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 mast cell, equipped with enzymes, chemotactic factors, a vasoactive amine, an anticoagulant, and lipid-derived proinflammatory products, may be essential in tissue modeling as well as in defense. Its primarily perivascular location in skin and the mucosa of the respiratory tract and the gut assures its availability to counter parasites. By the same token, the mast cell is responsible for interactions with inhaled, ingested, and injected antigens that comprise IgE-mediated allergic reactions. Abnormally high numbers of mast cells in the skin, either localized or generalized, result in urticaria pigmentosa or generalized cutaneous mastocytosis, respectively. Tissue infiltration by excessive mast cells, primarily in gut, bone, liver, and spleen, results in systemic mastocytosis; this may be accompanied by myelodysplasia or lymphoma and may eventuate in mast cell leukemia. Until the etiology of mastocytosis is understood, the treatment is symptomatic: histamine antagonism by H1 +/- H2 blockade for flushing, itching, and gastric distress; cyclooxygenase inhibition to prevent prostaglandin D2 (PGD2)-induced hypotension when indicated; and oral cromolyn to prevent gastrointestinal symptoms and bone pain.
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PMID:Mast cell disease. 149 Jun 22

We have identified the presence of functional prostaglandin H synthase (PGH synthase, E.C. 1.14.99.1, or cyclooxygenase) within canine mast cell granules by demonstrating the generation of prostaglandin (PG) D2 from isolated and purified granules incubated with substrate as arachidonic acid or stimulated with calcium ionophore, A23187. This confirms the presence of both enzyme and substrate within the granule. Localization of PGH synthase to the granule was confirmed by immunoblotting of the pure granule preparation and by immunocytochemistry using the whole cell. In functional studies, colchicine, a microtubule polymerization inhibitor, caused a fall of up to 70%, both in the amount of histamine released and in the amount of PGD2 generated. This suggests either that functional PGH synthase is closely associated and coactivated with granules or that there is an independent association of this enzyme with the microtubule system. Release of the preformed and newly formed mediators of the mast cell appear to be closely linked, and prevention of degranulation may therefore attenuate the effects of both classes of mediators.
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PMID:Prostaglandin D2 production and identification of prostaglandin H synthase within canine mast cell granule. 151 41

It has been proposed that exercise provokes bronchoconstriction in asthma by inducing mast cell degranulation, and that this occurs secondary to the hyperpnoea of exercise causing hypertonicity of the airway lining fluid. We investigated the contribution of the mast cell products, histamine and prostaglandins, to the bronchoconstriction induced by isocapnic hyperventilation (ISH) using single doses of terfenadine, a specific histamine H1-receptor antagonist, and flurbiprofen, a potent cyclooxygenase inhibitor. We also investigated the effect of flurbioprofen in single dose on bronchial histamine reactivity. Eleven asthmatics took part in a two phase, double-blind, randomized study. In phase 1, subjects attended on three occasions and received either terfenadine 180 mg, flurbiprofen 150 mg, or placebo, prior to 6 min of ISH. The mean maximum percentage fall in forced expiratory volume in one second (FEV1) induced by ISH was 31.5(+/- 3.2)% following placebo, 29.7(+/- 4.4)% following flurbiprofen (NS), and reduced to 16.6(+/- 3.7)% following terfenadine (p less than 0.01). In phase 2, subjects received bronchial challenge with histamine following either flurbiprofen 150 mg or placebo. No significant change in bronchial reactivity following flurbiprofen was seen. We conclude that as administered in this study, flurbiprofen has no effect on baseline bronchial reactivity to histamine. The inhibitory effect of terfenadine indicates that histamine, probably from airway mast cells, makes an important contribution to bronchoconstriction induced by isocapnic hyperventilation, whereas prostaglandin release has no significant role.
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PMID:The relative contributions of histamine and prostanoids to bronchoconstriction provoked by isocapnic hyperventilation in asthma. 157 46

Polyunsaturated fatty acids (PUFA: arachidonic and linoleic acid) release histamine from isolated purified rat serosal mast cells only in the presence of oxidizing systems such as phenobarbital-induced rat liver microsomes, prostaglandin-H-synthetase (PHS) or soybean lipoxygenase. The release of mast cell histamine by activated PUFA has a long time-course and the electron microscopical features are consistent with an exocytotic secretion in the case of arachidonic acid and cell lysis in the case of linoleic acid. The phenomenon is associated with a significant increase in malonyldialdehyde (MDA) and conjugated diene generation, suggesting a relationship between histamine release and membrane lipid peroxidation. The secretion of histamine was inhibited by anti-free radical interventions such as D-mannitol, reduced glutathione and alpha-tocopherol. Some cyclooxygenase and lipoxygenase inhibitors, cimetidine and carnitine derivatives, are differentially active in the inhibition of mast cell histamine release by activated arachidonic acid. These results suggest that free radical derivatives of PUFA, generated by metabolic activation, trigger mast cell histamine release.
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PMID:Histamine release from rat mast cells induced by metabolic activation of polyunsaturated fatty acids into free radicals. 169 7

