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)

The influence of specific antigen challenge on the excitability of C-cells in nodose ganglia isolated from actively sensitized guinea pigs was evaluated using intracellular recording techniques. Antigen (ovalbumin) caused a significant depolarization (approximately 8 mV) of the resting membrane potential. Antigen exposure had differing effects on the membrane input impedance; decreasing it in 15 neurons, increasing it in 6 neurons, and having no effect in 8 neurons. About 20% of guinea pig nodose C-cells reveal a long-lasting after-spike hyperpolarization (AHPslow). Antigen challenge reversibly blocked the AHPslow in 4 of 18 neurons studied in 18 ganglia. About 30% of the nodose ganglion neurons display a time- and voltage-dependent inward rectification at membrane potentials more negative than -75 mV. Exposing the ganglion to the sensitizing antigen consistently blocked this response in 8 of 8 neurons. Histological assessment of toluidine blue stained cells revealed that the nodose ganglion contained approximately 100 mast cells. Exposing the ganglion to ovalbumin stimulated mast cell degranulation, as measured by a decrease in number of stained cells, and evoked the release of histamine, PGD2, and immunoreactive peptidoleukotrienes from the tissue. The results support the hypothesis that endogenous inflammatory mediators released during the immediate hypersensitivity (allergic) reactions can modulate the excitability of primary C-fiber afferents. Mechanisms underlying antigen-induced neuromodulation of these neurons include depolarization of the resting membrane potential, changes in membrane resistance, blockade of a time- and voltage-dependent anomalous rectifier, and, in some cells, blockade of the AHPslow.
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PMID:Immunologically induced neuromodulation of guinea pig nodose ganglion neurons. 769 18

A series of cases of sudden unexpected post-neonatal deaths from two centres in the UK have been investigated for evidence of mast cell activation using the biochemical markers tryptase and 9 alpha,11 beta-PGF2. Tryptase was selected as a possible marker because it is a component of mast cell secretory granules and, unlike histamine, it is not released from basophils. The prostaglandin 9 alpha,11 beta-PGF2 is an initial and pharmacologically active metabolite of PGD2, the major mast cell-derived cyclooxygenase product. This prostaglandin was chosen to serve as a marker of newly generated mediator release. In the study, unexplained infant deaths were associated with a higher concentration of tryptase in serum compared with cases of unexpected, but subsequently explained death. However, 9 alpha,11 beta-PGF2 was found to be an unsuitable post mortem marker in this situation. These results provide direct evidence that mast cell degranulation, possibly as a result of anaphylaxis, may be occurring around the time of death in some cases of cot death.
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PMID:The anaphylaxis hypothesis of sudden infant death syndrome (SIDS): mast cell degranulation in cot death revealed by elevated concentrations of tryptase in serum. 788 24

Hypertonicity of airway lining fluid has been suggested as the stimulus for bronchoconstriction in exercise-induced asthma. We explored the airway effects of delivering a direct hypertonic stimulus to asthmatic airways via a fiberoptic bronchoscope, comparing hypertonic saline challenge by direct instillation with local aerosol delivery. A group of 18 asthmatic subjects responsive to inhaled hypertonic saline with a history of EIA were studied; the first 9 subjects received local challenge with hypertonic saline by direct instillation, and the next 9 subjects were challenged by local aerosol delivery. A control challenge with isotonic saline by either instillation or aerosol was performed at a same bronchoscopy. Local challenge with hypertonic saline by aerosol delivery was found to be more effective in inducing local bronchoconstriction (8 of 9 subjects) than instillation (2 of 6 subjects). Paired BAL fluid samples and bronchial biopsies were obtained in total of 11 and 9 subjects, respectively. Local challenge with hypertonic saline either by instillation or aerosol produced no significant change in histamine, tryptase, or PGD2 levels in BAL fluid or mast cell numbers and degranulation in bronchial biopsies. A significant correlation was observed between histamine levels in BAL fluid and airway responsiveness to inhaled hypertonic saline (rs = -0.59, p < 0.05). Bronchial biopsies showed evidence of extensive epithelial damage; however, this was not related to airway responsiveness to inhaled hypertonic saline.
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PMID:Airway effects of local challenge with hypertonic saline in exercise-induced asthma. 814 36

