15-HETE is the main eicosanoid present in mucus of ulcerative protocolitis

Abstract Prostaglandins, leukotrienes and mono-hydroxy acid products of arachidonic acid were measured in mucus of freshly recovered morning stools of a patient with an exacerbation of ulcerative proctocolitis. Eicosanoids in ether extracts were separated by high performance liquid chromatography and amounts determined by radioimmunoassay. Four hydroxy-eicosatetraenoic acids were detected, of which the most important one was identified as 15-hydroxy eicosatetraenoic acid (530 ng/g mucus). Leukotriene B4 was also present (21 ng/g mucus) and small amounts of immunoreactive leukotriene C4 (< 0.8 ng/g mucus). The prostaglandins 6-keto-PGF1α and PGE2 and thromboxane B2 were found in amounts of 3.7, 2.0 and 9.2 ng/g mucus, respectively

The leukotrienes : action on lung parenchymal strips and the formation by macrophages

In this thesis the history, biosynthetic pathways and biological activities of leukotrienes is being reviewed. Their contractile effects on lung parenchymal strips and their formation by macrophages are investigated. In addition the action of specific synthesis inhibitors is determined. These two approaches were chosen , firstly to investigate the mechanism of action of these potent bronchoconstrictive agents and secondly to determine the capacity of cells to generate the whole cascade of arachidonic acid products, to which leukotrienes belong. Leukotrienes belong to the so-called eicosanoids , which also comprise the group of prostaglandins and mono-hydroxy eicosatetraenoic acids. The results presented in chapters 3 and 4, show that the three main groups of eicosanoids have different biological effects and are able to interact with each other

Effects of short- and long-term feeding of L-carnitine and congeners on the production of eicosanoids from rat peritoneal leucocytes

The effect of short- and long-term feeding with L-carnitine, L-acetyl carnitine and L-propionyl carnitine on the production of eicosanoids front in vitro stimulated carrageenan-induced rat peritoneal macrophages was investigated. Both young (4 weeks) and old (18 months) rats were used. A lower number of cells was isolated from the peritonea of treated than control young rats after 4 d feeding, but after 60 d no differences were observed. A similar reduction in cell number was found when old animals were given L-acetyl carnitine or L-propionyl carnitine (acutely) or L-acetyl carnitine or L-carnitine (chronically). Plasma carnitine levels were higher in young rats given carnitine both chronically and acutely. Carnitine derivatives were without effect. In contrast, levels of total carnitine in the plasma of old rats given L-carnitine and L-acetyl carnitine for 4 d and 60 d were higher than in controls. There was no correlation between total plasma carnitine level and effects on prostaglandin, thromboxane and leukotriene B4 (LTB4) production. In young rats the most important changes were observed in relation to the production of prostacyclin (PGI2), measured as 6 keto-prostaglandin Flα. Prostacyclin production was higher in the groups given carnitine or its derivatives. The net result of the changes in PGI2 was that the 6 keto-prostaglandin F1α: thromboxane B2 and the 6 keto-prostaglandin Flα:LTB4 ratios tended to be higher in cells from young animals following short-term feeding with L-carnitine. When young rats were given carnitine compounds for 60 d PGI2 production was lower in cells from L-acetyl carnitine- and L-propionyl carnitine-fed animals. The net result of the changes in PGI2 was that the 6 keto-prostaglandin F1α: thromboxane B2 and the 6 keto-prostaglandin F1α:LTB4 ratios were lower in cells from animals fed with carnitine compounds. In old rats the PGI2 production was lower after short-term feeding with carnitine compounds and was higher after long-term feeding. LTB4 production was lower after L-carnitine and L-acetyl carnitine treatment for 4 d and also lower after 60 d treatment with L-acetyl carnitine. The net results of the changes in PGI2 were that the 6 keto-prostaglandin F1α: thromboxane B2 and the 6 keto-prostaglandin F1α:LTB4 ratios were lower after short-term feeding of all three compounds and higher after the long-term treatment with L-acetyl carnitine and L-propionyl carnitine in old rats. By long-term treatment with low-dose aspirin of patients with heart failure and claudication, the 6 keto-prostaglandin F1α: thromboxane B2 ratio is positively increased, which is a beneficial cardioprotective effect. The mechanism of action of carnitine in heart failure and claudication could also be achieved by an increase of this ratio. Our results suggest that elderly patients could be treated chronically by carnitine to obtain this beneficial effect

