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W F Stenson

Publications and source records attributed to W F Stenson.

At least 73 records · Page 4Linked to original sources
PubMed1987

Chemotactic activity in inflammatory bowel disease. Role of leukotriene B4.

An important histologic feature of inflammatory bowel disease (IBD) is infiltration of the colonic mucosa with neutrophils. To investigate the nature of the chemotactic agents responsible for this infiltration, colonic mucosa from three normals and nine patients with inflammatory bowel disease (seven ulcerative colitis, two Crohn's colitis) was assayed for chemotactic activity for human neutrophils in vitro in a Boyden chamber. There was more (greater than 10-fold more) chemotactic activity in homogenates of inflammatory bowel disease mucosa than in homogenates of normal colonic mucosa. Analysis of the chemotactic activity in the inflammatory bowel disease mucosa revealed that most was lipid extractable. Moreover, when the lipid extract was fractionated by reverse-phase high-pressure liquid chromatography, the only fraction with significant chemotactic activity was the fraction that coeluted with leukotriene B4. The chemotactic response to IBD mucosa was blocked by anti-LTB4 antisera. The amount of chemotactic activity in lipid extracts of different inflammatory bowel disease specimens correlated well with the concentration of leukotriene B4 measured by UV absorbance (250 ng/g of mucosa). These data suggest that leukotriene B4 is an important stimulus to neutrophil chemotaxis in inflammatory bowel disease and, thus, may play a major role in the amplification of the inflammatory response in this condition.

Adult↗
PubMed1986

Tissue differences in vascular permeability induced by leukotriene B4 and prostaglandin E2 in the rat.

The activity of synthetic LTB4 and PGE2, in increasing vascular permeability was tested simultaneously in seventeen different organs in the rat. Rats were injected in the aortic arch through a cannula in the carotid artery with 125I-albumin, 51Cr-erythrocytes, and 57Co-EDTA. The rats were then injected through the carotid artery cannula with LTB4, PGE2 or a combination of LTB4 and PGE2. Eight minutes later the rats were killed and the activity of 125I, 51Cr, and 57Co measured in different organs. Changes in vascular permeability were inferred from changes in the ratios of the isotope activities. LTB4 (15 micrograms/kg) induced enhanced permeability in caecum, small bowel, skin, fat pad, stomach, pancreas, and aorta, but not in the heart, brain, colon, testes, diaphragm, forelimb, cremaster muscle, lung, kidney or eye. A lower dose of LTB4, 3 micrograms/kg, enhanced vascular permeability in caecum, small bowel, skin, stomach, and aorta. PGE2 (1 microgram/kg) enhanced vascular permeability only in the caecum. A combination of LTB4 (3 micrograms/kg) and PGE2 (1 microgram/kg) was more potent than either alone. Rats depleted of neutrophils with anti-neutrophil serum were less sensitive to LTB4 than intact rats. These findings suggest that the vasculatures of different tissues in the rat vary markedly in their susceptibility to LTB4 induced increases in permeability.

Animals↗
PubMed1986

Inhibition of cytotoxicity by sulfasalazine. I. Sulfasalazine inhibits spontaneous cell-mediated cytotoxicity by peripheral blood and intestinal mononuclear cells from control and inflammatory bowel disease patients.

We have studied the effects of sulfasalazine and its metabolites on cell-mediated cytotoxicity by peripheral blood and intestinal mononuclear cells from both control and inflammatory bowel disease (IBD) patients. Sulfasalazine and sulfapyridine, as well as hydrocortisone and nordihydroguaiaretic acid inhibited spontaneous cell-mediated cytotoxicity by control and IBD peripheral blood cells. Sulfasalazine and nordihydroguaiaretic acid inhibited spontaneous cell-mediated cytotoxicity by control and IBD intestinal mononuclear cells cultured for 72 h in media alone. In contrast, 5-aminosalicylate, indomethacin and benzylimidazole had no effect on cytotoxicity by any cell population. Lectin-induced, antibody-dependent and interleukin-2-induced cell-mediated cytotoxicity, as well as lymphokine-activated killing were not inhibited by the drugs: inhibitory effects in these assays were primarily upon the underlying spontaneous cell-mediated cytotoxicity. The inhibition induced by sulfasalazine, sulfapyridine and nordihydroguaiaretic acid could not be reversed by adding the lipoxygenase metabolites leukotriene B4 or 12-hydroxyeicosatetraenoic acid. These findings demonstrate that spontaneous cell-mediated cytotoxicity by control and IBD mononuclear cells can be inhibited by sulfasalazine.

