like compounds are formed by the oxidation of docosahexaenoic acid, the most abundant unsaturated fatty acid in the brain. This indicates that oxidative stress occurs in the brain, and may cause some neurological diseases.

Ataxia-telangiectasia (A-T) is characterized by a markedly increased sensitivity to ionizing radiation, increased incidence of cancer, and neurodegeneration, especially of the cerebellar Purkinje cells. Ionizing radiation oxidizes macromolecules and causes tissue damage through the generation of reactive oxygen species (ROS). We therefore hypothesized that A-T is due to oxidative damage resulting from loss of function of the A-T gene product. To assess this hypothesis, we employed an animal model of A-T, the mouse with a disrupted Atm gene. We show that organs which develop pathologic changes in the Atm-deficient mice are targets of oxidative damage, and that cerebellar Purkinje cells are particularly affected. These observations provide a mechanistic basis for the A-T phenotype and lay a rational foundation for therapeutic intervention.

Cyclo-oxygenase-2(COX2)-derived prostacyclin (PGI(sub.2)) is helpful to embryo implantation in the mouse through PPARdelta. PGI(sub.2) is the main prostaglandin (PG) essential for implantation and decidualization. It appears from various lines of evidence, that effects of PGI(sub.2) are mediated by activation of the nuclear hormone receptor PPARdelta. This is the first reported biologic function of that receptor signaling route. It has been shown that COX2, rate-limiting enzyme in the biosynthesis of PGs, is required for decidualization and for blastocyst implantation. Mechanism and candidate PGs for participation have not been known.

Bradykinin appears to be involved in the action of ACE inhibitors, which are used to lower blood pressure in people with hypertension. Bradykinin is a naturally occurring chemical in the body that dilates blood vessels. Researchers measured blood pressure in 20 healthy people and seven people with hypertension after they took an ACE inhibitor. The measurement was repeated after they took a drug that blocks bradykinin in addition to the ACE inhibitor. The drop in blood pressure was less when the volunteers took the bradykinin inhibitor and the ACE inhibitor.

Halothane-anesthetized one-to-three-day-old piglets were studied to examine the influence of 8-isoprostaglandin F2-alpha (8-iso-PGF2-alpha) on the retinal vessels of the piglets. The retinal vasoconstriction caused by the 8-iso-PGF2-alpha was found to be mediated by the endothelin following the introduction of Ca2+ into the cells and the cyclooxygenase-produced formation of thromboxane. Retinal vasoconstriction to 8-isoprostanes may thus contribute in the production of ischemic retinopathies.

Nonsteroidal antiinflammatory drugs reduce the risk of colon cancer, possibly via cyclooxygenase (COX) inhibition. The growth factor-inducible COX-2, which is overexpressed in neoplastic colonic tissue, is an attractive target to mediate this effect. Herein we have exploited the ability of a human colon cancer cell line, HCA-7 Colony 29, to polarize when cultured on Transwell (Costar) filters to study COX-2 production and the vectorial release of prostaglandins (PGs). Administration of type [Alpha] transforming growth factor to the basolateral compartment, in which the epidermal growth factor receptor (EGFR) resides, results in a marked induction of COX-2 immunoreactivity at the base of the cells and the unexpected appearance of COX-2 in the nucleus. The increase in COX-2 protein is associated with a dose- and time-dependent increase in PG levels in the basolateral, but not apical, medium. Amphiregulin is the most abundantly expressed EGFR ligand in these cells, and the protein is present at the basolateral surface. EGFR blockade reduces baseline COX-2 immunoreactivity, PG levels, and mitogenesis in a concentration-dependent manner. Two specific COX-2 inhibitors, SC-58125 and NS 398, also, in a dose-dependent manner, attenuate baseline and type [Alpha] transforming growth factor-stimulated mitogenesis, although PG levels are decreased >90% at all concentrations of inhibitor tested. These findings show that activation of the EGFR stimulates COX-2 production and its translocation to the nucleus, vectorial release of PGs, and mitogenesis in polarized HCA-7 Colony 29 cells.

