Biomedical subjects

C Edenius

Publications and source records attributed to C Edenius.

23 records · Page 2Linked to original sources

PubMed1989

Effects of sulfasalazine and a sulfasalazine analogue on the formation of lipoxygenase and cyclooxygenase products.

A sulfasalazine analogue, 5'-(2,4-dichlorobenzoyl)2'-hydroxyphenylacetic acid (CL 42A), potently inhibited the formation of 5-lipoxygenase products (leukotrienes B4 and C4 and 5-hydroxyeicosatetraenoic acid) by human leukocytes. Half-maximal inhibition of leukotriene production was obtained with 5 and 10 microM CL 42A after stimulation with serum-treated zymosan or ionophore A23187, respectively. CL 42A was equipotent to nordihydroguaiaretic acid and about 50 times more potent than sulfasalazine and benoxaprofen in studies on the inhibition of LTB4 formation in leukocyte suspensions stimulated with serum-treated zymosan. Furthermore, CL 42A had no inhibitory effect on the production of 15-hydroxyeicosatetraenoic acid after incubation of human leukocytes with ionophore A23187 in the presence of exogenous arachidonic acid. Sulfasalazine inhibited the synthesis of 5-lipoxygenase products (5-hydroxyeicosatetraenoic acid and leukotriene B4: IC50 250 microM, leukotriene C4: IC50 100 microM) in a concentration-dependent manner but had no effect on 15-hydroxyeicosatetraenoic acid formation. The metabolites of sulfasalazine, sulfapyridine and 5-aminosalicylic acid, and the isomer, 4-aminosalicylic acid, were all less potent than sulfasalazine as inhibitors of leukotriene formation. Both CL 42A (IC50 20 microM) and sulfasalazine (IC50 500 microM) inhibited the synthesis of thromboxane B2 and hydroxyheptadecatrienoic acid in human platelet suspensions after arachidonic acid stimulation. However, while CL 42A inhibited cyclooxygenase, the inhibitory effect of sulfasalazine was exerted mainly on thromboxane synthase. The platelet formation of 12-hydroxyeicosatetraenoic acid was not inhibited by CL 42A whereas sulfasalazine had a weak inhibitory effect.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗

PubMed1988

Transcellular conversion of endogenous arachidonic acid to lipoxins in mixed human platelet-granulocyte suspensions.

Incubation of mixed human platelet/granulocyte suspensions with ionophore A23187 led to a platelet dependent formation of several lipoxin isomers from endogenous substrate. The major metabolite coeluted with authentic lipoxin A4 (5(S), 6(R), 15(S)-trihydroxy-7,9,13-trans-11-cis-eicosatetraenoic acid) in several HPLC-systems and showed an identical UV-spectrum. Furthermore, a similar profile of lipoxins was formed in pure platelet suspensions incubated with exogenous leukotriene A4 (5(S) -5, 6-oxido-7,9-trans-11,14-cis-eicosatetraenoic acid). The conversion of exogenous leukotriene A4 to lipoxin A4 was markedly increased in the presence of ionophore A23187.

Arachidonic Acid↗

PubMed1988

Novel transcellular interaction: conversion of granulocyte-derived leukotriene A4 to cysteinyl-containing leukotrienes by human platelets.

Human platelets dose-dependently converted exogenous leukotriene A4 to leukotriene C4 and efficiently metabolized this compound to leukotrienes D4 and E4. Neither of these compounds were produced after stimulation of human platelet suspensions with ionophore A23187. After LTA4 incubation of subcellular fractions, formation of leukotriene C4 was exclusively observed in the particulate fraction and was separable from the classical glutathione S-transferase activity. This suggested the presence of a specific leukotriene C4 synthase in human platelets. Addition of physiological amounts of autologous platelets to human granulocyte suspensions significantly increased ionophore A23187-induced formation of leukotriene C4. In contrast, the production of leukotriene B4 was decreased. After preincubation of platelets with [35S]cysteine, 35S-labeled leukotriene C4 was produced by A23187-stimulated platelet-granulocyte suspensions, strongly indicating a transcellular biosynthesis of this compound.

Blood Platelets↗

PubMed1988

Evidence for a novel pathway of leukotriene formation in human platelets.

The metabolism of arachidonic acid via lipoxygenase-catalyzed reactions in washed human platelets was investigated. In addition to the previously discovered lipoxygenase metabolites, 12-hydroxyeicosatetraenoic acid, 15-hydroxyeicosatetraenoic acid, 8,15-dihydroxyeicosatetraenoic acid and 14,15-dihydroxyeicosatetraenoic acid, several other products were formed. The compounds were all dihydroxylated metabolites of arachidonic acid, containing a conjugated triene structure, and identified as 11,12-dihydroxyeicosatetraenoic acid (two isomers) and 5,12-dihydroxyeicosatetraenoic acid (four isomers). The identification was based on ultraviolet spectroscopy and gas chromatography-mass spectrometry of native and hydrogenated compounds. Stereochemical analysis of the hydroxyl groups of the 5,12-dihydroxyeicosatetraenoic acids and experiments with 18O2 indicated that the compounds were formed by the 12-lipoxygenase pathway, probably via an unstable epoxide.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗

PubMedDate not supplied

Formation and effects of leukotrienes and lipoxins in human bone marrow.

The present results demonstrate leukotriene and lipoxin synthesis in human bone marrow and link these findings to biological effects in the same tissue. However, the mechanisms behind the described effects on myeloid progenitor cell growth are presently unknown. It is conceivable that both leukotrienes and lipoxins may act through modulation of endogenous cytokine production. However, it should be noted, that these lipoxygenase products totally failed to induce colony growth in the absence of GM-CSF. Moreover, the role of lipoxins in the bone marrow needs to be further clarified, since LXA4 induced both synergistic (with GM-CSF) and antagonistic (with LTC4) effects on progenitor cell growth. A possible pathophysiological role for leukotrienes and lipoxins may be suggested in chronic myelogenous leukemia. Thus, the capacity of hematological cells from CML patients to synthesize LTC4 was significantly increased. In addition, we have recently reported that CML platelets possessed a markedly decreased ability to participate in transcellular synthesis of the potential inhibitors of myelopoiesis, LXA4 and 5(S),12(S)-diHETE (Stenke et al., 1991b). Moreover, the production of these compounds was totally abolished in platelets obtained from CML patients in blastic crisis. Further studies should aim at defining the mechanisms behind the regulatory actions of leukotrienes and lipoxins in normal and leukemic human myelopoiesis.

Bone Marrow↗