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Biomedical subjects

J A Lindgren

Publications and source records attributed to J A Lindgren.

At least 55 records · Page 3Linked 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↗
PubMed1988

Increased leukotriene C4 production in chronic myelogenous leukemia.

The production of leukotrienes (LT) in peripheral blood leukocyte preparations from 9 patients with chronic myelogenous leukemia (CML) and 9 healthy controls was studied. Leukotriene generation was stimulated by the calcium ionophore A 23187 (1 mumol). Lipoxygenase products were separated and identified using a high performance liquid chromatography (HPLC) technique and computerized spectrophotometry. Leukotriene C4 (LTC4) was formed in significantly larger amounts by cells from the CML patients than cells from the controls; 14.4 +/- 4.3 pmol per 10(6) nucleated cells (mean +/- SE) and 4.0 +/- 1.2 pmol respectively (p less than 0.05). Seven of the 9 patients but none of the controls synthesized equal or higher amounts of LTC4 than LTB4. A highly significant difference in mean values of LTC4/(LTB4 + 20-OH-LTB4) ratios was observed; CML 0.69 +/- 0.08 versus controls 0.12 +/- 0.02, p less than 0.001. These findings suggest an increased LTC4 synthase activity in CML cells. In earlier studies we have found a decreased 12-lipoxygenase activity in CML bone marrow cells.

Calcimycin↗
PubMed1987

Isolation and identification of lipoxygenase products from the rat central nervous system.

Leukotrienes B4, C4, D4 and E4, together with five monohydroxyeicosatetraenoic acids, were isolated after incubation of chopped rat brain tissue with ionophore A23187. The monohydroxyeicosatetraenoic acids were 5-hydroxy-6,8,11,14-eicosatetraenoic acid, 9-hydroxy-5,7,11,14-eicosatetraenoic acid, 11-hydroxy-5,8,12,14-eicosatetraenoic acid, 12-hydroxy-5,8,10,14-eicosatetraenoic acid and 15-hydroxy-5,8,11,13-eicosatetraenoic acid. Identification of the compounds was performed using reversed-phase high-performance liquid chromatography, ultraviolet spectroscopy and gas chromatography-mass spectrometry. Formation of the compounds was inhibited by micromolar concentrations of nordihydroguaiaretic acid. Indomethacin specifically inhibited the formation of 11-hydroxy-5,8,12,14-eicosatetraenoic acid, suggesting that this compound was produced as a by-product during cyclooxygenase-catalyzed prostaglandin synthesis.

Animals↗
PubMed1987

Leukotrienes and lipoxins: structures, biosynthesis, and biological effects.

Arachidonic acid is released from membrane phospholipids upon cell stimulation (for example, by immune complexes and calcium ionophores) and converted to leukotrienes by a 5-lipoxygenase that also has leukotriene A4 synthetase activity. Leukotriene A4, an unstable epoxide, is hydrolyzed to leukotriene B4 or conjugated with glutathione to yield leukotriene C4 and its metabolites, leukotriene D4 and leukotriene E4. The leukotrienes participate in host defense reactions and pathophysiological conditions such as immediate hypersensitivity and inflammation. Recent studies also suggest a neuroendocrine role for leukotriene C4 in luteinizing hormone secretion. Lipoxins are formed by the action of 5- and 15-lipoxygenases on arachidonic acid. Lipoxin A causes contraction of guinea pig lung strips and dilation of the microvasculature. Both lipoxin A and B inhibit natural killer cell cytotoxicity. Thus, the multiple interaction of lipoxygenases generates compounds that can regulate specific cellular responses of importance in inflammation and immunity.

Animals↗
PubMed1987

Regional distribution of leukotriene and mono-hydroxyeicosatetraenoic acid production in the rat brain. Highest leukotriene C4 formation in the hypothalamus.

The regional distribution of ionophore A23187-induced synthesis of leukotrienes and mono-hydroxyeicosatetraenoic acids in the rat brain in vitro was investigated. Pronounced differences in leukotriene C4 formation were observed, with the highest synthetic capacity in the hypothalamus. The formation of leukotriene C4 was about 12-times higher in the hypothalamus as compared to the cerebellum. This finding is in agreement with a possible neuroendocrine role for leukotriene C4. In contrast, the activity of leukotriene B4 synthesis was widely distributed without pronounced regional differences in the rat brain. Formation of 5-, 9-, 11-, 12- and 15-monohydroxyeicosatetraeonoic acid was detected in all regions. The major lipoxygenase product in the hypothalamus and thalamus was 5-hydroxyeicosatetraenoic acid, while other monohydroxyeicosatetraenoic acids predominated in the remaining regions tested.

Animals↗
PubMed1987

Effects of immune complexes, zymosan preparations and ionophore A 23187 on leukotriene formation in human leukocytes.