Peroxynitrite activates the cyclooxygenase activities of constitutive and inducible prostaglandin endoperoxide synthases by serving as a substrate for the enzymes' peroxidase activities. Activation of purified enzyme is induced by direct addition of peroxynitrite or by in situ generation of peroxynitrite from NO coupling to superoxide anion. Cu,Zn-superoxide dismutase completely inhibits cyclooxygenase activation in systems where peroxynitrite is generated in situ from superoxide. In the murine macrophage cell line RAW264.7, the lipophilic superoxide dismutase-mimetic agents, Cu(II) [(3,5-diisopropylsalicylic acid).sub.2], and Mn(III) tetrakis(1-methyl-4-pyridyl)porphyrin dose-dependently decrease the synthesis of prostaglandins without affecting the levels of NO synthase or prostaglandin endoperoxide synthase or by inhibiting the release of arachidonic acid. These findings support the hypothesis that peroxynitrite is an important modulator of cyclooxygenase activity in inflammatory cells and establish that superoxide anion serves as a biochemical link between NO and prostaglandin biosynthesis.

Cigarette smoking appears to oxidize fats, which could ultimately lead to atherosclerosis. Researchers took blood and urine samples from 10 smokers before and after they smoked three cigarettes in a 30-minute period. They also took blood and urine samples from 10 nonsmokers. All samples were tested for a group of chemicals called F2-isoprostanes, which are formed in the body when fats are oxidized. Seven of the smokers had higher blood levels of F2-isoprostanes than nonsmokers, even before they smoked the three cigarettes. They also had higher levels of F2-isoprostane metabolites in their urine, and lower levels of vitamin C in their blood. When eight of the smokers stopped smoking for two weeks, their blood levels of F2-isoprostane dropped significantly. Some of the smokers had blood levels of F2-isoprostanes that were not significantly higher than in nonsmokers, indicating that some people may be naturally resistant to the effects of smoking.

Physiological levels of glutathione (GSH) influence the metabolism of arachidonic acid (AA) by the constitutive (Cox-1) and the mitogen inducible (CoX-2) isoforms of prostaglandin H2 synthase to generate 12-hydroxyheptadecatrienoic acid (12-HHT) as the major product. GSH and cytosolic GSH peroxidase inhibits the oxidation of AA by CoX-1, but exerts no influence on the catalytic activity of COX-2. Cleavage of 8,9 and 11,12-carbon-carbon bonds of the enzyme accounts for the formation of 12(S)-HHT.

Data on the effect of vitamin E and selenium deficiency on lipid peroxidation in vivo have been limited. F2-isoprostanes are novel prostanoids that, free in plasma and esterified to phospholipids in tissues, are markers of lipid peroxidation in vivo. To address the importance of vitamin E and selenium in defense against lipid peroxidation in vivo, we determined F2-isoprostane concentrations in the plasma and organs of rats fed diets deficient in one or both nutrients. Weanling rats were fed a vitamin E- and selenium-deficient diet for 12 wk and then divided into four groups. One group continued to receive the doubly deficient diet, and the other three groups were fed the diet supplemented with vitamin E, selenium or both nutrients (control diet) for 4 wk. Plasma F2-isoprostanes in rats fed the doubly deficient diet were 5.2-fold higher than in animals changed to a control diet. In addition, there were significant differences in liver, lung, kidney, heart and skeletal muscle phospholipid-esterified F2-isoprostanes between these two groups. Lesser increases were noted in the group fed the vitamin E-deficient diet. Selenium deficiency alone was not associated with greater lipid peroxidation. Lipid peroxidation occurs in tissues of rats fed a vitamin E-deficient diet and is increased by concomitant selenium deficiency.

New areas of investigation into the study of the biology of thromboxane A2 (TxA2) and of the tissue injury mediated by free radicals is provided by the existence of F2-isoprostane receptors on rat vascular smooth muscle cells. Free oxygen radicals are used in the catalysis of the nonenzymatically generated prostanoids manufactured in humans and rats which yield isoprostanes specific binding sites for the H3 concentration SQ and for 125I concentration BOP. They were found to have a TxA2 antagonist by the use of cultured rat aortic smooth muscle cells.

