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)

Prostaglandins and related compounds comprise an ubiquitous biological system which utilizes arachidonic acid (5,8,11,14-eicosatetraenoic acid) as a common cellular precursor to synthesize a great number of substances with a broad range of activities, including participation in the cellular and humoral events of inflammation and allergy. Briefly, prostaglandins and thromboxanes (TX) are formed in reactions initiated by the aspirin-sensitive fatty acid cyclooxygenase, whereas leukotrienes (LT) and several other compounds are generated by different lipoxygenases present in human tissues. In the field of asthma, the mast cell-derived PGD2 alpha, as well as PGF2 alpha and TXA2 are known as reasonably potent bronchoconstrictors, and asthmatics are remarkably hyperreactive to inhalation of PGF2 alpha. However, the therapeutic failure of aspirin and related cyclooxygenase inhibitors in the treatment of asthma suggests that these compounds are less likely to be primary mediators. On the other hand, several lines of evidence indicate that three closely related leukotrienes, LTC4, LTD4 and LTE4, previously known as slow-reacting substance of anaphylaxis (SRS-A), have the potential to be major mediators of the airway perturbations characteristic of bronchial asthma. Thus, as documented both in experimental animals and in man, these leukotrienes are exquisitely potent in causing bronchial smooth muscle contraction, mucosal edema, and secretion of mucus into the lumen. In particular, LTC4, LTD4 and LTE4 have been linked to allergic asthma because allergen challenge is a potent stimulus for their release from, e.g., lung tissue of asthmatics. In fact, it has been documented that inhibition of leukotriene formation can block allergen-induced contractions of isolated human bronchi.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Leukotrienes and other eicosanoids as mediators of airway obstruction. 356 14

Mast cells are prominent in the airways and have been implicated in the pathophysiology of asthma. The ability of mast cells to generate or release the vasoactive/spasmogenic mediators histamine, adenosine, PGD2, sulfidopeptide leukotrienes, and platelet-activating factor is thought relevant to immediate bronchospastic responses in association with mucus secretion and airway edema. Mast cell elaboration of chemotactic factors and release of enzymes with both tryptic and chymotryptic specificity is held responsible for later reactions in which airway inflammation is prominent and nonspecific bronchial hyperreactivity is present. Recent evidence indicates that in addition to direct effect of these mast cell products some mast cell mediators themselves modulate inflammatory mediator production. Thus, adenosine, by interacting with A2 receptors on the surface of mast cells, markedly augments mast cell release of preformed granule associated mediators. Mast cell-derived chemotactic factors, exemplified by low molecular weight eosinophil directed molecules, can induce cell specific synthesis of inflammatory lipids such as platelet-activating factor. These findings only begin to suggest the richness of possibilities for mast cell regulation of the inflammatory response and underline the reality that the inflammatory response in lung as in all tissue is extremely complex and dependent upon cell-to-cell communication for its full expression.
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PMID:The regulation of inflammatory mediator production by mast cell products. 359 17

We have demonstrated that kinins are generated following nasal challenge with allergen of allergic (5.6 +/- 0.17 ng/m-), but not nonallergic (0.04 +/- .02 ng/ml), individuals (n = 8 in each case). The presence of kinin was highly correlated with that of histamine and TAME-esterase activity and with clinical symptoms (p less than 0.001). In a double blind, placebo-controlled study, topical administration of the drug Azatadine, which inhibits mast cell mediator release in vitro, reduced the clinical response to allergen challenge and reduced the concentrations of kinins, histamine, and TAME-esterase activity observed following allergen challenge. In addition to the immediate response to allergen, some individuals experience a recurrence of symptoms some 3-12 hours after challenge; in seven such individuals (13.5 +/- 3.2 ng kinin/ml in the immediate reaction), there was a second increase in nasal kinins (2.95 +/- 1.4 ng/ml) during this late reaction, again correlating with increases in histamine and TAME-esterase activity. HPLC analysis revealed that a mixture of bradykinin and lysylbradykinin is produced during both responses. Finally, 12 subjects with a history of nasal symptoms upon exposure to cold, dry air (CDA) were compared to five asymptomatic individuals in a nasal challenge system involving nasal breathing of CDA and warm, moist air (WMA). For the symptomatic group the levels of kinin in nasal lavages were significantly increased after CDA (2.9 +/- 0.8 ng/ml) compared to baseline (0.06 +/- 0.01 ng/ml) or WMA (0.3 +/- 0.07 ng/ml). Kinin generation again correlated with increases in histamine, PGD2 and TAME-esterase activity and with onset of symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Kinins as mediators of human allergic reactions. 381