The symptoms and hemodynamic alterations that accompany episodes of systemic mast cell activation have been largely attributed to excessive prostaglandin (PG)D2 release. Quantification of the major urinary metabolite of PGD2 has been invaluable in elucidating a role for PGD2 in these clinical entities and in the biochemical evaluation of systemic mastocytosis. With the use of a modified mass spectrometric assay for the major urinary metabolite of PGD2, this metabolite was detected in plasma from 10 normal volunteers (3.5 +/- 1.4 pg/ml). Ingestion of niacin, which induces endogenous release of PGD2, increased plasma levels of this metabolite 6.3 to 33 times above the upper limit of normal by 2 hours. Thereafter, levels declined gradually but remained elevated for up to 6 to 8 hours. In contrast, circulating levels of 9 alpha, 11 beta-PGF2, the initial metabolite of PGD2, peaked by 30 minutes and returned to baseline by 2 hours. The clinical utility of measuring the major urinary metabolite in the circulation was demonstrated by detection of markedly increased levels in plasma and serum from patients with systemic mastocytosis and a patient with a severe type I allergic reaction. Thus in the biochemical evaluation of episodes of systemic mast cell activation and endeavors to further elucidate the role of PGD2 in human disease, there are kinetic advantages of measuring the major urinary metabolite of PGD2 in the circulation. One particular advantage is the evaluation of clinical events, which only in retrospect are suspected to be associated with excessive release of PGD2, yet plasma or serum was obtained proximate to the event.
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PMID:Detection of the major urinary metabolite of prostaglandin D2 in the circulation: demonstration of elevated levels in patients with disorders of systemic mast cell activation. 818 21

Mast cells can release arachidonic acid (AA) metabolites as well as preformed mediators with IgE mediated stimulation, and these mediators are considered to play an important role in allergic reactions. The coincident release of preformed mediators and AA metabolites suggests that AA metabolism is related to mast cell degranulation. To clarify the relationship between mast cell degranulation and AA metabolism, the effects of various A cascade inhibitors on rat basophilic leukemia cell (RBL) mediator release induced by either anti-IgE or A23187 were examined. 5,8,11,14-eicosatetraynoic acid (ETYA) inhibited both PGD2 and LTC4/D4 generation, and partially inhibited serotonin release. Nordihydroguaiaretic acid (NDGA) caused complete inhibition of LTC4/D4 generation, and partial inhibition of PGD2 generation and serotonin release. The cyclooxygenase inhibitor, indomethacin, and the specific 5-lipoxygenase inhibitor, L-651,392 completely inhibited PGD2 and LTC4/D4 generation, respectively, without affecting release of other mediators. Both PGD2 and LTC4/D4 generation were abolished by the combination of indomethacin and L-651,392, however, serotonin release remained intact. HPLC analysis showed that no shift to other AA metabolites occurred after the treatment with these inhibitors. Mepacrine, a phospholipase A2 inhibitor, completely inhibited PGD2 and LTC4/D4 generation, as well as AA release itself, without affecting serotonin release. Therefore, neither AA metabolism nor AA release is necessary for RBL degranulation.
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PMID:Effects of inhibitors of arachidonic acid metabolism on serotonin release from rat basophilic leukemia cells. 850 Sep 85