We investigated the effects of terfenadine, a histamine H1-receptor antagonist, and flurbiprofen, a cyclooxygenase inhibitor, on exercise-induced bronchoconstriction to assess the contribution of the mast cell products histamine and prostaglandins. Eight asthmatics were studied on 4 occasions with treadmill exercise tests. Terfenadine or placebo was administered 3 h prior to exercise, and flurbiprofen or placebo was administered 2 h prior to exercise, in a double-blind randomized trial. Airway calibre was determined by measurement of the forced expiratory volume in one second (FEV1) immediately prior to exercise challenge, and over 30 min post-exercise. Following placebo, the mean maximum percentage fall in FEV1 was 39%. This fell to 25% after terfenadine (p less than 0.05), 27% after flurbiprofen (p less than 0.05), and 30% after the active combination (NS). Analysis of the areas under curves of percentage falls in FEV1 over 30 min showed significant inhibition on all 3 active drug days (p less than 0.05). We conclude that histamine release and prostaglandin generation contribute to exercise-induced bronchoconstriction, although the interaction between these mediators appears complex.
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PMID:Evidence for the roles of histamine and prostaglandins as mediators in exercise-induced asthma: the inhibitory effect of terfenadine and flurbiprofen alone and in combination. 169 77

The effects of two degranulators of mast cells and intestinal anaphylaxis on jejunal myoelectric activity were compared in rats fasted for 15 hours. Attempts to antagonize the motility changes were performed using antagonists of histamine and serotonin and a cyclooxygenase and lipoxygenase inhibitor. Hooded Lister rats were chronically fitted with electrodes implanted in the jejunal wall. A group of rats was sensitized to egg albumin and challenged 14 days later by intraduodenal infusion of antigen. Sensitized animals had serum titers greater than or equal to 1:64. The other group was administered with mast cells degranulators. Both 48/80 (1 mg/kg), a degranulator of connective mast cells, and bromolasalocid (2 mg/kg), acting on connective and mucosal mast cells, induced a phase of total spiking inhibition followed by a progressive irregular spiking activity until the recovery of migrating myoelectric complex pattern (about 3 hours after injection). In contrast, antigen challenge disrupted the migrating myoelectric complex pattern, which was replaced by a peculiar pattern characterized by propagated spike burst, lasting 98 +/- 11.3 minutes. Chlorpheniramine (1 mg/kg) antagonized only the inhibitory phase induced by degranulators and was ineffective on the intestinal anaphylaxis-induced motor changes. Methysergide (1 mg/kg) and indomethacin (5 mg/kg) significantly reduced the degranulator effects as well as the anaphylaxis-induced alterations of intestinal motility. It is concluded that anaphylaxis-induced motor disturbances are relevant to mucosal mast cell degranulation involving 5-hydroxytryptamine and arachidonic acid derivative products, whereas histamine release appears to be a minor component.
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PMID:Relationship between mast cell degranulation and jejunal myoelectric alterations in intestinal anaphylaxis in rats. 172 48

To study the potential of inflammatory mediators to alter colonic motility, we characterized the response of distal colonic smooth muscle to antigen challenge. Addition of ovalbumin to isolated segments of circular smooth muscle obtained from sensitized guinea pigs produced a biphasic contraction. The initial response consisted of a rapid contraction followed by a late response, which was a more sustained but smaller increase in tone and phasic activity. Interestingly, these two responses could be antagonized differentially. Pretreatment with mepyramine (10 microM) inhibited the initial response, whereas the leukotriene antagonist WY 48252 (10 microM) inhibited the late response. The mast cell stabilizer doxantrazole (0.1 microM) reduced only the late response. Inhibition of cyclooxygenase with meclofenamic acid (1 microM) potentiated both responses, whereas blocking neuronal activity with tetrodotoxin (1 microM) only enhanced the initial response. These data indicate clear differences between the inflammatory mediators important in the initial vs. the late response. The initial response is probably mediated by the release of histamine, with enteric neuronal interactions important in attenuating the magnitude of this response. In contrast, the late response appears to be mediated by the release of peptidyl leukotrienes. In this system, cyclooxygenase products apparently function to decrease the response of the smooth muscle to these mediators. These results suggest that release of mediators during an inflammatory response could profoundly alter colonic motility and that these alterations may be important in the pathophysiological manifestations associated with colonic inflammation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of the antigen-induced contraction of colonic smooth muscle from sensitized guinea pigs. 173 61

