Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Indomethacin was administered subcutaneously to rats, 4 mg/kg/day for 4 consecutive days in order to produce erosions of the small intestine which were scored at necropsy on day 5. Orally administered phenidone (up to 250 mg/kg/day), a mixed cycloocygenase-lipoxygenase inhibitor, failed to produce intestinal erosions, but tended to exacerbate indomethacin-induced erosions. A 5-LO inhibitor, diphenyldisulfide, provided significant protection at 10-100 mg/kg when given orally to indomethacin-treated rats. Sulfasalazine, auranofin and cyproheptadine, but not cimetidine, also protected, suggesting a role for mast cell activation and leukotriene generation in indomethacin-induced ulcerogenesis.
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PMID:Diphenyldisulfide inhibits indomethacin-induced ulcerogenesis in rats. 368 86

A neoplastic mast cell tumor was grown in mice which had been raised since birth on a diet enriched with eicosapentaenoic acid. Intact harvested mastocytoma cells were stimulated with calcium ionophore A23187 to produce lipoxygenase products from the polyunsaturated fatty acids liberated from the cellular membranes. Leukotriene B4, B5, C4, and C5 were isolated and characterized by HPLC retention time, ultraviolet absorption spectrometry and mass spectrometry. The arachidonic acid content of the mast cell tumor lipids was altered from 9.2 to 3.9 mole % while eicosapentaenoic acid increased from 0.5 to 4.5 mole % in response to the fish oil-supplemented diet. The relative amounts of arachidonic and eicosapentaenoic acids (3.9 and 4.5 mole % respectively) were associated with similar amounts of LTB4 and LTB5 synthesized by the cells. These results suggest that the epoxide leukotriene (LIA) derivative can be made efficiently from either arachidonic or eicosapentaenoic acids when both are present in cellular lipids. In contrast, the ratio of LTC4 to LTC5 (10 to 1) indicates that the reaction of LTA with glutathione may be critically dependent upon the structure of the unsaturated fatty acid with the ratio of LTC4/LTB4 (2.0) more than 10 times greater than that (0.16) for LTC5/LTB5.
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PMID:Tetraene and pentaene leukotrienes: selective production from murine mastocytoma cells after dietary manipulation. 611 40

The immediate-type, IgE-mediated rhesus monkey model of asthma due to aerosol challenge with ascaris has been developed to the status of an analytic system for agents capable of inhibiting the antigen-induced airway response. Two antigen-challenge systems have been developed. The standard ascaris challenge uses a dose of antigen that will induce an airway response in all reactive animals. In the threshold antigen-challenge system, the threshold dose of antigen that will induce an airway response is determined and is relatively constant for the individual animal. Both of these types of response were inhibited by 5,8,11,14-eicosatetraynoic acid (ETYA). This action may be through the inhibition of the lipoxygenase and cyclooxygenase metabolic pathways of arachidonic acid and possibly through inhibition of production of slow-reacting substance. ETYA also inhibits cutaneous immediate-type reactivity to ascaris antigen in a dose-response relationship. This may be the result of inhibition of mast cell histamine release or the inhibition of production of other vasoactive mediators. An alternative explanation for the action of ETYA in the airway and skin responses is that ETYA may act as an end-organ antagonist to released bioactive mediators. ETYA is the first agent, other than beta agonists or cromolyn, that we have been able to demonstrate as clearly having an inhibitory action on the rhesus monkey model of asthma.
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PMID:Inhibition of immunoglobulin E-mediated, antigen-induced monkey asthma and skin reactions by 5, 8, 11, 14-eicosatetraynoic acid. 616 Nov 46

Recent studies indicate that both arachidonic acid (AA) metabolism and phospholipid (PL) metabolism are markedly stimulated during the release of mediators from mast cells. The relationship between stimulated AA metabolism and stimulated PL metabolism in isolated rat mast cells was investigated and then correlated with the secretory process. ETYA (5,8,11,14-eicosatetraynoic acid, a known inhibitor of cyclooxygenase and lipoxygenase pathways of AA metabolism) inhibited 32PO4 incorporation into phosphatidic acid (PA), phosphatidylinositol (PI), and phoshodidylcholine (PC) in both unstimulated mast cells and mast cells stimulated by cross-linking of surface IgE molecules. ID50 values for inhibition of mediator release and of basal and stimulated 32PO4 incorporation into PL were 50 to 60 microM ETYA. Indomethacin (1 to 10 microM) and aspirin (10 to 100 microM) had no significant effect on 32PO4 incorporation or on mediator release. AA (10 microM) inhibited PL labeling in resting mast cells and rendered the cells less responsive to secretory signals. Preincubation of the cells with indomethacin (1 microM) blocked both of these AA effects. When AA was added to stimulated mast cells, however, both PL labeling and mediator release were enhanced. Thus, each of the alterations in AA metabolism caused parallel changes in mast cell PL metabolism and in mediator release. Since both basal and stimulated PL metabolism were modified by ETYA and AA, some form of direct regulation of mast cell PL metabolism by AA metabolites seems likely. The close parallelism of effects on mediator release and on PL metabolism suggests that modulation of mast cell function by AA metabolites may be mediated at lest in part by effects on lipid metabolism.
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PMID:Lipid metabolism during mediator release from mast cells: studies of the role of arachidonic acid metabolism in the control of phospholipid metabolism. 616 27