General anesthetics and radiocontrast media (RCM) can cause anaphylactic or anaphylactoid reactions. These are usually underdiagnosed and underreported, but their incidence is apparently rising. Their pathogenesis is complex and not completely understood, but the release of vasoactive mediators from basophils and mast cells plays a central role. The recent development of in vitro techniques to study the release of preformed (histamine and tryptase) and de novo synthesized mediators (PGD2, LTC4, and PAF) from purified basophils and mast cells has made it possible to quantify the mediator-releasing activity of anesthetics such as muscle relaxants, general anesthetics, opioids, and benzodiazepines and RCM on human basophils and mast cells isolated from lung, skin and heart tissues. The majority of general anesthetics and RCM tested induced only the release of preformed mediators (histamine and tryptase), not of the de novo synthesized eicosanoids. There was wide variability in the response of basophils and mast cells from different donors to the same drug or RCM, presumably due to the releasability parameter. Hyperosmolality is probably not the only factor responsible for basophil and mast cell activation by RCM. The in vitro release of histamine induced by anesthetic drugs and RCM was correlated with the release of tryptase. Given the longer half-life of tryptase than histamine in plasma, measurements of plasma tryptase may become a useful diagnostic tool for identifying adverse reactions to anesthetics and RCM.
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PMID:Role of mast cells, basophils and their mediators in adverse reactions to general anesthetics and radiocontrast media. 864 73

Mast cells are present in normal and even more abundant in diseased human heart tissue and their localization is of particular relevance to their function. Within heart tissue mast cells lie between myocytes and in close contact with blood vessels. They are also found in the coronary adventitia and in the shoulder regions of a coronary atheroma. The density of cardiac mast cells is markedly higher in some patients with myocarditis and dilated cardiomyopathy than in accident victims without cardiovascular diseases. More importantly, in some of these conditions there is in situ evidence of mast cell activation. We have described an original technique to isolate and purify HHMC for in vitro study. This procedure gives viable cells and after stimulation with immunological or non-immunological stimuli they release performed (histamine and tryptase) and newly generated mediators (PGD2 and LTC4). We have demonstrated that HHMC differ from those in other anatomical districts in that they are activated by specific immunological and non-immunological stimuli, and in their relation to the arachidonic acid metabolism, suggesting that the local microenvironment can influence their phenotypic and biochemical characteristics. Our own and other findings suggest that HHMC have complex and significant roles in different pathophysiological conditions involving the cardiovascular system. Direct activation of HHMC by therapeutic and diagnostic substances injected intravenously explains some of the anaphylactoid reactions caused by these agents. HHMC possess Fc epsilon RI and IgE bound to the surface and C5a receptors, which could explain how cardiac mast cells are involved in systemic and cardiac anaphylaxis. Cardiac mast cells and those in human coronary arteries also play a role in the early and late stages of atherogenesis and during ischemic myocardial injury. In conclusion, although studies of HHMC are in their infancy, their in vitro isolation may be useful in identifying additional mediators synthesized and released, stimuli relevant to human pathophysiology, and pharmacological agents selectively modulating the activation of these cells and their mediators. Drugs specifically acting on HHMC or on their mediators may eventually be useful in treating different cardiovascular diseases.
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PMID:Immunological characterization and functional importance of human heart mast cells. 865 85

Prostaglandin (PG)D2 is a major product of arachidonic acid metabolism in pulmonary mast cells. We therefore attempted to determine whether measurement of the stable urinary metabolite of PGD2, 9 alpha, 11 beta-PGF2, could serve as a marker of mast cell activation in the lungs. A commercially available enzyme immunoassay was validated and found to be specific and sensitive when applied to unpurified urine. There was no diurnal variation in the levels of 9 alpha, 11 beta-PGF2 in healthy volunteers. Morning baseline values of urinary 9 alpha, 11 beta-PGF2 were measured in three groups--healthy volunteers (n = 9), patients with atopic asthma (n = 14), and aspirin-intolerant patients with asthma (n = 12)--and found to be very similar, 54 +/- 9, 62 +/- 6, and 71 +/- 15 ng/mmol creatinine, respectively (means +/- SEM). Urinary excretion of 9 alpha, 11 beta-PGF2 was increased threefold immediately after allergen-induced bronchoconstriction in nine patients with atopic asthma. Bronchial challenge with inhaled lysine aspirin in eight aspirin-intolerant patients with asthma produced bronchoconstriction without extrapulmonary symptoms and was also followed by a significant increase in the urinary excretion of 9 alpha, 11 beta-PGF2. In addition, challenge with a higher dose of aspirin produced an even greater increase in urinary 9 alpha, 11 beta-PGF2, supporting dose-dependent release of PGD2 during aspirin-induced bronchoconstriction. In contrast, the postchallenge levels of urinary 9 alpha, 11 beta-PGF2 were not increased when bronchoconstriction was induced by histamine challenge in the aspirin-intolerant patients with asthma. The study confirms mast cell involvement in allergen-induced bronchoconstriction and provides novel data, which strongly support the hypothesis that pulmonary mast cells are activated during aspirin-induced airway obstruction. It is finally suggested that measurement of urinary 9 alpha, 11 beta-PGF2 with enzyme immunoassay may be used as a new noninvasive strategy to monitor mast cell activation in vivo.
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PMID:Increased urinary excretion of the prostaglandin D2 metabolite 9 alpha, 11 beta-prostaglandin F2 after aspirin challenge supports mast cell activation in aspirin-induced airway obstruction. 875 20