Purified human lung mast cells released histamine, leukotrienes, prostaglandin (PG) D2, thromboxane B2 (TxB2), and PGF2 alpha in response to anti-IgE stimulation. Incubation of the cells for 24 h with 10(-6) M dexamethasone, a treatment that inhibits mediator release from human basophils, had no effect on the release of these mediators from mast cells. Dexamethasone treatment of human lung fragments led to little or no inhibition of anti-IgE-induced release of the mast cell-derived mediator, histamine, but produced a significant inhibition of the release of PGE2, PGF2 alpha, and 6-keto-PGF1 alpha. As was the case with purified mast cells, the steroid did not inhibit the release of PGD2 or TxB2 from human lung fragments. Comparison of the quantities of PGD2 and TxB2 produced by purified cells and human lung fragments reveals that the mast cells produce quantities of these metabolites sufficient to account for the entire amount produced by challenged lung fragments. Dexamethasone inhibited spontaneous release from lung fragments of all cyclooxygenase products measured. These results suggest that the human lung parenchymal mast cell phospholipase is not inhibited by dexamethasone, whereas other phospholipase(s) in the lung are inhibited by the steroid. These results may be useful in explaining the resistance of acute allergic reactions, including anaphylaxis, to steroids, despite the potent antiinflammatory activity of steroids on subacute and chronic inflammation, such as in bronchial asthma, which may be initiated by IgE-dependent mechanisms.
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PMID:Effects of dexamethasone on mediator release from human lung fragments and purified human lung mast cells. 613 55

Enzymatically dispersed human lung parenchymal cells were fractionated according to size by countercurrent centrifugation elutriation. Human lung mast cells eluted throughout the procedure indicating heterogeneity of mast cell diameters. In seven individual lung elutriations, the mean histamine content ranged from 2.5 +/- 0.5 pg/mast cell for the smallest diameter mast cells (8-10 microns) to 10 +/- 2.5 pg/mast cell for the largest (16-20 microns). Intermediate sized mast cells had correspondingly intermediate histamine contents. The maximum release of histamine after anti-IgE stimulation varied with mast cell size. Small mast cells consistently released less histamine (10 +/- 3.6% net) than the largest diameter mast cells (38 +/- 6% net). This differential histamine release could not be explained by cell surface IgE content which was similar in mast cells of all sizes. The concentration of anti-IgE for maximum histamine release was the same (2 micrograms/ml) for mast cells of all sizes. The generation of PGD2, the predominant cyclooxygenase metabolite of the human lung mast cell, also was correlated positively with mast cell size and to the quantity of histamine released. Studies to date indicate no clear pattern in agonist receptor activities as judged by the inhibition of histamine release by PgE2, the beta-adrenergic agonist, fenoterol, and adenosine. We conclude that human lung mast cells are heterogeneous with regard to size and function.
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PMID:Heterogeneity of human mast cells. 619 21

Proteolytic digestion of human lung tissue dispersed a population of cells (HDLC) containing 1 to 8% mast cells but which were free from bronchial and vascular smooth muscle. Incubation of HDLC with anti-human IgE, which released a net 24.8 + 4.3% of mast cell-derived histamine, stimulated a 14-fold increase in the generation of PGD2, a seven-fold increase in TXB2, and less than a twofold increase in PGF2 alpha, immunoreactive PGE, (i-PGE) and 6-keto-PGF1 alpha. A similar profile of prostanoid release was observed when cells were challenged with epsilon-specific anti-IgE, indicating that the response was specific to the coupling of IgE Fc receptors. The calcium ionophore A23187 also released prostanoids from HDLC in approximately the same proportions as anti-IgE. This stimulus, however, released only 50% as much PGD2 per nanogram histamine than did IgE-dependent activation, thereby showing a fundamental difference in the mechanisms by which the two agents activate mast cells and liberate arachidonic acid for oxidative metabolism. In concentration-response and time course experiments, both secretory stimuli released prostanoids and histamine in parallel. After separation of lung cells by isopyknic centrifugation, challenge with anti-IgE or A23187 released PGD2 only from those fractions containing mast cells, the amount released corresponding closely to both the mast cell concentration and net histamine release. On pooling data from all experiments, the closest correlation was found between release of PGD2 and histamine when cells were stimulated with either anti-IgE (r = 0.813, p less than 0.001) or A23187 (r = 0.763, p less than 0.001), supporting a mast cell origin for PGD2. The release of other prostanoids in fractions not containing mast cells demonstrates that macrophages, monocytes, and lymphocytes have the capacity to generate TXB2, PGF2 alpha, and i-PGE both in the absence and presence of mast cells. Thus, although mast cells are likely to be the major source of PGD2 generated upon IgE-dependent stimulation of HDLC, other cells dispersed from lung tissue have the capacity to generate prostanoids directly after activation of their IgE-Fc receptors and, indirectly after the secretion of mast cell mediators.
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PMID:Anaphylactic- and calcium-dependent generation of prostaglandin D2 (PGD2), thromboxane B2, and other cyclooxygenase products of arachidonic acid by dispersed human lung cells and relationship to histamine release. 620 53