The lipoxygenase inhibitors HTYA (5,8,11,14-henicosatetraynoic acid, 25-150 microM) and ITYA (4,7,10,13-icosatetraynoic acid, 25-75 microM), inhibited histamine secretion from rat mast cells evoked by concanavalin A but that elicited by compound 48/80 or polymyxin B. Arachidonic acid (100 microM) did not inhibit concanavalin A-induced histamine secretion. The results are consistent with the notion that lipoxygenase inhibitors affect an early stage of stimulus-secretion coupling in the mast cell, peculiar to antibody-directed secretagogues, perhaps that involving calcium influx.
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PMID:Lipoxygenase inhibitors exert secretagogue-specific effects on mast cell exocytosis. 617 11

Purified mature rat peritoneal mast cells, on exposure to zymosan or latex beads, phagocytize these particles, although less efficiently than macrophages. During phagocytosis, histamine, beta-glucuronidase, and eosinophil chemotactic factor are released from mast cells in a time-, temperature- and dose-dependent fashion. Complement components, cytochalasin B (5 microgram/ml), and indomethacin (10-6M), enhanced mediator release, whereas compound BW 755C (20 microgram/ml), a cyclooxygenase and lipoxygenase inhibitor of arachidonate metabolism, totally abolished this process. Phagocytosis of mast cell thus activates intracellular mechanisms that closely resemble those observed with other phagocytic cells. These observations add a new perspective to the role of mast cells in inflammatory events.
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PMID:Release of mediators from purified rat mast cells during phagocytosis. 618 56

Arachidonic acid metabolism has been explored in preparations of purified human lung mast cells prelabeled with arachidonic acid (AA). Cells were of 83 to greater than 96% purity, and each experiment was performed with four to six different preparations of mast cells. After overnight culture of the purified cells in the presence of 3H-AA, followed by extensive washing in buffer, mast cell uptake of labeled AA was 61.4 +/- 14.8 pmol/10(6) cells with 21 +/- 2.4% of the label in phospholipids, 73 +/- 2.1% in neutral lipids, and 3.6 +/- 0.8% as free AA. Analysis of the distribution of radioactivity in phospholipid classes revealed 51.4 +/- 5.5% of the label in phosphatidylcholine, 14.5 +/- 1.6% in phosphatidylinositol, 12.0 +/- 3.0% in phosphatidylethanolamine, and 9.1 +/- 2.4% in sphingomyelin, with the rest in other phospholipid classes. Challenge of these cells with an optimal concentration of anti-IgE led to the release of 20 +/- 4.0% of cellular histamine and to a reduction in labeled phosphatidylcholine and phosphatidylinositol to 75.5 +/- 8.8% and 84.2 +/- 4.5% of the control levels, respectively, (p less than 0.05); anti-IgE challenge produced no statistically significant change in the quantities of other labeled phospholipids. Activation of human lung mast cells with anti-IgE led to the release of 3.4 +/- 1.3% of the cellular 3H as AA and AA metabolites (1.5 +/- 0.6% as unmetabolized AA) in conjunction with 16 +/- 4.3% of the cellular histamine. Although activation of human lung mast cells with ionophore A23187 caused 70 +/- 1.1% histamine release, a similar quantity of AA and AA metabolites was released (a total of 4.0 +/- 0.8% with 2.3 +/- 1.5% as unmetabolized AA). Analysis of the released metabolites by liquid scintillation spectrometry after high performance liquid chromatography separation showed that approximately equal amounts of metabolites were produced after mast cell activation with anti-IgE and ionophore A23187. In this series of experiments approximately equal amounts of cyclooxygenase and lipoxygenase products were generated.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Arachidonic acid metabolism in purified human lung mast cells. 619 20