Astudy was done to investigate the possibility that F2-isoprostanes could be formed in situ on phospholipids. F2-isoprostanes are bioactive prostaglandin F2-like compounds produced in vivo via the free radical peroxidation of arachidonic acid independent of the cyclooxygenase enzyme. The results showed that unlike prostanoids derived via the action of cyclooxygenase, F2 isoprostanes are formed in situ on phospholipids. The formation of these highlydistorted molecules in lipid bilayers due to oxidant injury could have effects on the integrity of cellular membranes.

The most common type of fish poisoning is caused by eating spoiled tuna, bonito, mackerel and other scombroid fish (scombrotoxism). Other fish, including mahi-mahi, bluefish, amberjack, herring, sardines, and anchovies have caused scombrotoxism, as has cheese on rare occasions. This is one of the major chemical food-borne illnesses in the United States, according to the Centers for Disease Control, and can be prevented by proper handling and refrigeration of the fish. If the fish becomes warm at any time after it is caught, bacteria thrive and poisoning can occur even though the fish looks and smells fresh. Symptoms begin within an hour of eating the fish, and include flushing, sweating, digestive upset, headache, palpitation, dizziness, rash, and sometimes swelling of the face and tongue. Occasionally respiratory distress can occur. Histamine has been suspected as the cause for almost 50 years, but proof was lacking because it did not produce illness when given to healthy subjects. By measuring the urinary levels of histamine in three subjects with fish poisoning, it was found that the levels were much greater than those caused by histamine excess. It seems that the histamine came from the fish (marlin), and was not the result of excessive release of histamine from body tissues. Whether histamine is in the fish or released by the body, histamine is the cause. This finding should be the basis for a general public health policy recommendation that scombroid poisoning should be treated with an antihistamine, specifically, antagonists to both H1 and H2 receptors in combination. (Consumer Summary produced by Reliance Medical Information, Inc.)

Endogenous DNA adducts may contribute to the etiology of human genetic disease and cancer. One potential source of endogenous DNA adducts is lipid peroxidation, which generates mutagenic carbonyl compounds such as malondialdehyde. A sensitive mass spectrometric method permitted detection and quantitation of the major malondialde- hyde-DNA adduct, a pyrimidopurinone derived from deoxyguanosine. DNA from disease-free human liver was found to contain 5400 adducts per cell, a frequency comparable to that of adducts formed by exogenous carcinogens., DNA damage is implicated in a variety of human diseases, including cancer (1-6). Until recently, it has been assumed that the major sources of DNA damage in humans are activated [...]

A study was conducted to examine the effects of carbohydrate supplements and rest on hormonal and oxidative changes during intense exercise. The results showed that carbohydrate supplement during intense exercise decreased oxidative stress, although short rest periods did not affect it.

* Objective.--To test the hypothesis that quantification of cerebrospinal fluid (CSF) [F.sub.2]-isoprostanes ([F.sub.2]-IsoPs), in vivo biomarkers of free radical damage, along with CSF A[[Beta].sub.42] and tau levels improves laboratory diagnostic accuracy for Alzheimer disease (AD). Participants.--Patients with probable AD (n = 19), dementias other than AD (n = 8), and age-matched controls (n = 10). Main Outcome Measures.--Cerebrospinal fluid concentrations of A[[Beta].sub.42] and tau were determined by a commercially available test (Athena Diagnostics, Worcester, Mass). Cerebrospinal fluid [F.sub.2]-IsoP levels were quantified by gas chromatography/mass spectrometry. Results.--Individuals were classified as AD or non-AD by a published method using CSF A[[Beta].sub.42] and tau levels (95% sensitivity, 50% specificity), by CSF [F.sub.2]-IsoP levels greater than 25 pg/mL and A[[Beta].sub.42] concentrations less than 1125 pg/ mL (90% sensitivity, 83% specificity), and by combined analysis using CSF [F.sub.2]-IsoP, A[[Beta].sub.42], and tau levels (84% sensitivity, 89% specificity). Conclusion.--Cerebrospinal fluid [F.sub.2]-IsoP quantification may enhance the accuracy of the laboratory diagnosis of AD. (Arch Pathol Lab Med. 2001;125:510-512), Recent efforts have concentrated on determining markers to screen for increased susceptibility to Alzheimer disease (AD), to discriminate AD from other forms of dementia, and to quantify the efficacy of [...]

