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)

Airway damage secondary to eosinophil activation is thought to contribute to the development of asthma. Using the fluorescent dye FURA-2 to measure the concentration of cytosolic calcium, we found that supernatants from anti-IgE-stimulated human lung mast cells increased cytosolic calcium in human eosinophils. We then examined the major mast cell mediators (histamine, PGD2, platelet-activating factor (PAF), eosinophil chemotactic factor of anaphylaxis (ECF-A), leukotriene (LT)C4 and LTB4) for their ability to increase cytosolic calcium in eosinophils. We found that both PAF (5 x 10(-9) to 5 x 10(-6) M) and PGD2 (two of five donors responsive at 1 x 10(-9) M) were potent stimuli for calcium mobilization. LTB4 (10(-8), 10(-7) M) and histamine were also active, although higher concentrations of histamine were required to see a response (3 x 10(-7) to 10(-5) M). LTC4, val-ECF-A, and ala-ECF-A were inactive. The effects of PGD2 and histamine were specific for eosinophils, although LTB4 and PAF increased calcium in both neutrophils and eosinophils. The histamine-induced increase in intracellular calcium was not blocked by the H1 or H2 antagonists pyrilamine or cimetidine (10(-4) M), respectively; however, the response to 10(-6) M histamine was completely blocked by the specific H3 antagonist thioperamide (10(-6) M). To evaluate the relative contribution of these stimulatory mast cell mediators on the calcium mobilizing activity in supernatants from anti-IgE-stimulated human lung mast cell (HLMC), we examined the effect of supernatants from HLMC pretreated with indomethacin and/or the 5-lipoxygenase pathway inhibitor MK886. These supernatants were added to FURA-2-loaded eosinophils that had been preincubated with thioperamide and/or the PAF antagonist WEB-2086. We found that the increase in eosinophil calcium in response to supernatants from anti-IgE-stimulated-HLMC was totally inhibited only when the mast cells were challenged in the presence of indomethacin and MK886, and the eosinophils were preincubated with thioperamide. WEB-2086 had little effect. When we examined the effect of these mediators on eosinophil secretory function, we found that PGD2 (not histamine) primed eosinophils for enhanced release of LTC4 in response to the calcium ionophore A23187. We conclude that the activation of eosinophils by PGD2 and other mast cell products may contribute to airways inflammation that is characteristic of asthma.
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PMID:Mast cell mediators prostaglandin-D2 and histamine activate human eosinophils. 158 43

The atopic diseases--allergic rhinitis, asthma, and atopic dermatitis--are chronic inflammatory diseases characterized by an exacerbating and remitting course and can only rarely be associated causally with allergen exposure. The challenge to ascribe an allergic basis to these diseases is derived from the apparent inability to reconcile these chronic inflammatory features with a process thought to be initiated by the rapid release of mediators after the interaction of allergen with IgE-coated mast cells. The traditional understanding has been that mast cell activation results in the release of a series of preformed and rapidly synthesized substances that mediate the immediate onset of vasodilatation, vascular leakage, smooth muscle contraction, and irritant nerve receptor stimulation. These mediators, however, are rapidly degraded and are not thought to be associated with a significant inflammatory component. Recent studies, however, have established that the interaction of allergen with the immune system is, in fact, far more complex (Fig. 4). In addition to mast cell activation, allergen can interact with and activate T-lymphocytes and mononuclear phagocytic cells, leading to the secretion of cytokines and other inflammatory substances. Furthermore, the interaction of allergen with the mast cell may be far more complex, with the potential to stimulate the delayed release of newly synthesized cytokines. The interaction of allergen with the immune system also promotes the secondary release of inflammatory neuropeptides. Thus, the known spectrum of mediators released after allergen exposure has vastly been expanded. These include numerous still uncharacterized chemotactic and activating peptides; eicosanoids such as 5-HETE, 12-HETE, and leukotriene B4; platelet-activating factor; several proteases; neuropeptides and, most importantly, the cytokines. These mediators recruit and activate neutrophils, monocytes, basophils, and eosinophils, attract additional lymphocytes and mononuclear phagocytic cells, and induce mast cell proliferation with further mast cell degranulation. A vicious cycle subsequently develops, with further inflammation and tissue destruction. Thus, the interaction of allergen with the immune system has become a complex cascade capable of producing the chronic inflammatory changes characteristic of allergic diseases.
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PMID:Inflammation and the allergic response. 161 34