Catechols↗
PubMed1986

Inhibition of cytotoxicity by sulfasalazine. II. Sulfasalazine and sulfapyridine inhibit different stages of the NK and NKCF lytic processes.

Sulfasalazine and sulfapyridine but not 5-aminosalicylate inhibit spontaneous cytotoxicity mediated by human natural killer (NK) cells. The aim of this study was to determine which stage(s) of the NK cytotoxic reaction is inhibited by these compounds. Effector/target cell binding studies performed in parallel with cytotoxicity assays using purified large granular lymphocytes indicated that inhibition is a post-binding event. The kinetic profile of inhibition in a calcium pulse assay showed that inhibition continues long after the effector cell triggering stage and that although sulfasalazine may have some inhibitory effect on the calcium-dependent events of the programming phase, sulfapyridine continues to inhibit during the calcium-independent or lethal hit phase of the cytotoxic sequence. The NK soluble cytotoxic factor (NKCF) assay was used as a measure of the lethal hit since the time course of this assay permits study of the various substages of this terminal event in the lytic sequence. Sulfasalazine and sulfapyridine but not 5-aminosalicylate inhibited NKCF-mediated target cell lysis. Different substages of the NKCF-induced lytic reaction were affected by these agents. Sulfasalazine appears to inhibit binding of NKCF to the target cell whereas sulfapyridine predominantly inhibits early post-binding events.

Aminosalicylic Acids↗
PubMed1985

Metabolism of arachidonic acid in acetic acid colitis in rats. Similarity to human inflammatory bowel disease.

We recently reported that human inflammatory bowel disease mucosa contains large amounts of leukotriene B4, a potent chemotactic agent formed from arachidonic acid through the lipoxygenase pathway. To more fully evaluate the role of arachidonic acid metabolites in the mediation of intestinal inflammation, we studied arachidonate metabolism in an animal model: acetic acid colitis in the rat. Incubation of acetic acid colitis mucosa with arachidonic acid resulted in the production of leukotriene B4 and a series of monohydroxy fatty acids, all products of the lipoxygenase pathway, plus much smaller amounts of cyclooxygenase products including prostaglandin E2. All of these metabolities were made in significantly greater quantities by mucosa from acetic acid-treated rats than by controls. The pattern of arachidonate metabolism in acetic acid colitis was strikingly similar to that in human inflammatory bowel disease. Moreover, the concentration of leukotriene B4 in acetic acid-treated mucosa was almost identical to that in human inflammatory bowel disease mucosa and was 50 times greater than that in normal rat colonic mucosa. These data indicate that lipoxygenase products, including leukotriene B4, may be important mediators of intestinal inflammation in a wide variety of inflammatory conditions. Moreover, the similarities in the metabolism of arachidonate by human inflammatory bowel disease and by acetic acid colitis may allow the use of this model, and perhaps other animal models of intestinal inflammation, in the screening of potential therapeutic agents for inflammatory bowel disease.

Acetates↗
PubMed1985

Studies of leukotriene B4-specific binding and function in rat polymorphonuclear leukocytes: absence of a chemotactic response.

