leukotriene-b4 and Pre-Eclampsia

We carried out a longitudinal study to compare leukotriene B4 (LTB4), lipoxin A4 (LXA4), and resolvin D1 (RvD1) levels in pregnant women with risk factors for PE - who did (N = 11) or did not develop (N = 17) this clinical condition.. For both groups, plasma levels of the lipid mediators were measured using immunoassays at 12-19, 20-29, and 30-34 weeks of gestation.. LTB4 tended to be upregulated throughout gestation in women who developed PE. Moreover, this increase was significant at 30-34 weeks. Although LXA4 levels also tended to be higher in the PE group, this difference was not significant for the evaluated gestational periods. Pregnant women with PE had lower RvD1 levels and a low RvD1/LTB4 ratio at 30-34 weeks, compared to those in the normotensive pregnant women. Contrarily, RvD1 levels increased at weeks 12-19 in pregnant women who developed PE. Particularly, LXA4 and RvD1 levels were higher at 30-34 weeks than those at 20-29 weeks considering both groups of women. We observed an interaction between the gestational outcome and the gestational period in case of RvD1.. The imbalance among LTB4, LXA4, and RvD1 levels in these preeclamptic women is consistent with the excessive inflammation that underlies the pathogenesis of PE. Although our data highlight the potential for the use of these lipid mediators as clinical markers for PE development, future longitudinal studies must be carried out to confirm these findings.

Topics: Adolescent; Adult; Docosahexaenoic Acids; Female; Humans; Leukotriene B4; Lipoxins; Longitudinal Studies; Pre-Eclampsia; Pregnancy; Risk Factors

Pre-eclampsia (PE) affects 2-8% of pregnancies worldwide. Despite identification of numerous possible biomarkers, accurate prediction and early diagnosis of PE remain challenging. We examined the potential of leukotriene B4 (LTB4) and 15-hydroxyeicosatetraenoic acid (15(S)-HETE) as biomarkers of PE by comparing serum levels at three gestational age (GA) groups between normotensive pregnancies and asymptomatic women who subsequently developed preterm or term-PE.. This is a case-control study drawn from a prospective study of adverse pregnancy outcomes with serum samples collected at 19-24 weeks (n = 48), 30-34 weeks (n = 101) and 35-37 weeks (n = 54) GA. LTB4 and 15(S)-HETE levels were determined by ELISA. Serum level multiples of the median (MoM) were compared between normal and PE-pregnancies. Association between LTB4 and 15(S)-HETE and GA at delivery was investigated with Cox proportional-hazards models.. Serum LTB4 levels were lower in women of East-Asian ethnicity, higher in women with PE history, and increased with GA in normotensive pregnancies, but not in PE. LTB4 was elevated at 19-24 weeks in women who developed preterm-PE. There was a negative association between LTB4 MoM and interval between sampling and delivery with PE at 19-24 weeks only. Serum 15(S)-HETE levels were not influenced by GA at testing and were elevated in women of South-Asian ethnicity. Median 15(S)-HETE levels were unchanged in preterm and term-PE at any GA.. LTB4 was higher at 19-24 weeks in pregnancies that developed preterm-PE versus unaffected pregnancies, suggesting it is a potentially useful predictive marker of preterm PE in the second trimester.

Topics: Adult; Biomarkers; Case-Control Studies; Early Diagnosis; Female; Gestational Age; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Maternal Serum Screening Tests; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Pregnancy Trimester, Second; Pregnancy Trimester, Third; Prognosis