Although lipid peroxidation in the subendothelial space has been hypothesized to play a central role in atherogenesis, the role of vitamin E in preventing lipid peroxidation and lesion development remains uncertain. Here we show that in atherosclerosis-susceptible apolipoprotein E knockout mice, vitamin E deficiency caused by disruption of the [Alpha]-tocopherol transfer protein gene (Ttpa) increased the severity of atherosclerotic lesions in the proximal aorta. The increase was associated with increased levels of isoprostanes, a marker of lipid peroxidation, in aortic tissue. These results show that vitamin E deficiency promotes atherosclerosis in a susceptible setting and support the hypothesis that lipid peroxidation contributes to lesion development. [Ttpa.sup.-/-] mice are a genetic model of vitamin E deficiency and should be valuable for studying other diseases in which oxidative stress is thought to play a role. antioxidants

Chen, Kent, Jung Suh, Anitra C. Carr, Jason D. Morrow, John Zeind, and Balz Frei. Vitamin C suppresses oxidative lipid damage in vivo, even in the presence of iron overload. Am J Physiol Endocrinol Metab 279: E1406-E1412, 2000.--Ascorbate is a strong antioxidant; however, it can also act as a prooxidant in vitro by reducing transition metals. To investigate the in vivo relevance of this prooxidant activity, we performed a study using guinea pigs fed high or low ascorbate doses with or without prior loading with iron dextran. Iron-loaded animals gained less weight and exhibited increased plasma [Beta]-N-acetyl-D-glucosaminidase activity, a marker of tissue lysosomal membrane damage, compared with control animals. The iron-loaded animals fed the low ascorbate dose had decreased plasma [Alpha]-tocopherol levels and increased plasma levels of triglycerides and [F.sub.2]-isoprostanes, specific and sensitive markers of in vivo lipid peroxidation. In contrast, the two groups of animals fed the high ascorbate dose had significantly lower hepatic [F.sub.2]-isoprostane levels than the groups fed the low ascorbate dose, irrespective of iron load. These data indicate that 1) ascorbate acts as an antioxidant toward lipids in vivo, even in the presence of iron overload; 2) iron loading per se does not cause oxidative lipid damage but is associated with growth retardation and tissue damage, both of which are not affected by vitamin C; and 3) the combination of iron loading with a low ascorbate status causes additional pathophysiological changes, in particular, increased plasma triglycerides. antioxidant; ascorbate; [F.sub.2]-isoprostanes; guinea pigs; lipid peroxidation

Cyclooxygenase (COX)-derived prostaglandins (PGs) regulate numerous maternal-fetal interactions during pregnancy. PGs stimulate uterine contractions and prepare the cervix for parturition, whereas in the fetus, PGs maintain patency of the ductus arteriosus (DA), a vascular shunt that transmits oxygenated placental blood to the fetal systemic circulation. However, the origin and site of action of these PGs remain undefined. To address this, we analyzed mice lacking COX-1 (null mutation) or COX-2 (pharmacologic inhibition) or pups with a double null mutation. Our results show that COX-1 in the uterine epithelium is the major source of PGs during labor and that [COX-1.sup.-/-] females experience parturition failure that is reversible by exogenous PGs. Using embryo transfer experiments, we also show that successful delivery occurs in [COX-1.sup.-/-] recipient mothers carrying wild-type pups, establishing the sufficiency of fetal PGs for parturition. Although patency of the DA is PG dependent, neither COX-1 nor COX-2 expression was detected in the fetal or postnatal DA, and offspring with a double null mutation died shortly after birth with open DAs. These results suggest that DA patency depends on circulating PGs acting on specific PG receptors within the DA. Collectively, these findings demonstrate the coordinated regulation of fetal and maternal PGs at the time of birth but raise concern regarding the use of selective COX inhibitors for the management of preterm labor.

Preeclampsia may be initially caused by a decrease in prostacyclin, which is a naturally occurring chemical in the body that relaxes blood vessels. Preeclampsia is a potentially serious complication of pregnancy. Researchers measured blood levels of prostacyclin in 134 pregnant women who developed preeclampsia and 139 pregnant women who didn't. Those who developed preeclampsia had much lower prostacyclin levels long before they developed the condition. This would cause blood vessels to constrict. This may explain why aspirin does not prevent preeclampsia because aspirin has no effect on prostacyclin.