Rat PMN isolated from peripheral blood show a small amount of high-affinity (specific) binding of [3H]-LTB4 at nanomolar concentrations. This binding is reversible and has a stereospecificity similar to rat PMN aggregation in response to several LTB4 analogs. This population of binding sites shares many characteristics with a population of high-affinity binding sites in human PMN; however, human PMN bind a significantly greater amount of [3H]-LTB4 to a second population of specific binding sites that is not present in rat PMN. The aggregation responses of human and rat peripheral blood PMN to LTB4 are similar in magnitude and specificity, but unlike human PMN, LTB4 fails to elicit a chemotactic response in rat PMN at concentrations from 10(-10) M to 10(-6) M. Rat PMN also fail to metabolize exogenous LTB4 when compared with human PMN. These data suggest that different PMN functions, such as chemotaxis and aggregation, may involve different classes of specific receptors. The finding that rat PMN do not exhibit chemotaxis to LTB4 calls for a reevaluation of the relevance to inflammation in humans of studies of inflammation performed in rat models.

Animals↗
PubMed1984

Leukotriene B formation by neutrophils from essential fatty acid-deficient rats.

Analysis of neutrophil phospholipids from rats fed an essential fatty acid-deficient diet revealed a 33% reduction in arachidonate and a 90% reduction in linoleate compared to neutrophil phospholipids of rats fed a normal diet. The neutrophil phospholipids from rats fed the essential fatty acid-deficient diet also contained significant amounts of 5,8,11-eicosatrienoate, a fatty acid not found in the neutrophils of rats fed a normal diet. Analysis of the production of leukotrienes of the B series by ionophore-stimulated neutrophils from rats fed an essential fatty acid-deficient diet revealed a 87% reduction in leukotriene B4 compared to neutrophils from rats fed a normal diet even though the arachidonate content was reduced by only 34%. Essential fatty acid-deficient neutrophils converted endogenous 5,8,11-eicosatrienoic acid to leukotriene A3 and its nonenzymatic degradation products, but little or no leukotriene B3 was formed. Neutrophils from rats fed a normal diet incubated with ionophore and exogenous 5,8,11-eicosatrienoate also produced leukotriene A3 and its nonenzymatic degradation products but little or no leukotriene B3. Exogenous 5,8,11-eicosatrienoate incubated with ionophore-stimulated normal neutrophils caused a dose-dependent inhibition of leukotriene A hydrolase resulting in diminished production of leukotriene B4 from endogenous arachidonate. Assays of leukotriene A hydrolase in the 10,000 X g supernatant fraction of a homogenate of RBL-1 cells revealed that a lipoxygenase metabolite of 5,8,11-eicosatrienoate rather than 5,8,11-eicosatrienoate itself is the inhibitor of leukotriene A hydrolase. Thus the finding that leukotriene B4 production by neutrophils from essential fatty acid-deficient rats is diminished out of proportion to the decrease in arachidonate content appears to be due to inhibition of leukotriene A hydrolase by a lipoxygenase metabolite.

8,11,14-Eicosatrienoic Acid↗
PubMed1984

Sulfasalazine inhibition of binding of N-formyl-methionyl-leucyl-phenylalanine (FMLP) to its receptor on human neutrophils.

Sulfasalazine, a drug useful in the therapy of inflammatory bowel disease, was found to block N-formyl-methionyl-leucyl-phenylalanine (FMLP)-induced arthritis in rabbits as well as FMLP-induced superoxide production and chemotaxis in human neutrophils in vitro. Sulfasalazine was also found to block FMLP binding to human neutrophils with an I50 of 10 microM. The dose-response curve for the inhibition of binding was very similar to the dose-response curves for the inhibition of FMLP-induced neutrophil activation.

Animals↗
PubMed1984

Quantitative assay for acute intestinal inflammation based on myeloperoxidase activity. Assessment of inflammation in rat and hamster models.