Previous studies have shown that perturbation of the mast cell IgE-Fc receptor activates adenylate cyclase so as to raise cellular levels of cyclic AMP and to activate cyclic AMP-dependent protein kinase. Theophylline, an inhibitor of cytoplasmic cyclic nucleotide phosphodiesterase, raises cellular cyclic AMP levels, activates Type I and Type II cytoplasmic cyclic AMP-dependent protein kinase isoenzymes, and inhibits immunologic mediator release in a dose-dependent fashion. Since the EC50 values for each of these effects are similar (8 to 9.5 mM), it seems likely that a relationship exists between the activation of cyclic AMP-dependent protein kinase and the inhibition of mediator release. Such inhibition could be due to either to the uncovering of an inhibitory protein by phosphorylation or to the depletion of cyclic AMP-dependent protein kinase holoenzyme, which is essential for productive IgE-Fc receptor-induced activation-secretion coupling. PGD2, which also raises mast cell cyclic AMP levels in a dose-dependent fashion and interacts synergistically with theophylline in this regard, fails to suppress mediator release alone or to add to the inhibitory effect of theophylline. The finding that PGD2 also fails to activate cyclic AMP-dependent protein kinase suggests that the adenylate cyclase stimulated by this agonist is not linked to the mast cell activation-secretion response.
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PMID:Effects of prostaglandin D2 and theophylline on rat serosal mast cells: discordance between increased cellular levels of cyclic AMP and activation of cyclic AMP-dependent protein kinase. 626 8

An in vivo model of human allergic disease has been developed in which nasal challenge with antigen leads to physiologic changes, together with a release of increased amounts of inflammatory mediators into nasal secretions obtained by washing the nose with saline. In 105 experiments involving 35 subjects, only allergic subjects consistently demonstrated an increase in the concentrations of the mast cell mediator, histamine, and the putative mast cell mediators, TAME-esterase and PGD2. The release of each mediator was significantly (p less than 0.001) related to the physiologic change (sneezing). The release of each mediator also correlated significantly with the release of the other 2 mediators (p less than 0.001). This system, for the first time, clearly relates an in vivo symptom and mediator release and thus should provide an excellent tool for the further study of the allergic response and nasal pathophysiology.
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PMID:Mediator release after nasal airway challenge with allergen. 635 22

Dapsone (diaminodiphenylsulfone) has been used therapeutically for a variety of disorders in which mast cell participation has been demonstrated, including bullous pemphigoid and some form of necrotizing vasculitis. The mechanism of action of dapsone in these disorders is unknown but potentially relates to inhibition of mast cell activation and prevention of generation and/or release of mast cell mediators. Evidence for this possibility has been obtained in rat mast cells in which dapsone in a concentration-dependent manner prevented generation of prostaglandin D2 PGD2 from exogenous or endogenous arachidonic acid with 50% inhibition achieved at 1 and 0.2 to 0.4 mM, respectively. Dapsone inhibited cyclooxygenase conversion of arachidonic acid to PGD2 but not the GSH-dependent conversion of 14C-PGH2 to PGD2 by PGH-D isomerase in broken cell preparations. Dapsone prevented the immunologic generation of PGD2 from antigen-challenged rat mast cells but did not affect the release of histamine. Thus dapsone may exert some of its therapeutic effects by prevention of mast cell PGD2 generation.
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PMID:Inhibition of rat mast cell arachidonic acid cyclooxygenase by dapsone. 641 66

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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