Asthma is characterised by bronchial hyperresponsiveness. This feature of the asthmatic diathesis predisposes patients to wheezing in response to a number of different factors. These precipitating factors include specific allergen acting via sensitised mediator cells through an IgE-dependent mechanism. There are irritants which may work through a non-specific manner, or stimuli such as exercise and hyperventilation, which probably also act through mediator release via a non-IgE-dependent manner. The mechanism whereby physical stimuli such as exercise induce bronchoconstriction is of interest, because it increases the context in which the mast cell may participate in acute asthmatic bronchoconstriction. Respiratory infections also commonly provoke asthma, especially in infants and may, indeed, precipitate the asthmatic state itself. Finally, drugs can often trigger asthma attacks and the mechanisms of asthma precipitated by non-steroidal anti-inflammatory drugs such as aspirin have been the subject of recent research.
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PMID:Precipitating factors of asthma. 161 89

The mast cell's association with asthma has a long history dating back to the turn of the century, when Dale and Laidlaw described histamine as a spasmogen for guinea-pig airways and a proposed mediator of acute anaphylaxis. Almost half a century elapsed before histamine was localised to the granules of mast cells, although the release of this and other mediators of the acute allergic reaction were known to involve reagin subsequently identified as IgE. The biochemical mechanisms involved in transduction signalling not only results in the calcium and energy-dependent release of preformed mediators by degranulation but also the generation and subsequent release of an array of newly formed products, many of which are derived from phospholipid precursors.
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PMID:Asthma. The mast cell. 161 93

A cross-sectional investigation for allergology was performed of 15 painters exposed to high concentrations of toluene diisocyanate (TDI) (0.07-0.17 ppm) during the process of handling polyurethane varnish in a furniture manufacturing factory. Asthmatic reactions such as dyspnea, wheezing related to workshifts and contact dermatitis were observed in four and three cases respectively by questionnaire survey. Lung function tests on the painters showed significant decline in FEV1, %FEV1 and MMF compared to the referents. An increment in mast cell degranulation percentage could be seen in the painters. And also, patch testing with TDI were positive in five cases. From the results, it was suggested that both allergic pulmonary effects and contact sensitization had occurred in TDI-exposed painters in this factory.
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PMID:Allergologic evaluation for workers exposed to toluene diisocyanate. 166 72

Subcutaneous immunotherapy (SI) was administered to 148 patients (76 males, 72 females; aged 6-48 years) with allergic asthma to house dust and mites (D. pteronyssinus). Skin tests were positive to both allergens. Treatment was performed with allergenic extracts of house dust (61 patients) and allergenic extracts to house dust mites (87 patients) over a period of at least one year (mean 2.8 years). The selection criteria were: past history (including positive natural provocation test), intense skin response to mite extracts (> 10 mm) and favorable response to therapy with disodium cromoglycate and/or ketotifen. None of the patients selected presented long-lasting infections or other complications in the evolution of asthma. During treatment it was necessary in 46% of the patients to add other drugs such as mast cell degranulators or corticosteroid products over short periods when occasional cases of respiratory infections occurred. Favorable results were obtained in 86% of the cases, with the best results being obtained in patients who exactly fulfilled the selection criteria and in whom SI was administered over a period of at least 3 years.
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PMID:Clinical study on value and limitations of subcutaneous immunotherapy (specific hyposensitization) in allergic asthma to house dust mite, based on a personal algorithm of selection. 166 71

Over the past ten years there have been considerable advances in our understanding of the pathogenesis of asthma. This understanding has been accompanied by the introduction and increased usage of a whole range of new therapies for the treatment of asthma. Unfortunately he increased understanding and available therapy has done very little to prevent asthma from being considered the only 'preventable' disease whose morbidity and mortality are still on the increase in most parts of the world. Why does this paradox occur? I will try to put forward a plausible scientific explanation for this paradox. I fell that this is to be found in a long recognised but little publicised pharmacological effect of beta 2 agonists, a widely prescribed drug class in the treatment of bronchial asthma, that is the ability of these drugs to inhibit mast cell degranulation. Through this mechanism beta 2 agonists may be inhibiting a natural anti-inflammatory mechanism mediated by mast cell products and thus be contributing to the worldwide increase in asthma morbidity and mortality.
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PMID:Are mast cells all bad? 168 62

