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)

Cells dispersed from human foreskin were passively sensitized with IgE and then depleted or enriched in mast cells by density gradient centrifugation. Arachidonic acid metabolism was initially studied by radio-high-performance liquid chromatography analysis of incubation media from cells that had been prelabeled with [3H] arachidonic acid. In subsequent experiments with unlabeled cells the eicosanoids were quantified by radioimmunoassay. Prostaglandin (PG)D2 was the major cyclooxygenase product released from purified mast cells challenged with anti-IgE or A23187. In density gradient studies there was a significant correlation between PGD2 and histamine release (r = 0.52, p less than 0.01) and between PGD2 release and the numbers of mast cells (r = 0.42, p less than 0.02). There was no correlation with the total numbers of nucleated cells. Other cyclooxygenase products were also detected, the formation of 6-keto-PGF1 alpha and PGE2 being principally associated with gradient fractions containing endothelial cells. Leukotriene (LT)C4 was the major lipoxygenase product detected, reaching a maximum of 3.87 +/- 0.56 ng/10(6) mast cells upon activation with anti-IgE compared with 35.37 +/- 7.22 ng/10(6) mast cells of PGD2. When normalized to histamine release and expressed in molar terms, skin mast cells released approximately 20-fold more PGD2 than LTC4. Thus, the cutaneous mast cell is one likely source of the PGD2 and LTC4 released during cutaneous immediate hypersensitivity reactions.
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PMID:The IgE- and calcium-dependent release of eicosanoids and histamine from human purified cutaneous mast cells. 250 19

Human bronchial epithelial cells were isolated from macroscopically normal bronchi obtained from lobectomy specimens. Cells were grown in nutrient F12 medium, and after the third or fourth subculture they were stimulated with arachidonic acid, histamine, leukotrienes (LT) C4, D4, or E4, prostaglandin (PG) D2, anti-IgE, acetylcholine, bradykinin, or phorbol myristate acetate (PMA). Neither mast cell mediators (i.e., histamine, LTC4, LTD4, LTE4, or PGD2) nor anti-IgE stimulated the release of arachidonic acid metabolites from the epithelial cells. However, arachidonic acid, acetylcholine, bradykinin, and PMA stimulated the release of 15-hydroxyeicosatetraenoic acid (15-HETE) as major and prostaglandin E2 (PGE2) as minor products. The maximal release of 15-HETE and PGE2 occurred in 1 h with arachidonic acid stimulation and in 2 h with other stimuli. Arachidonic acid at 30 microM caused the release of 258 +/- 76 ng and 29 +/- 15 ng (n = 12) of 15-HETE and PGE2, respectively, from 10 x 10(6) epithelial cells, whereas acetylcholine, bradykinin, or PMA caused the release of approximately 2- to 10-fold less 15-HETE and PGE2. These results demonstrate that human bronchial epithelial cells selectively generate 15-HETE as the predominant arachidonic acid product and PGE2 as a minor metabolite. The role of bronchial epithelial cells and their mediators in the pathogenesis of bronchial hyperresponsiveness needs further study.
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PMID:Release of 15-hydroxyeicosatetraenoic acid (15-HETE) and prostaglandin E2 (PGE2) by cultured human bronchial epithelial cells. 251 53