An assay was devised to quantitate acute intestinal inflammation based on the assessment of myeloperoxidase activity. Myeloperoxidase is an enzyme found in neutrophils and, in much smaller quantities, in monocytes and macrophages. Myeloperoxidase was solubilized with hexadecyltrimethylammonium bromide and myeloperoxidase activity was measured with a dianisidine-H2O2 assay. In neutrophil suspensions, myeloperoxidase activity was directly related to cell number down to as few as 500 cells. Myeloperoxidase activity was assayed in two animal models of inflammation: acetic acid-induced colitis in rats and Clostridium difficile enterotoxin-induced enteritis in hamsters. In both models, the activity of myeloperoxidase solubilized from the inflamed tissue was directly proportional to the number of neutrophils seen in histologic sections. Histologic evaluation of neutrophil accumulation was performed by counting the number of neutrophils in a histologic section 0.18 mm long and 5 micron thick. In both animal models, myeloperoxidase activity was linearly related to neutrophil number from 400 and 4000 cells/mm. Myeloperoxidase activity from chronically inflamed colon, in which both neutrophils and histiocytes were present, was directly related to neutrophil content. Histiocytes did not contribute significantly to myeloperoxidase activity. The determination of myeloperoxidase activity in the intestine is a simple biochemical assay that can be used to quantitate inflammation.

Acetates↗
PubMed1984

Leukotrienes.

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Anti-Inflammatory Agents↗
PubMed1984

Enhanced synthesis of leukotriene B4 by colonic mucosa in inflammatory bowel disease.

Leukotriene B4, an arachidonic acid metabolite, is a potent chemotactic agent, and is thought to be an important mediator of inflammation. To investigate the role of this compound as a mediator of inflammation in inflammatory bowel disease, arachidonic acid was incubated with ionophore and colonic mucosa from patients with inflammatory bowel disease and from normal subjects. Mucosa from patients with inflammatory bowel disease converted 2.17% of exogenous arachidonate to leukotriene B4; mucosa from normal subjects converted 0.37%. The production of leukotriene was blocked by sulfasalazine. To determine if inflammatory bowel mucosa contained endogenous leukotriene B4, lipid extracts were analyzed by high pressure liquid chromatography. Mucosa from patients with inflammatory bowel disease contained 254 ng of leukotriene B4 per gram and mucosa from normal subjects contained less than 5 ng of leukotriene B4 per gram. The presence of significant amounts of leukotriene B4 in colonic mucosa in patients with inflammatory bowel disease, combined with the known biologic effects of leukotriene B4, suggests that it may be an important mediator of inflammation in inflammatory bowel disease.

Adolescent↗
PubMed1983

Inhibition of platelet thromboxane synthetase by sulfasalazine.

Sulfasalazine is a potent antiinflammatory drug used in the treatment of ulcerative colitis. The mechanism of action of sulfasalazine is unknown but a recent study [W. F. Stenson and E. Lobos, J. clin. Invest. 69, 494 (1982)] demonstrated that sulfasalazine, at therapeutic concentrations, blocks human neutrophil lipoxygenase, suggesting that its antiinflammatory effects may be mediated in part by the inhibition of the synthesis of the chemotactic lipids 5-hydroxy-6,8,11, 14-eicosatetraenoic acid (5-HETE) and leukotriene B4 (LTB4). In the present study the effect of sulfasalazine on metabolism of exogenous arachidonic acid by human platelets was investigated. Sulfasalazine inhibited platelet thromboxane synthetase (IC50 = 0.9 mM) and partially inhibited cyclooxygenase. A methylated analog of sulfasalazine also inhibited thromboxane synthetase (IC50 = 0.3 mM) and partially inhibited cyclo-oxygenase. Neither of the cleavage products of sulfasalazine (5-aminosalicylate and sulfapyridine) inhibited thromboxane synthetase although 5-aminosalicylate blocked cyclooxygenase (IC50 = 5 mM). Neither sulfasalazine nor the methylated analog nor the cleavage products inhibited platelet lipoxygenase. This is in contrast to the inhibitory effects of sulfasalazine on neutrophil 5-lipoxygenase. The concentration of sulfasalazine in the colons of treated patients is several-fold greater than the IC50 for thromboxane synthetase.

Aminosalicylic Acids↗