Omega-3 and omega-6 fatty acids can be endogenously converted into mediators with pro-inflammatory (eg, leukotriene B4/LTB4) or anti-inflammatory/pro-resolving activities (eg, resolvin D1/RvD1 and maresin 1/MaR1). Recent data indicate an imbalance of LTB4 and MaR1 levels in pre-eclampsia (PE), but the relative production of these mediators, including RvD1, and the role of these mediators in the disease pathogenesis remain unclear. Therefore, this study aimed to investigate the plasma levels of LTB4, RvD1, and MaR1 in pregnant women with or without PE and non-pregnant controls and their association with clinical/laboratory parameters of PE women.. LTB4, RvD1, and MaR1 plasma levels were measured by competitive enzyme immunoassay in 19 non-pregnant, 20 normotensive pregnant, and 21 PE women.. Plasma concentrations of LTB4 were higher and RvD1 were lower in PE women than in normotensive pregnant women, who presented higher levels of LTB4 and similar levels of RvD1 to non-pregnant women. MaR1 levels did not differ among the groups. Pre-eclampsia women had decreased RvD1/LTB4 and MaR1/LTB4 ratios. Considering only the PE group, positive correlations were observed among all the mediators tested, between LTB4 and white blood cell count and between RvD1 and creatinine levels. However, all lipid mediators correlated negatively with body mass index before pregnancy. LTB4 also correlated negatively with maternal age.. Our findings suggest that the PE state results in systemic overproduction of LTB4 in relation to RvD1 and MaR1, and that these lipid mediators may be involved with the disease pathogenesis.

Topics: Adult; Body Mass Index; Docosahexaenoic Acids; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Female; Humans; Inflammation; Inflammation Mediators; Leukotriene B4; Pre-Eclampsia; Pregnancy; Young Adult

To investigate whether serum levels of 19 eicosanoids are associated with pre-eclampsia.. A case-control study was performed using data for pregnant women with pre-eclampsia, normotensive pregnant women, and nonpregnant women, for all of whom serum samples had been collected at a hospital in Shanghai, China, between December 2012 and December 2013. Ultra-performance liquid chromatography-tandem mass spectrometry was used to measure the serum levels of 19 eicosanoids.. Overall, 49 pregnant women with pre-eclampsia, 26 normotensive pregnant women, and 14 nonpregnant women were included. Women with pre-eclampsia had significantly higher serum levels of 11,12-epoxyeicosatrienoic acid (11,12-EET), the hydroxyeicosatetraenoic acids 5-HETE, 8-HETE, 12-HETE, and 15-HETE, and leukotriene B4 than did women with a normal pregnancy and nonpregnant women, both before and after the onset of pre-eclampsia (P<0.01 for all comparisons). Women with severe pre-eclampsia had significantly higher serum levels of 5-HETE, 15-HETE, and leukotriene B4 than did women with mild pre-eclampsia, women with a normal pregnancy, and nonpregnant women (P<0.01 for all comparisons).. The eicosanoids 11,12-EET, 5-HETE, 8-HETE, 12-HETE, 15-HETE, and leukotriene B4 might play important parts in the occurrence and development of pre-eclampsia.

Topics: Adult; Case-Control Studies; China; Eicosanoids; Female; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Pre-Eclampsia; Pregnancy; Young Adult

Preeclampsia is associated with oxidative stress, elevated plasma levels of linoleic acid (LA), and increased vascular smooth muscle expression of the inflammatory chemokine, interleukin-8 (IL-8). We hypothesized that increased levels of LA under conditions of oxidative stress would increased production of IL-8 by vascular smooth muscle cells because LA is the dietary precursor to arachidonic acid (AA) and its metabolites that mediate inflammation. We also hypothesized that oleic acid (OA), which is not metabolized to AA metabolites, would not increase IL-8 under conditions of oxidative stress.. To test this hypothesis, we cultured placental arterial smooth muscle (PASM) cells with an oxidizing solution enriched with LA (OxLA) or OA (OxOA). Media concentrations were analyzed for IL-8 and AA metabolites. Inhibitors were used to block the lipoxygenase and cyclooxygenase pathways.. Exposure of cells to OxLA, but not to OxOA, significantly increased production of IL-8. OxLA also significantly increased production of AA metabolites. Nordihydroguaiaretic acid, an inhibitor of the lipoxygenase pathway, blocked IL-8 and leukotriene B4 (LTB4) production induced by OxLA, whereas indomethacin, an inhibitor of the cyclooxygenase pathway, blocked IL-8, prostaglandin E2 (PGE2), and thromboxane B2 (TXB2) production. Reverse transcriptase-polymerase chain reaction (RT-PCR) demonstrated gene expression in PASM cells for representative lipoxygenase (LTB4) and cyclooxygenase (thromboxane) metabolite receptors.. PASM cells produced IL-8 in response to LA, but not OA, under conditions of oxidative stress. The IL-8 response was mediated by AA metabolites.