The abundance of mast cells in human dermis, together with their ability to release a variety of vasoactive and pro-inflammatory mediators following cross-linkage of their cell-surface receptors for IgE, enables these cells to provide an effective defence mechanism within this organ. A similar defensive function is attributed to mast cells of other human organs such as intestine and lung which are in contact with the external environment and therefore susceptible to infiltration by foreign allergens and micro-organisms. However, mast cells of the skin apparently differ from those present in lung and intestine in being activated for histamine release by a variety of endogenous neuropeptides which stimulate the rapid release of histamine in the virtual absence of eicosanoids. This would provide a mechanism of neurogenic control of a variety of homeostatic functions such as blood flow, angiogenesis and fibroblast proliferation. Such processes would aid in the remodelling of tissue during wound healing, and increased numbers of mast cells have been noted around healing wounds of rat skin and areas of developing fibrosis. Neuropeptides modulate the activity of a variety of immuno-competent leucocytes including macrophages, monocytes and lymphocytes. The findings that skin mast cells are activated by neuropeptides suggest that these cells may also be included amongst those involved in neuro-immune interactions. Activation of skin mast cells by non-immunological stimuli may contribute to the aetiology of some forms of skin disease. Patients with chronic idiopathic urticaria appear to have enhanced vascular responsiveness to intradermal injections of the histamine liberator codeine suggesting that this disease may involve hyper-responsiveness of their mast cells to endogenous non-immunological stimuli. The findings of large increases in histamine accompanied by small increases in PGD2 in venous effluent of thermally challenged limbs of patients with cold- or heat-induced urticaria may suggest that their mast cells had been activated by a non-immunological stimulus. However, the interpretation of results gained using such relatively complex in-vivo systems are difficult, as the cellular origin of the detected mediators is by no means clear. However, it is hoped that in the future the alliance of newly developed in-vitro techniques to investigate mast cell function together with in-vivo methods to investigate their interaction with elements in their tissue environment will greatly increase our understanding of the role of the human skin mast cell in health and disease.
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PMID:The human skin mast cell. 266 2

A diagrammatic representation of the interactions between mediators of hypersensitivity and leukocytes in early, late-phase, and ongoing asthma is shown in Figure 1. Early phase or immediate reactions are largely the result of bronchoconstriction consequent to the release of mediators such as histamine, PGD2, LTC4/D4, and PAF. The principal mediator cell (MC) is the mast cell (although other IgE receptor-bearing cells such as the macrophage, eosinophil, and platelet might also be involved in this immediate response). The stimulus for mediator cell activation may be either immunologic (IgE-dependent) or nonimmunologic (i.e., changes in osmolarity as a result of the respiratory water loss associated with exercise-induced asthma). Late-phase reactions appear to be a consequence of infiltration with neutrophils (N), eosinophils (E), and macrophages (M phi). These cells are recruited and activated either by mast cell-associated chemotactic factors [such as LTB4, PAF, the eosinophil chemotactic factor of anaphylaxis (ECF-A), or high-molecular weight neutrophil chemotactic activity (NCA (HMW))] and/or "lymphokines" derived from T-helper cells (TH) which have been stimulated by antigen processed by the antigen-processing cells (APC). These mononuclear cell interactions are under the control of regulatory T cells [T suppressor (TS) cells] and it is speculated that the availability of these subsets may determine the magnitude of the late-phase response. Lymphokines and monokines which selectively activate neutrophils, eosinophils, and monocytes include LIF, EAF, and IFN-gamma, respectively. Macrophage-derived tumor necrosis factor (TNF) also amplifies the inflammatory response by its capacity to enhance eosinophil cytotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inflammatory cells in bronchial asthma. 270 38

In this study, we have investigated the contribution of cholinergic-mediated bronchoconstriction in the airway response provoked by inhaled prostaglandin (PG)D2, its metabolite 9 alpha, 11 beta-PGF2, and PGF2 alpha, which are generated during mast cell activation in vivo and are potent bronchoconstrictor agonists in humans. The effect of prior inhalation of 1 mg ipratropium bromide (IB) on the bronchoconstrictor response to inhaled methacholine (MCh), PGD2, 9 alpha, 11 beta-PGF2, and PGF2 alpha was determined in 7 allergic asthmatic subjects by measuring changes in SGaw, FEV1, and Vmax30. Methacholine, PGD2, and 9 alpha, 11 beta-PGF2 caused concentration-related bronchoconstriction with PGD2 and 9 alpha, 11 beta-PGF2 being between 45 and 112 times more potent than MCh (p less than 0.05), depending on the method used to measure airway caliber. Preinhalation of IB displaced the concentration response curves to MCh between 69- and 196-fold to the right, and this was significantly greater than that observed with PGD2 (12- to 23-fold, p less than 0.02) and 9 alpha, 11 beta-PGF2 (12- to 22-fold, p less than 0.02). Ipratropium bromide inhibited the bronchoconstriction achieved with the highest concentration of agonist by 73 to 91% with MCh, 46 to 79% with PGD2, and 32 to 38% with 9 alpha, 11 beta-PGF2. Ipratropium bromide did not affect the bronchoconstriction pattern to inhaled PGF2 alpha, irrespective of the nature of the response. We conclude that although PGD2 and 9 alpha, 11 beta-PGF2 are potent contractile agonists of human smooth muscle in vitro, bronchoconstriction observed with these mediators in vivo results from a combination of both direct and cholinergic-mediated mechanisms.
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PMID:Cholinergic-mediated bronchoconstriction induced by prostaglandin D2, its initial metabolite 9 alpha,11 beta-PGF2, and PGF2 alpha in asthma. 296 Feb 56