The effect of arachidonic acid (AA) metabolism on histamine release and SRS (leukotrienes) production has been studied in guinea-pig lung using anaphylactic reaction and Ca2+ ionophore as the triggering agents in vitro. AA and L-cysteine enhanced SRS production without any appreciable effect on histamine release. Two nonsteroid anti-inflammatory agents, indomethacin and ketoprofen, which block prostaglandin production by the cyclooxygenase pathway, stimulated SRS production but had hardly any effect on histamine release, indicating that SRS synthesis is more sensitive to prostaglandin regulation. Enhancement of SRS production was more pronounced for antigen than for Ca2+ ionophore. This might be related to different cellular origin of SRS with the two triggering agents. Using rat peritoneal cells, both mast cells and the other cells were found to produce SRS in response to Ca2+ ionophore, the amount formed by the latter type of cells being higher. Inhibition of lipoxygenase by 5,8,11,14-eicosatetraynoic acid and nordihydroguaiaretic acid depressed SRS production, but had no effect on histamine release. SRS production triggered by Ca2+ ionophore was more sensitive, possibly because of different cellular origin of SRS in response to the two stimuli. The explanation for the discrepancy between the effect on SRS production and histamine release may also have to be sought in their different origins. SRS may mainly stem from cells, which are more sensitive to the inhibitors than the mast cell, which is the source of histamine.
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PMID:Effect of arachidonic acid metabolism on the release of histamine and SRS (leukotrienes) from guinea-pig lung. 620 64

We have studied the ability of leukotrienes and other lipoxygenase products of arachidonic acid (AA) to influence complement-dependent killing of schistosomula of Schistosoma mansoni in vitro by human neutrophils or eosinophils. These lipid mediators, which included LTB4, LTC4, LTD4, 5-HETE and 5-HPETE, had no apparent effect, by themselves, on schistosomular motility or viability. However, in the presence of granulocytes and fresh serum (as a source of complement) LTB4 (but not LTC4, LTD4, 5-HETE or 5-HPETE) enhanced neutrophil- and (to a much lesser extent) eosinophil mediated, complement-dependent killing. These effects varied with the concentration of LTB4, the dilution of complement and time of incubation. The percentage of LTB4-induced enhancement obtained with neutrophils was greater than that observed with eosinophils (although the latter were obtained from patients with helminthic parasitic disease). The synthetic bacterial analogue f-Met-Leu-Phe, also known to amplify complement associated granulocyte events, was comparable to LTB4 in its ability to enhance neutrophil- and eosinophil-mediated, complement-dependent killing of schistosomula. These results indicate that LTB4, which is released in mast cell associated reactions and promotes cell locomotion and enhancement of complement receptors in vitro, increases neutrophil- and eosinophil-mediated, complement-dependent damage of schistosomula, possibly through enhancement of C3b receptors and that this may be an important amplification mechanism in IgE related immunity to migrating helminthic larvae.
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PMID:Enhancement of neutrophil- and eosinophil-mediated complement-dependent killing of schistosomula of Schistosoma mansoni in vitro by leukotriene B4. 630 58

The events which lead to airway narrowing in bronchial asthma are complex. There is little doubt that mast cell-derived pharmacological agents are involved, at least in part, in the initiation of the asthmatic response. However, the inflammatory response which follows mast cell activation might have more relevance to the daily pattern of asthma than the direct effects of mediators on bronchial tissue. Although the IgE mediated release of mediators from sensitized mast cells seems to play a role in pathogenesis in some individuals for some of the time, there is now increasing awareness that mast cells are also triggered by a number of non-immunological stimuli such as exercise/cold air, infection and agents which activate the complement system. Mast cell mediators are either pre-formed within granules or generated from membrane-bound phospholipids. The pre-formed mediators include histamine, various chemotactic peptides including ECF-A and the high molecular weight neutrophil chemotactic factor (NCF), proteases, glycosidases, and the heparin proteoglycan. The membrane-derived agents include the lipoxygenase products (e.g. LTB4 and the "SRS-A" leukotrienes-LTC4/D4/E4), prostaglandins and thromboxane in addition to the PAF-ace-tether (AGEPC). The mediators are diverse both in chemical composition and modes of actions. However, many of the pathological features of bronchial asthma can be explained on the basis of their recognised actions. These can be summarised as follows. Bronchial smooth muscle constriction (histamine, LTC4, LTD4, LTE4, PGF2 alfa, PGD2 and PAF); mucosal oedema (increased permeability--histamine, LTC4, LTD4 and PAF; vasodilation--PGD2, PGE2); mucous plugging (histamine, mono-HETEs and LTC4); inflammatory cell infiltrate (NCF, ECF-A peptides, HETEs, LTB4 and PAF); desquamation of epithelium (proteases, glycosidases, together with lysosomal enzymes, and basic proteins derived from neutrophils and eosinophils). It is likely that mild, easily reversible, episodic asthma is due largely to bronchial smooth muscle contraction whereas the late sustained response is more indicative of an inflammatory response, and dependent on the infiltration of neutrophils and eosinophils as the result of mediators which recruit and activate leucocytes. Much of the evidence for this is based on the demonstration that NCF concentrations in the serum are elevated during early and late phase, antigen- and exercise-induced asthma. Moderate to severe asthma is likely to be largely dependent on a subacute/chronic inflammation of the bronchi with eosinophils and mononuclear cells being prominent.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mediators of hypersensitivity and inflammatory cells in the pathogenesis of bronchial asthma. 641 59


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