Polycationic mast cell activators, such as compound 48/80 and substance P, have been reported to activate connective tissue-type mast cells specifically by interacting directly with the Gi family of trimeric GTP-binding protein. We now demonstrate that mouse bone marrow-derived mast cells (BMMC) developed in IL-3, an immature mast cell population lacking responsiveness to the Gi-coupled polycationic mast cell activators, underwent maturation toward a connective tissue-type mast cells-like phenotype that responded to polycationic compounds after only 4 to 6 days of coculture with Swiss 3T3 fibroblasts in concert with recombinant soluble c-kit ligand (KL), whereas 3T3 or KL alone was insufficient to mediate this process. Under optimal conditions, cocultured BMMC released approximately 30% beta-hexosaminidase and generated approximately 1 ng of PGD2/10(6) cells within a few minutes in response to compound 48/80 or substance P. Furthermore, these cells expressed cytokines, such as IL-1beta and IL-6, and PG endoperoxide synthase-2 1 to 4 h after stimulation with compound 48/80 or substance P. All these responses were suppressed effectively by pertussis toxin, implicating functional Gi coupling. Regardless of the remarkable change in polycationic compound sensitivity, there was only a minimal change in the constitutive expression of Gi3 alpha after coculture. These results together with the observation that before coculture BMMC responded to thrombin through its Gi-coupled receptor suggest that the alteration in a certain step(s) distinct from the level of Gi3 alpha protein expression is important for the acquisition of responsiveness to the polycationic compounds by the synergistic action of KL and 3T3 fibroblast-derived factor. Several lines of evidence have revealed that 3T3-derived factor appears to differ from the known cytokines, prostanoids, and adhesion molecules and is a labile soluble substance.
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PMID:Mouse bone marrow-derived mast cells undergo exocytosis, prostanoid generation, and cytokine expression in response to G protein-activating polybasic compounds after coculture with fibroblasts in the presence of c-kit ligand. 897 15

Adenosine, a naturally occurring purine nucleoside, elicits dose-related bronchoconstriction in asthmatic subjects when administered by inhalation and it is recovered in increased amounts from the bronchial lavage fluid of subjects with active asthma when compared to normal controls. Although the mechanism by which adenosine mediates bronchoconstriction in asthmatic subjects is not clear, recent data indicate an important role for mast cell mediator release. We have recently shown that local airway challenge with adenosine in subjects with asthma and rhinitis provokes an increase in the levels of PGD2, histamine and tryptase. However, airway responsiveness and atopic status are the most important determinants of adenosine-induced responses, regardless of any increases in mast cell mediators in airway fluids. New discoveries suggest that the airway response to adenosine may be an index of mast cell priming and therefore may provide a useful tool to further explore the inflammatory processes in allergic asthma and rhinitis. Therefore adenosine provocation may gain increasing acceptance as an additional measure of disease activity in asthma and rhinitis.
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PMID:Purine derivatives in the study of allergic inflammation in respiratory diseases. 918 54


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