The functional and biochemical characterization of rat bone marrow derived mast cells (RBMMC) confirms both species-related differences between rat and mouse bone marrow-derived mast cells (MBMMC) as well as mast cell heterogeneity in a single species. Such RBMMC have the staining characteristics of mucosal mast cells and contain the mucosal mast cell protease. The RBMMC release the preformed granule mediator beta-hexosaminidase both in response to immunologic stimulation with 200 ng Ag (net release 15.8 +/- 3.8%) and in response to 1 microM calcium ionophore A23187 (net release 21.8 +/- 6.8%). However, compound 48/80, substance P, and somatostatin did not induce mast cell degranulation. In experiments with optimal beta-hexosaminidase release, the RBMMC generated similar quantities of the newly formed arachidonic acid metabolites leukotriene C4 and PGD2 when stimulated with either Ag or calcium ionophore A23187. The RBMMC incorporate [35S]sulfate into proteoglycans consisting of 90% chondroitin sulfates and 10% heparin. The chondroitin sulfates were comprised of chondroitin 4 sulfate and chondroitin sulfate diB sulfated disaccharides in a ratio of 4/1. Although we show that RBMMC and MBMMC share a low histamine content, functional IgE receptors and unresponsiveness to cromolyn and selective secretagogues (compound 48/80, substance P, and somatostatin), we also provide evidence that RBMMC differ from MBMMC in their profile of newly generated mediators, preformed granule proteoglycan, and lack of proliferative response to mouse IL-3.
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PMID:Functional and biochemical characterization of rat bone marrow derived mast cells. 297 57

It is now recognized that, in addition to the preformed mast cell granule mediators, newly generated lipid compounds are likely to be exceedingly important in the mediation of allergic asthma and other atopic diseases. That the initiating event in allergic diseases evokes a far more complex set of biochemical events than those that only lead directly to the release of histamine and other preformed mediators, and that the functional efficacies of the leukotrienes, PGD2, and PAF are significant for allergic pathobiology mandate that the latter compounds will necessarily be subject to efforts for future therapeutic intervention in allergic patient populations.
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PMID:Leukotrienes and other lipid mediators of asthma. 298 Oct 59

A diagrammatic representation of the interactions between mediators of hypersensitivity and leucocytes in early-, late-phase, and ongoing asthma is shown in Fig. 1. Early-phase or immediate reactions are largely the result of bronchoconstriction consequent to the release of mediators such as histamine, PGD2, LTC4/D4 and PAF. The principal mediator cell (MC) is the mast cell (although other IgE receptor-bearing cells such as the macrophage, eosinophil and platelet might also be involved in this immediate response). The stimulus for mediator cell activation may be either immunologic (IgE-dependent) or non-immunologic (i.e. changes in osmolarity as a result of the respiratory water loss associated with exercise-induced asthma). Late-phase reactions appear to be a consequence of infiltration with neutrophils (N), eosinophils (E) and macrophages (MO). These cells are recruited and activated either by mast cell-associated chemotactic factors [such as LTB4, PAF, the eosinophil chemotactic factor of anaphylaxis (ECF-A) or high molecular weight neutrophil chemotactic activity (NCA (HMW]] and/or "lymphokines" derived from T helper cells (TH) which have been stimulated by antigen processed by the antigen processing cells (APC). These mononuclear cell interactions are under the control of regulatory T cells [T suppressor (TS) cells] and it is speculated that the availability of these subsets may determine the magnitude of the late-phase response. Lymphokines and monokines which selectively activate neutrophils, eosinophils and monocytes include LIF, EAF and INF-gamma respectively. Macrophage-derived tumour necrosis factor (TNF) also amplifies the inflammatory response by its capacity to enhance eosinophil cytotoxicity. Eosinophil-derived agents such as PAF, LTC4, MBP and ECP might be responsible for submucosal oedema and non-specific bronchial hyperreactivity which are characteristic features of late-phase reactions. T cell-derived lymphokines such as EDF (IL-5), together with GM-CSF, might lead to eosinophilopoiesis and account for the prolonged eosinophilia of ongoing chronic asthma. The T cell is prominent in the pathology of chronic asthma and is possibly "chronically activated". Thus lymphocytes, driven by as yet undetermined "antigens" (possibly viral), may perpetuate the inflammatory response in and around the bronchi. IL-5-like products from these putative activated lymphocytes might perpetuate (a) eosinophil production by the bone marrow, (b) its release into the circulation, (c) its migration into bronchial tissue and (d) activation to release PAF, LTC4, MBP, etc.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Leucocytes in asthma. 306 26