Recent evidence suggests that neural transmitters, including neuropeptides, may modulate the release of mast cell mediators. Because neuropeptide Y (NPY) has recently been recognized as a putative cotransmitter in noradrenergic neurons, we studied the effect of NPY on purified rat peritoneal mast cells. NPY induced mast cell degranulation, as assessed by a dose-dependent increase in net release of beta-hexosaminidase. The concentration that produced 50% of the maximal effect, approximately 10 mumol/L, evoked a 40% +/- 3% release. As previously reported for other neuropeptides, release was fast with maximal release already achieved at 60 seconds. Release was at 4 degrees C. In contrast to its effects on mast cell degranulation, NPY had no effect on the generation of prostaglandin D2, the major mast cell cyclooxygenase product. By comparison, the calcium ionophore A23187, at doses (4 mumol/L) that evoked comparable release of beta-hexosaminidase, stimulated a net release of 37 +/- 9 ng of PGD2 per 10(6) mast cells. These results raise the possibility that NPY may act as a modulator between the autonomic nervous system and mast cells. The results also imply that with neuropeptide stimulation, the release of preformed and newly formed mast cell mediators are mediated through independent pathways.
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PMID:Neuropeptide Y, a putative cotransmitter in noradrenergic neurons, induces mast cell degranulation but not prostaglandin D2 release. 182 2

Rapid incorporation of exogenous arachidonic acid into phospholipid has been detected in conjunction with eicosanoid synthesis by purified mast cell granules [Chock, S. P. & Schmauder-Chock, E. A. (1988) Biochem. Biophys. Res. Commun. 156, 1308-1315]. The species of phospholipid formed has now been identified primarily as phosphatidylinositol. A calcium-dependent phospholipase A2 has also been detected in the secretory granule. This enzyme, like the cyclooxygenase [Schmauder-Chock, E. A. & Chock, S. P. (1989) J. Histochem. Cytochem. 37, 1319-1328], appears to bind tightly to the granule matrix components. It is heat resistant and requires millimolar concentrations of calcium for optimal activity. It prefers phosphatidylinositol over phosphatidylcholine as substrate. Since the granule contains a large amount of phospholipid, the action of this phospholipase A2 can provide the required substrate for the arachidonic acid cascade. These findings provide the basis for linking phospholipase A2 to the production of eicosanoids during granule exocytosis. Since the granule also contains both an active acylating system that can rapidly reacylate lysophosphatidylinositol to form phosphatidylinositol, and an active phospholipase A2 which hydrolyzes phosphatidylinositol, a rapid turnover involving the fatty acid at the sn-2 position of phosphatidylinositol may occur. These findings are consistent with our postulation that the secretory granule is the source and/or the cause of many of the early biochemical events associated with the process of stimulus-secretion coupling.
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PMID:Linking phospholipase A2 to phospholipid turnover and prostaglandin synthesis in mast cell granules. 190 Feb 37

Dog mastocytomas (anatomic and biochemical features comparable to normal dog and human mast cells) were used to study actions of mast cell mediators on several airway effector systems. We showed mastocytoma cell adherence to both cultured tracheal epithelial cells and tracheal tissue sections for greater than 48 h that was abolished completely by pretreatment of mast cells with proteases. This mast cell-epithelial cell adhesion-interaction reaction is probably mediated by a mast cell plasma membrane protein. Mast cell mediators stimulate short circuit current and ion flux across dog tracheal epithelia mounted in Ussing chambers. Pretreatment of epithelia with indomethacin blocks this effect, probably by inhibiting LTC4-induced activation of epithelial cyclooxygenases. Mastocytoma cells also increase secretion from cultured serous submucosal gland cells. Blockade of cyclooxygenase and lipoxygenase pathways in mastocytoma cells activated by calcium ionophore does not alter secretion of the serous cells induced by mastocytoma supernatant, but secretion induced by mastocytoma supernatant or purified mast cell chymase is markedly reduced by an inhibitor of chymase. These results suggest that mast cells can alter airway secretions not only by actions on ion flux in epithelial cells but also by actions on submucosal gland secretion; this latter action appears to be mediated by mast cell chymase. Finally, supernatants from mastocytoma cells stimulated by calcium ionophore greatly increase the sensitivity and magnitude of the contractile response of dog bronchial smooth muscle to histamine. These effects are blocked by an inhibitor of mast cell tryptase.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mast cells and cell-to-cell interactions in airways. 190 Jun 81


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