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2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) adversely affects many mammalian organs and tissues. These effects are mediated by the aryl hydrocarbon receptor (AHR). CYP1A1, CYP1A2 and CYP1B1 are upregulated by the liganded AHR. These (and other) cytochromes P450 can metabolize arachidonic acid into a variety of bioactive eicosanoids. Towards investigating a potential role of eicosanoids in TCDD toxicity, arachidonic acid, two other unsaturated long-chain fatty acids, and up to twenty-five eicosanoids were measured in five organs/tissues of male and female wild-type and Ahr null mice treated or untreated with TCDD. TCDD generally increased the levels of the four dihydroxyeicosatrienoic acids (DHETs) and (where measured) 5,6-epoxyeicosatrienoic acid and 18-, 19- and 20-hydroxyeicosatrienoic acids (HETEs) in the serum, liver, spleen and lungs, but not the heart, of both sexes, and increased the levels in the serum, liver and spleen of several metabolites that are usually considered products of lipoxygenase activity, but which may also be generated by cytochromes P450. TCDD also increased the levels of the esterified forms of these eicosanoids in the liver in parallel with the corresponding free forms. The levels of prostanoids were generally not affected by TCDD. The above changes did not occur in Ahr null mice, and are therefore mediated by the AHR. TCDD increased the mRNA levels of Cyp1a1, Cyp1a2, Cyp1b1 and the Pla2g12a form of phospholipase A(2) to varying degrees in the different organs, and these increases correlated with some but not all the changes in eicosanoids levels in the organs, suggesting that other enzymes may also be involved., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Amphibian blood cells play an important role in eicosanoid synthesis. Formation of eicosanoids during clotting of whole human blood but not frog blood has been reported. Amphibian blood cell numbers are affected by cold exposure; therefore eicosanoid production may reflect these changes. Blood cell changes during warm, and short- and long-term-cold exposure periods were recorded and the formation of leukotriene B4 (LTB4), LTC4, thromboxane (TXB2), and prostaglandin E2 (PGE2) was measured during blood clotting by using radioimmunoassay. Short-term (1 day) cold exposure (5 degrees) did not significantly decrease blood cell number or eicosanoid production during clotting. However, following exposure to cold (5 degrees) for 10 or 30 days, blood cell number and production of LTB4, TXB2, and PGE2 during clotting decreased when compared with warm acclimated controls (22 degrees). LTC4 levels during blood clotting decreased significantly only after 30 days of cold exposure. The results demonstrate that eicosanoid synthesis can be correlated with blood cell number in warm- and cold-exposed bullfrogs.

Low-dose aspirin (acetylsalicylic acid; ASA), inhibiting platelet thromboxane production in favor of endothelium formation of prostaglandins, is successfully used as primary or secondary prophylaxis against myocardial infarction. Although prognosis may be improved, effects of long-term ASA treatment on wound healing and cardiac remodeling are not well understood. The aim of the present study was to mimic the clinical situation by inducing myocardial infarction in low-dose ASA (25 mg/kg/day, i.p.) pretreated rats, and to determine effects on plasma eicosanoid levels, cardiac hypertrophy and collagen deposition, and left ventricular function during continued ASA treatment. The effects of this dose were verified to selectively inhibit platelet thromboxane production, and lower plasma levels of thromboxane, but did not affect plasma levels of prostacyclin and prostaglandin E2 during the acute inflammatory stage following myocardial infarction. As measured by heart dry weight/body weight, cardiac hypertrophy was not affected by ASA treatment. However, interstitial fibrosis in the spared myocardium as well as perivascular fibrosis, associated with infarction-induced cardiac remodeling, were affected by ASA treatment. Replacement fibrosis in the infarct itself, considered as representing wound healing, was not significantly influenced by ASA treatment. Wall thinning following infarction was not aggravated, nor did treatment influence left ventricular cavity diameter in a relaxed state. Results from in vitro left ventricular function measurements showed no effects on left ventricular peak velocity of contraction or relaxation after ASA treatment. In conclusion, although low-dose ASA may not be expected to have anti-inflammatory action, it did influence post-infarct cardiac remodeling by affecting interstitial and perivascular fibrosis. ASA treatment did not have effects on in vitro left ventricular dysfunction.

Recombinant human C5a (rHuC5a), produced by a synthetic gene expressed in Escherichia coli, causes a decrease in dynamic lung compliance and an increase in pulmonary resistance when injected intravenously in anesthetized mechanically ventilated guinea pigs over a dose range of 5-20 micrograms/kg. Intravenous injection of rHuC5a also caused an immediate decrease in mean arterial blood pressure followed by a transient increase. The purpose of this study was to determine the mediators responsible for these effects. To assess the role of histamine, plasma levels of histamine were monitored and the effects of the H1 antagonist pyrilamine were assessed. rHuC5a caused a significant increase in plasma histamine. However, the H1 antagonist did not alter the maximum or the time course of the bronchoconstrictor response indicating that histamine did not play a major role. The LTD4 antagonist L-649,923 did not inhibit the rHuC5a-induced bronchoconstriction whereas the cyclo-oxygenase inhibitor indomethacin did. Thus, to assess the role of cyclo-oxygenase products, plasma levels of thromboxane (TX) B2, prostaglandin (PG) D2 and PGF2 alpha were monitored after injection of rHuC5a. In addition, guinea pigs were treated with either the TX synthetase inhibitor U-63557A or with the TX receptor antagonist SQ 29,548. rHuC5a challenge caused an increase in plasma concentrations of TXB2, PGD2 and PGF2 alpha which peaked before the maximum of the bronchoconstriction. SQ 29,548 significantly inhibited the maximum of the bronchoconstrictor response, whereas U-63557A did not inhibit the maximum but did inhibit the time course of the response.(ABSTRACT TRUNCATED AT 250 WORDS)