Topics: Arachidonic Acid; Cells, Cultured; Female; Gene Expression; Humans; Interleukin-8; Leukotriene B4; Linoleic Acid; Lipoxygenase; Muscle, Smooth, Vascular; Oleic Acid; Oxidative Stress; Pre-Eclampsia; Pregnancy; Prostaglandin-Endoperoxide Synthases; Reverse Transcriptase Polymerase Chain Reaction; Thromboxane B2; Up-Regulation

We hypothesized that aspirin Mg++, and dihydralazine affect the release of vasoactive agents from cultured human placental trophoblast.. Cytotrophoblasts isolated from placentas of preterm or term deliveries of 14 healthy control women and 15 preeclamptic women were cultured in Dulbecco's modified Eagle's medium for 5 days in the presence or absence of either 0.1 mmol/L aspirin, 3 mmol/L magnesium chloride, or 136 ng/ ml dihydralazine. Vasoactive substances were quantitated by radioimmunoassay with mean +/- SEM percentage of untreated cells (= 100%) compared by the Mann-Whitney U test and analysis of variance.. Aspirin inhibited (p < 0.01) both thromboxane and prostacyclin on days 1 and 2 in culture but not on days 3 to 5 unless the Dulbecco's modified Eagle's medium was supplemented with arachidonic acid. Aspirin inhibition was greater (p < 0.01) for thromboxane in cells cultured 24 hours after preeclamptic pregnancy (preterm 29.9% +/- 6.8%, term 20.1% +/- 5.9%) compared with normal controls (preterm 66.3% +/- 10.6%, term 68.9% +/- 11.6%). Aspirin reduced (p < 0.01) the ratio of thromboxane to prostacyclin in media of cells from preeclampsia (untreated 27.8 +/- 7.2, aspirin 13.3 +/- 4.4), but aspirin had no effect on this ratio in cultures from control normal pregnancies (untreated 6.8 +/- 2.9, aspirin 4.8 +/- 1.1). Neither magnesium chloride nor dihydralazine affected trophoblast prostanoid production, and no drug altered the media levels of angiotensin II, endothelin-1, or leukotriene B4.. Aspirin selectively inhibits trophoblast prostanoid production. This inhibition depends on the availability of arachidonic acid and the presence or absence of preeclampsia. Magnesium and dihydralazine effects in pregnancy are not related to altered release of trophoblast vasoactive compounds.

Topics: Angiotensin II; Antihypertensive Agents; Aspirin; Cells, Cultured; Cyclooxygenase Inhibitors; Dihydralazine; Endothelin-1; Epoprostenol; Female; Humans; Leukotriene B4; Magnesium Chloride; Pre-Eclampsia; Pregnancy; Thromboxane B2; Trophoblasts

The aim of the study was to investigate whether pre-eclampsia is associated with an altered release of vasoactive substances from trophoblastic cells in vitro. Trophoblastic cells from 15 uncomplicated control pregnancies and 18 pre-eclamptic pregnancies at preterm (weeks 31-36; n = 12) and term (weeks 37-40; n = 21) were cultured for 5 days. The concentrations of angiotensin II (AII), endothelin-1,2 (ET-1,2), thromboxane B2 (TXB2), 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and leukotriene B4 (LTB4) were measured daily in culture media for 5 days by radioimmunoassay. In pre-eclampsia, concentrations of ET-1,2 were decreased (P < 0.01) at both preterm and term, TXB2 concentrations were increased (P < 0.05) only at preterm and the TXB2-6-keto-PGF1 alpha ratio was increased at both preterm and term (P < 0.01) as compared with the controls. Concentrations of AII, 6-keto-PGF1 alpha and LTB4 were similar to the controls. The data suggest that pre-eclampsia is associated with a decreased release of ET-1 and an increased release of TXB2 from trophoblastic cells in vitro.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Cell Survival; Cells, Cultured; Endothelins; Epoprostenol; Female; Humans; Immunohistochemistry; Leukotriene B4; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Third; Radioimmunoassay; Thromboxane A2; Thromboxane B2; Trophoblasts; Vasodilator Agents