The effects of antiinflammatory steroids on arachidonic acid metabolite release from human lung fragments were analyzed. Incubation of lung fragments for 24 hr with 10(-6) M dexamethasone inhibited the net release of the prostacyclin metabolite 6-keto-PGF1 alpha, PGE2, and PGF2 alpha from lung fragments stimulated with anti-IgE but failed to inhibit the anti-IgE-induced release of PGD2, TXB2, and iLTC4. The IC50 of dexamethasone for inhibition of both spontaneous and anti-IgE-induced 6-keto-PGF1 alpha release was approximately 2 X 10(-8) M, and a 6-hr preincubation with the drug was required for 50% inhibition of prostaglandin release. Other agents were tested for activity in stimulating arachidonic acid metabolite release from human lung fragments. FMLP (fmet-leu-phe) stimulated the release of all metabolites tested (6-keto-PGF1 alpha, PGD2, PGE2, PGF2 alpha, TXB2, iLTC4); platelet-activating factor (PAF), but not lysoPAF, stimulated the release of PGD2, TXB2, and iLTC4. In contrast to the case with anti-IgE, where dexamethasone failed to inhibit net PGD2 and TXB2 release, the steroid inhibited the release of these metabolites stimulated by both FMLP and PAF. The steroid inhibited iLTC4 release induced by the highest concentration of PAF (10(-6)M) but did not inhibit iLTC4 release stimulated by either 10(-7) M PAF, FMLP, or anti-IgE. Because neither FMLP nor PAF caused the release of PGD2 or TXB2 from purified human lung mast cells, and because they also failed to induce histamine release from lung fragments, it is suggested that these stimuli produce PGD2 and TXB2 release in lung fragments through an action on a cell distinct from the mast cell. This suggestion is supported by the selective inhibition of the release of these arachidonic acid metabolites by dexamethasone. We suggest that the inhibitory action of steroids on arachidonic acid metabolite in human lung fragments contributes to their therapeutic efficacy in pulmonary diseases.
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PMID:Selective inhibition of arachidonic acid metabolite release from human lung tissue by antiinflammatory steroids. 308 76

In order to assess the role of arachidonic acid metabolites in the early reaction to antigen, we challenged six allergic individuals with and without premedication with aspirin and recorded their clinical response, as indicated by number of sneezes, and measured the levels of inflammatory mediators. The early reaction to antigen was associated with increases in the levels of histamine, N-alpha-tosyl-L-arginine methyl esterase (TAME-esterase) activity, prostaglandin (PG) D2, leukotriene C4, PGE, and thromboxane. Aspirin significantly inhibited the increases in the cyclooxygenase metabolites PGE, PGD2, PGF2 alpha, 6-keto-PGF1 alpha, and thromboxane but did not affect the amount of sneezing or the levels of histamine, TAME-esterase activity, or leukotrienes. The pattern of the metabolites and their response to pretreatment with aspirin parallel the response of purified human lung mast cells, supporting the notion that the early phase of allergic rhinitis is a mast cell-dominated event.
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PMID:Arachidonic acid metabolites during nasal challenge. 309 12


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