Incubation of human leukocytes with opsonized zymosan or IgG immune complexes led to a time dependent release of leukotrienes (LT) B4 and C4. After 3-4 min, the levels of LTB4 were 93 and 35 pmol/3*10(7) cells, respectively [corrected]. These amounts were 2-4 times lower than those released by leukocytes stimulated with the calcium ionophore A 23187. The levels of LTC4 were 8 and 20 times lower than those of LTB4 after incubation with opsonized zymosan or immune complexes, respectively. Heat-inactivation of the serum prior to zymosan coating decreased the effect of opsonized zymosan. Uncoated zymosan was an even weaker stimulus of leukotriene formation. These results suggest that both complement factors and immunoglobulins play a pivotal role in activating leukotriene synthesis in a mixed suspension of human leukocytes.

Antigen-Antibody Complex↗
PubMed1987

Leukotriene production by fresh human bone marrow cells: evidence of altered lipoxygenase activity in chronic myelocytic leukemia.

The metabolism of arachidonic acid through the lipoxygenase pathway was studied in suspensions of fresh human bone marrow cells from eight patients with chronic myelocytic leukemia (CML) and 10 normal controls. After the cells were incubated with the calcium ionophore A23187 and arachidonic acid, a technique including reverse- and straight-phase high-pressure liquid chromatography (HPLC) was employed to isolate and detect different lipoxygenase-mediated compounds. The detected compounds included leukotriene B4 (LTB4), with its two major nonenzymatic isomers 6-trans-LTB4 and 12-epi-6-trans-LTB4 5S,12S-DHETE, and the monohydroxy eicosatetraenoic acids 5-HETE, 12-HETE, and 15-HETE. The pattern of lipoxygenase-mediated products from the bone marrows was similar to that previously described from human peripheral blood. Of eight bone marrow samples from CML patients, five expressed values above 600 ng LTB4/10(8) nucleated cells, as compared to only one out of 10 controls. In contrast, the CML patients produced significantly lower amounts of both the double-dioxygenation product 5S,12S-DHETE (56.8 +/- 16.0 ng [mean +/- SE] versus 146.1 +/- 31.3 ng; p less than 0.05) and the monohydroxy acid 12-HETE (965 +/- 351 ng versus 4390 +/- 1801 ng; p less than 0.05), indicating a 12-lipoxygenase deficiency. The present results show that leukotrienes are formed by human bone marrow cells and further suggest the existence of altered lipoxygenase activity in CML.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1986

Leukotriene C4 binding sites in the rat central nervous system.

Binding sites for [3H]LTC4 were observed in crude membrane preparations of rat central nervous system tissue. Equilibrium binding studies indicated one high affinity [3H]LTC4 binding site with a KD of 31.4 +/- 3.4 nM for whole brain preparations. The binding was highly specific for [3H]LTC4 and could be inhibited by the SRS-A antagonist FPL 55172. Specific binding was increased with both mono- and di-valent ions. Regional distribution studies revealed a three-fold difference in binding capacity within different regions of the brain with the highest binding capacity in the brainstem (94.1 +/- 6.9 fmol/mg of protein) and the lowest in the hypothalamus (29.6 +/- 12.8 fmol/mg of protein). In addition, weak low capacity binding was observed for [3H]LTB4 and [3H]LTE4, while no saturable binding was observed for [3H]LTD4. The order of selectivity in inhibiting [3H]LTC4 binding was LTC4 much greater than LTD4 = LTE4 greater than LTB4.

Animals↗
PubMed1985

Opsonized bacteria stimulate leukotriene synthesis in human leukocytes.

Incubation of human leukocytes with opsonized bacteria led to leukotriene formation. The main products identified were leukotriene B4, 20-OH leukotriene B4 and 20-COOH leukotriene B4. A lesser amount of leukotriene C4 was formed. In contrast, only minor amounts of leukotrienes were formed by leukocytes challenged with uncoated bacteria. However, both opsonized and unopsonized bacteria stimulated the synthesis of 5S,12S-DHETE and 5S,12S,20-THETE. Opsonized bacteria caused a transient elevation of leukotriene B4 levels, with a maximum after 5 min. After 20 min of incubation the levels of 20-OH leukotriene B4, and 20-COOH leukotriene B4 were 7- and 20-times higher than those of leukotriene B4, showing that the leukocytes effectively degrade leukotriene B4 via omega-oxidation. In the light of the profound biological effects of leukotrienes, the present report indicates that leukotriene formation induced by opsonized bacteria might be important in the host defense against microorganisms.

Chromatography, High Pressure Liquid↗
PubMed1985

Different populations of rheumatoid adherent cells mediate activation versus suppression of T lymphocyte proliferation.

Adherent cells from synovial tissue of rheumatoid arthritis patients were fractionated on Percoll density gradients and analyzed to determine phenotypes, effects on allogeneic T lymphocyte proliferation, and production of prostaglandin E2 (PGE2). Cells expressing HLA-DR predominated in all fractions, and esterase-positive cells were enriched in light fractions. Heavy cells were potent stimulators in the mixed lymphocyte reaction and produced little PGE2, whereas light cells suppressed the mixed lymphocyte reaction and produced a large quantity of PGE2. These results suggest that macrophage-like synovial cells that suppress T helper lymphocyte activity are generated secondary to synovial lymphocyte activation in rheumatoid arthritis.

Arthritis, Rheumatoid↗