Eicosanoid production in experimental alcoholic liver disease is related to vitamin E levels and lipid peroxidation

We investigated the association between vitamin E, lipid peroxidation and eicosanoid production in experimental alcoholic liver injury. We used the intragastric feeding rat model in which animals were fed corn oil and ethanol (CO+E) and corn oil and dextrose (CO+D) for 2 and 4 week periods. At sacrifice, we measured plasma levels of alpha-tocopherol, 8-isoprostane, thromboxane B₂(TXB₂) and 6-ketoprostaglandin F₁(6-KetoPGF₁). Animals fed CO+E had significantly lower concentrations of -tocopherol and higher concentrations of 8 isoprostane at both 2 and 4 weeks. a significant inverse correlation was seen between -tocopherol concentrations and the TXB₂: PGF₁ ratio (r=0.72, p<0.01). A positive correlation was seen between the TXB₂: PGF₁ ratio and 8 isoprostane levels (r=0.84, p<0.001). These results suggest that vitamin E depletion and enhanced lipid peroxidation may affect eicosanoid metabolism in experimental alcoholic liver disease in such a way so as to increase the thromboxane to prostacyclin ration.Abbreviations PGH₂ Prostaglandin H₂ - PGL₂ Prostacyclin - CO+E Corn Oil and Ethanol - CO+D Corn Oil and Dextrose - TXB₂ Thromboxane B₂ - TXA₂ Thromboxane A₂     

Potentiation of sympathetic neurotransmission in bovine isolated irides by isoprostanes

Isoprostanes (IsoP) are formed by free radical catalyzed peroxidation of arachidonic acid independent of the cyclooxygenase enzyme. In the present study, we examined the effect of IsoP on norepinephrine (NE) release from the bovine isolated iris. Furthermore, we studied the role of IsoP's in hydrogen peroxide (H₂O₂)-induced enhancement of NE release from this tissue. Isolated bovine irides were prepared for studies of [³H]NE release using the superfusion method. Release of [³H]NE was induced via electrical field stimulation. Both 8-iso-prostaglandin E₂ (E₂-IsoP) and 8-iso-prostaglandin F_2α (F₂-IsoP) produced a concentration-related enhancement of field-stimulated [³H]NE release from isolated bovine irides, an effect that was mimicked by the thromboxane (Tx) receptor agonist, U46619 and by H₂O₂. The Tx-receptor antagonist, SQ 29548 inhibited responses to E₂-IsoP (10μM) with an IC₅₀ of 370±50 nM. SQ 29548 (10μM) also blocked the enhancement of electrically-evoked [³H]NE release induced by U46619 (10μM) but not that caused by H₂O₂ (300μM). The Tx synthetase inhibitor, carboxyheptylimidazole (10μM) prevented the stimulatory effect of E₂-IsoP on evoked [³H]NE release without affecting responses induced by H₂O₂. We conclude that IsoP's can enhance sympathetic neurotransmission in the bovine isolated iris, an effect that can be blocked by a Tx-receptor antagonist. Furthermore, endogenously produced Tx's mediate the stimulatory effect of IsoP's on NE release. However, endogenously generated IsoP's or Tx's are not involved in H₂O₂-induced potentiation of sympathetic neurotransmission.     

Effect of Isoprostanes on Sympathetic Neurotransmission in the Human Isolated Iris-Ciliary Body

Isoprostanes (IsoP's) are prostaglandin-like compounds that are derived from free-radical catalyzed peroxidation of arachidonic acid independent of the cyclcooxygenase enzyme. In the present study, we investigated the effect of IsoP's on norepinephrine (NE) release from human isolated iris-ciliary bodies. Isolated human iris-ciliary bodies were prepared for studies of [³H]NE release using the superfusion method. Both 8-iso-prostaglandin F₂ (F₂-IsoP) and the thromboxane (Tx) receptor agonist, U46619 enhanced field-stimulated [³H]NE release from isolated, superfused human iris-ciliary bodies without affecting basal tritium efflux. On the other hand, an equimolar concentration (10 M) of 8-iso-prostaglandin E₂ (E₂-IsoP) inhibited evoked [³H]NE overflow. The Tx-receptor antagonist, SQ 29548 blocked the enhancements of electrically-evoked [³H]NE release induced by F₂-IsoP and U46619. However, the inhibitory responses elicited by E₂-IsoP was not antagonized by SQ 29548. We conclude that IsoP's can produce both excitatory and inhibitory effects on sympathetic neurotransmission in human isolated iris-ciliary bodies. The stimulatory effects of IsoP' on NE release may be mediated by Tx-receptors.     

Lead disrupts eicosanoid metabolism, macrophage function, and disease resistance in birds

Lead (Pb) affects elements of humoral and cell-mediated immunity, and diminishes host resistance to infectious disease. Evidence is presented supporting a hypothesis of Pb-induced immunosuppression stemming from altered fatty acid metabolism, and mediated by eicosanoids and macrophages (MØ). Chronic Pb exposure increases the proportion of arachidonate (ArA) among fatty acids in lipid from avian tissues, and this change provides precursors for eicosanoids, the oxygenated derivatives of ArA that mediate MØ acute inflammatory response. In the current study, we showed that the concentration of ArA in phospholipids of MØ elicited from turkey poults fed 100 ppm dietary Pb acetate was twice that of controls. In vitro production of eicosanoids by these MØ was substantially increased, and this effect was most pronounced following lipopolysaccharide stimulation: prostaglandin F_2α was increased 11-fold, thromboxane B₂ increased threefold, and prostaglandin E₂ increased by 1.5 times. In vitro phagocytic potential of these MØ was suppressed, such that the percentage of MØ engulfing sheep red blood cell (RBC) targets was reduced to half that of control MØ. In vivo susceptibility of Pb-treated and control birds to Gram-negative bacteria challenge was also evaluated. The morbidity of chicks inoculated withSalmonella gallinarum and fed either control or 200 ppm Pb acetate-supplemented diets was similar, except early in the course of the disease when mortality among Pb-treated birds was marginally greater. In these studies, effects of Pb that could influence immunological homeostasis were demonstrated for MØ metabolism of ArA, for production of eicosanoids, and for phagocytosis. There was also the suggestion that these in vitro indices of immune function are related to in vivo disease resistance.