Subjects with asthma demonstrate hyperresponsive airways to histamine and require only small quantities of this mediator to demonstrate changes in their pulmonary functions. The discovery of drugs that could compete with and antagonize the target-tissue effects of histamine has provided a method of testing whether histamine contributes as a mediator of asthma. Now, there are potent and selective anti-H, drugs which are relatively non sedating. Some of them inhibit the bronchoconstrictions induced either by allergen or exercise (e.g. terfenadine, astemizole, azelastine); some others, moreover, inhibit mast cell degranulation (e.g. azelastine). Finally, some others (e.g. cetirizine, ketotifen) display some inhibitory actions on eosinophil functions, an important cell in allergic cellular recruitment and inflammation. Some studies with H1 antihistamines in asthma have demonstrated some therapeutic benefits. However, additional carefully controlled studies are required to confirm their efficacy in asthma.
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PMID:Antihistamines and allergic asthma. 168 22

In order to assess the role of mast cell-derived mediators in the pathogenesis of exercise-induced asthma (EIA), we completed pre- and postexercise bronchoalveolar lavage (BAL) in seven atopic subjects with EIA. The study subjects were defined as having EIA if they exhibited a greater than 15% decrease in FEV1 after completing 6 min of treadmill exercise. There were no significant differences between mean preexercise and mean postexercise mast cell-derived BAL histamine (186 +/- 67 versus 148 +/- 36 pg/ml), tryptase (4.5 +/- 2.0 versus 2.8 +/- 2.0 ng/ml), prostaglandin D2 (26 +/- 11 versus 32 +/- 25 pg/ml), or leukotriene C4 (less than 100 versus less than 100 pg/ml). In addition, mast cells present in BAL fluid after exercise contained similar amounts of cellular histamine compared with BAL mast cells obtained before exercise (preexercise BAL cellular histamine, 26.6 +/- 12.3 ng/10(6) BAL cells; postexercise BAL cellular histamine, 22.7 +/- 9.1 ng/10(6) BAL cells), indicating that depletion of preformed mast cell mediators are unlikely to account for the refractory period in EIA. This study suggests that the cellular pathogenesis of EIA (mast cell-independent) differs from current theories of the pathogenesis of extrinsic allergen-induced asthma (mast cell-dependent).
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PMID:Airway levels of mast cell-derived mediators in exercise-induced asthma. 168 74

Several lines of evidence suggest a possible role for mast cell proteases in modulating the biologic effects of neuropeptides. To explore the potential of such interactions in human airway, we examined the activity of human tryptase, the major secretory protease of human lung mast cells, against several neuropeptides with proposed regulatory functions in human airway. Using highly purified tryptase obtained from extracts of human lung, we determined the sites and rats of hydrolysis of vasoactive intestinal peptide (VIP), peptide histidine-methionine (PHM), calcitonin gene-related peptide (CGRP), and the tachykinins substance P (SP), neurokinin A (NKA), and neurokinin B (NKB). Tryptase hydrolyzes VIP rapidly at several sites (Arg12, Arg14, Lys20, and Lys21) with an overall kcat/Km of 1.5 x 10(5) M-1 s-1 and hydrolyzes PHM primarily at a single site (Lys20) with a kcat/Km of 1.9 x 10(4) M-1 s-1. Tryptase also rapidly hydrolyzes CGRP at two sites (Arg18 and Lys24) with a kcat/Km of 2.7 x 10(5) M-1 s-1. The tachykinins are not hydrolyzed by tryptase. These observations raise the possibility that tryptase-mediated degradation of the bronchodilators VIP and PHM combined with exaggerated mast cell release of tryptase may contribute to the increase in bronchial responsiveness and the decrease in immunoreactive VIP in airway nerves associated with asthma. The favorable rates of hydrolysis of CGRP suggest that tryptase may also terminate the effects of CGRP on bronchial and vascular smooth muscle tone and permeability.
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PMID:Degradation of airway neuropeptides by human lung tryptase. 169 72


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