Nicotine inhibits cytokine synthesis by mouse colonic mucosa

We examined the in vivo effect of nicotine on the synthesis of (pro-)inflammatory mediators by mouse colonic mucosa. The synthesis of lipid mediators such as the prostanoids prostaglandin E2, 6-keto-prostaglandin F1α and thromboxane B2, the 5-lipoxygenase products leukotriene B4 and leukotriene C4 and the platelet activating factor was not affected, whereas the synthesis of the pro-inflammatory cytokines interleukin-1 β and tumor necrosis factor α was completely abolished. The beneficial effects of smoking and nicotine in ulcerative colitis could be attributed to this inhibition

Eicosanoid and amino acid metabolism in transient acute psychoses with psychedelic symptoms

It has been hypothesized that a disturbance of glutathione (GSH) metabolism might be a common factor in many psychiatric disorders. The aim of the present study was to test this hypothesis in transient acute psychotic patients with distorted perceptions. Since the metabolism of GSH is related to that of thromboxane B 2 (TXB 2), prostaglandin E (PGE) and some amino acids, we determined these substances in the plasma of 15 patients and 17 normal controls. Plasma concentrations of TXB 2 were significantly higher and concentrations of serine and tryptophan were significantly lower in patients than in controls. Large variation was observed in plasma PGE levels in patients, although mean values did not differ significantly from controls. These results are consistent with the hypothesis that the metabolism of GSH is impaired in transient psychotic states

Chronic sleep reduction in adolescents - clinical cut-off scores for the Chronic Sleep Reduction Questionnaire (CSRQ)

The Chronic Sleep Reduction Questionnaire is a validated questionnaire that measures symptoms of prolonged insufficient and/or poor sleep and therefore accounts for individuals’ sleep need and sleep debt. This study extends its psychometric properties by providing cut-off scores, using a matched sample of 298 healthy adolescents (15.38 ± 1.63 years, 37.9% male, mean Chronic Sleep Reduction Questionnaire score: 32.98 ± 6.51) and 298 adolescents with insomnia/delayed sleep–wake phase disorder (15.48 ± 1.62 years; 37.9% male, mean Chronic Sleep Reduction Questionnaire score: 42.59 ± 7.06). We found an area under the curve of 0.84 (95% confidence interval: 0.81–0.87). Cut-off scores for optimal sensitivity, optimal specificity and based on Youden's criterion are provided. These cut-off scores are highly relevant for use of the Chronic Sleep Reduction Questionnaire in future studies and clinical practice

Species differences in the pattern of eicosanoids produced by inflamed and non-inflamed tissue

The synthesis of14C labelled arachidonic acid metabolites was measured in colonic tissues obtained from mice, rats, guinea pigs, rabbits, piglets and in colonic biopsies from humans during colonoscopy. The main eicosanoids formed after stimulation with calcium ionophore A23187 were: in humans, 15-hydroxy-eicosatetraenoic acid (15-HETE); in mice, 12-HETE; in rats, 12-HETE, 12-hydroxy-5,8,10-heptadecatrienoic acid (HHT) and 6-keto-prostaglandine F1α (6kPGF1α); in guinea pigs, PGD2; in rabbits, 6kPGF1α, PGE2 and 15-HETE; and in pigs PGE2 and 12-HETE. In inflamed 15-HETE production was increased in man, HHT and 12-HETE production in rats and overall eicosanoid production in mice

Production of inflammatory mediators by human macrophages obtained from ascites

Ascites is a readily available source of human macrophages (Mø), which can be used to study Mø functions in vitro. We characterized the mediators of inflammation produced by human peritoneal Mø (hp-Mø) obtained from patients with portal hypertension and ascites. The production of the cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) was found to be lipopolysaccharide (LPS) concentration dependent (0–10 μg/ml) with a maximal production at 10 μg/ml and also dependent on the time of exposure to the stimulus (0–36 h). IL-1β, IL-6 and TNF-α production after LPS administration reached a plateau at 24 h. In vitro stimulation for 24 h with LPS does not influence the eicosanoid production from endogenous arachidonate. 13 min of exposure of the cells to the calcium ionophore A23187 gives a significant increase in eicosanoid production from both exogenous and endogenous arachidonate. The main eicosanoids produced are the 5-lipoxgenase products LTB4 and 5-hydroxyeicosatetraenoic acid (HETE). The increase in production of the other eicosanoids is not significant. The eicosanoid production depends on the stimulus concentration. The optimal A23187 concentration is 1 μM. Oxygen radical production was measured in the Mø by a flowcytometric method. The fluorescence intensity of phorbol 12-myristate 13-acetate stimulated and dihydro-rhodamine 123 loaded. hp-Mø increases significantly after 15 min. We conclude that LPS stimulation of hp-Mø from liver disease results in similar production of IL-1β, IL-6 and TNF-α, but that the profile of the eicosanoid production of these Mø stimulated with LPS and A23187 differs from Mø of other origin and species