The amount of Leukotriene B4 (LTB4) released from neutrophilic leukocyte activated by calcium ionophore was measured to examine neutrophilic functions regarding the changes during normal pregnancy and differences between normal pregnant women and preeclamptic women. In addition, we examined the arachidonic acid (AA) content and fatty acid composition of neutrophilic phospholipid in normal pregnant women. In a normal pregnancy, the amount of LTB4 released decreased significantly with gestation. In preeclamptic women, the amount of LTB4 released was significantly higher than that in normal pregnant women, but there was no significant difference from non-pregnant women. Normal pregnant women showed a significantly decreased AA content with gestation. Regarding other fatty acids, as to fatty acid composition, there was increased saturated fatty acid and decreased unsaturated fatty acid with gestation. The results suggested that the LTB4 released was inhibited more in pregnant women than in non-pregnant women, and pregnant women also had decreased AA content. In addition, changes in fatty acid compositions showed signs of decreased fluidity of the cell membrane. This phenomenon is thought to be due to a mechanism to inhibiting the activation of neutrophilic leukocytes accompanied by a decrease in the amount of LTB4 released. Conversely, no similar inhibition was observed in preeclamptic women, and the failure of this mechanism seemed to contribute to the development of preeclampsia.

Topics: Adult; Calcimycin; Cells, Cultured; Fatty Acids; Female; Humans; Ionophores; Leukotriene B4; Neutrophils; Pre-Eclampsia; Pregnancy

Topics: Adolescent; Adult; Female; gamma-Glutamyltransferase; Glutathione; Humans; Leukotriene B4; Leukotriene C4; Lipid Peroxidation; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular

Preeclampsia is characterized by imbalances in the production rates of several arachidonic acid metabolites. There is a considerable amount of evidence to indicate that PGI2 production is decreased in preeclampsia. PGI2 is a potent vasodilator, an inhibitor of platelet aggregation, and an inhibitor of uterine contractility. Evidence is accumulating that TX production in preeclampsia is either increased or unchanged so that the ratio of TX to PGI2 favors TX. TX opposes the actions of PGI2 in that it is a potent vasoconstrictor, a stimulator of platelet aggregation, and a stimulator of uterine contractility. Therefore, an imbalance of increased TX/decreased PGI2 production can account for the major clinical symptoms of preeclampsia. There is now preliminary evidence that the placenta produces lipoxygenase, as well as cyclooxygenase compounds. The hydroxyeicosatetranoic acids (5-HETE, 12-HETE, 15-HETE) and LTB4 have been identified as placental products. The preeclamptic placenta appears to be deficient in the 5- and 12-lipoxygenase enzymes, as indicated by placental production of 5-HETE and 12-HETE. Little is known about the regulation of arachidonic acid metabolites in normal or preeclamptic pregnancies. Steroids are known to affect cyclooxygenase product production. Progesterone, for example, inhibits PGI2 production. Although circulating and urinary concentrations of progesterone do not differ between normal and preeclamptic pregnancies, there is one report that placental progesterone concentrations are higher in preeclampsia; this may partially explain the decreased placental production of PGI2. There is a considerable amount of evidence in various tissues that regulatory interactions exist between the cyclooxygenase and lipoxygenase metabolites of arachidonic acid, but the role of these interactions in preeclampsia is not known. There is still much to be learned about the etiology of preeclampsia, but it is certain that aberrations in the production of arachidonic acid metabolites play an important role. It is likely that the effective treatment of preeclampsia will come from understanding the regulation of the arachidonic acid metabolites during pregnancy, and, therefore, the ability to specifically treat the production imbalances that characterize this disorder.

Topics: Arachidonic Acids; Aspirin; Blood Platelets; Epoprostenol; Female; Hemodynamics; Humans; Leukotriene B4; Lipoxygenase; Maternal-Fetal Exchange; Pre-Eclampsia; Pregnancy; Prostaglandins E; Prostaglandins F; Thromboxanes; Trophoblasts