Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The generation of slow reacting substance (SRS) from ionophore A23187-stimulated rat peritoneal mast cells was enhanced by arachidonic acid (AA). This SRS generation was inhibited by 5,8,11,14-eicosatetraynoic acid (ETYA), an acetylenic analogue of AA and an inhibitor of both fatty acid cyclooxygenase and lipoxygenase. Indomethacin, a fatty acid cyclooxgenase inhibitor, had an enhancing effect upon SRS generation. This suggests SRS generation occurred through an ETYA sensitive step--perhaps a lipoxygenase. Radiolabel from [14C]-AA was incorporated into SRS with comigration of radioactivity and bioreactivity in silicic acid and thin layer chromatographies. Upon silicic acid chromatography, the active principle was eluted in the methanol fraction. Two-dimensional thin layer chromatography revealed chromatographic separation from other known spasmogenic substances and phospholipids. Mast cell SRS was found to display physiochemical properties similar to those of rat basophilic leukemia cell SRS, namely: that mast cell SRS generation was 1) enhanced by arachidonic acid; 2) inhibited by ETYA but not by indomethacin; 3) incorporation of [14C]-AA into the active principle; and 4) similar behavior during purification in silicic acid and thin layer chromatographies.
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PMID:Slow reacting substance (SRS) from ionophore A23187-stimulated peritoneal mast cells of the normal rat. II. Evidence for a precursor role of arachidonic acid and further purification. 37 31

We examined contractility of longitudinal muscle strips of jejunum from control rats and rats infected 34-85 days previously with Trichinella spiralis. Antigen prepared from T. spiralis larvae contracted muscle from previously infected but not control rats. Contraction was specific for the sensitizing agent because antigen from Nippostrongylus brasiliensis did not induce contraction. Contraction was resistant to atropine or tetrodotoxin but was inhibited by the 5-hydroxytryptamine (5-HT) antagonist cyproheptadine and by 5-HT desensitization. Neither histamine antagonists, diphenhydramine (H1-receptor antagonist) or ranitidine (H2-receptor antagonist), nor indomethacin, a prostaglandin synthase inhibitor, influenced the antigen response. In Trichinella-infected rats there was a significant increase in mast cell number in the muscle layers, and the contraction induced by T. spiralis antigen was inhibited by the mast cell stabilizer doxantrazole. In addition, anti-rat immunoglobulin E serum, compound 48/80, and concanavalin A each contracted muscles from rats previously infected with T. spiralis. These results are consistent with the hypothesis that T. spiralis infection leads to mast cell proliferation in the muscle layers and that subsequent exposure to antigen results in mast cell degranulation, 5-HT release, and contraction of smooth muscle.
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PMID:Antigen-induced contraction of jejunal smooth muscle in the sensitized rat. 320 67

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

We have previously established a relationship between mast cell degranulation and hypoxic pulmonary vasoconstriction (HPV). In the present study, we investigated the possible role of slow-reacting substance of anaphylaxis (SRS-A) in the mediation of HPV. In 18 conscious sheep, pulmonary artery pressure, pulmonary arterial wedge pressure, and cardiac output were measured for the calculation of pulmonary vascular resistance (PVR) along with arterial oxygen tension (PaO2) while breathing room air and while breathing 13% O2 (balance, N2). Before and during 13% O2 breathing (pretreatment), Group 1 received an intravenous infusion of cromolyn sodium (3 mg/kg-1/min-1) and Group 2 was infused with FPL-57231, a SRS-A antagonist (2 mg/kg-1/min-1); Groups 3 and 4 received infusions of cromolyn sodium or FPL-57231 after induction of HPV. During 13% O2 breathing (mean PaO2, 47 mmHg), mean PVR increased to 190% of baseline. Pretreatment with cromolyn sodium prevented HPV, whereas infusion of cromolyn sodium after induction of HPV failed to reverse it; FPL-57231 both prevented HPV (pretreatment) and reversed it when infused after induction of HPV. Pretreatment with the prostaglandin synthetase inhibitor indomethacin (2 mg/kg) 1 h before the experiment failed to modify the FPL-57231-induced reversal of hypoxic vasoconstriction, thus excluding the release of inhibitory prostaglandins by this compound. We conclude that cromolyn sodium prevented HPV, presumably by inhibiting the release of SRS-A, which mediates pulmonary vasoconstriction directly or indirectly through other mechanisms.
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PMID:Does slow-reacting substance of anaphylaxis mediate hypoxic pulmonary vasoconstriction? 640 64

We used pharmacologic and histologic techniques to investigate the role of mast cells in the mediation of hypoxic pulmonary vasoconstriction in conscious sheep. Breathing a hypoxic gas mixture (13%, 02, 87% nitrogen) caused hypoxic pulmonary vasoconstriction (HPV) with increases in mean pulmonary artery pressure and pulmonary vascular resistance by 97 and 90%, respectively. Intravenous pretreatment with the mast cell membrane stabilizing agent cromolyn sodium (3 mg/kg/min) completely blocked HPV, whereas the H1-histamine receptor antagonist chlorpheniramine, alone or in combination with the H2-receptor antagonist metiamide and the prostaglandin synthetase inhibitor indomethacin, failed to prevent HPV. Cromolyn sodium failed to modify the pulmonary pressor response to infusions of norepinephrine (alpha-agonist), tyramine (catecholamine-releasing agent), and histamine, indicating the specificity of cromolyn sodium action on the mast cells. Electromicroscopic studies of pulmonary perivascular mast cells showed that a 90-min exposure to the hypoxic gas mixture reduced the total number of granules per mast cell to 75% of control. This was blocked by cromolyn sodium pretreatment. We conclude that in conscious sheep], HP[V is initiated by the liberation of a mast cell product (other than histamine) that either directly or indirectly causes pulmonary vasoconstriction.
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PMID:Hypoxic pulmonary vasoconstriction in conscious sheep: role of mast cell degranulation. 680 79

Aggregation of IgE cell surface receptors on MMC-34 cells, a murine mast cell line, induces the synthesis and secretion of prostaglandin D2 (PGD2). Synthesis and secretion of PGD2 in activated MMC-34 cells occurs in two stages, an early phase that is complete within 30 min after activation and a late phase that reaches a maximum about 6 h after activation. The early and late phases of PGD2 generation are mediated by prostaglandin synthase 1 (PGS1) and prostaglandin synthase 2 (PGS2), respectively. Arachidonic acid, the substrate for both PGS1 and PGS2, is released from membrane phospholipids by the activation of phospholipases. We now demonstrate that in activated mast cells (i) secretory phospholipase A2 (PLA2) mediates the release of arachidonic acid for early, PGS1-dependent synthesis of PGD2; (ii) secretory PLA2 does not play a role in the late, PGS2-dependent synthesis of PGD2; (iii) cytoplasmic PLA2 mediates the release of arachidonic acid for late, PGS2-dependent synthesis of PGD2; and (iv) a cytoplasmic PLA2-dependent step precedes secretory PLA2 activation and is necessary for optimal PGD2 production by the secretory PLA2/PGS1-dependent early pathway.
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PMID:Prostaglandin synthase-1 and prostaglandin synthase-2 are coupled to distinct phospholipases for the generation of prostaglandin D2 in activated mast cells. 901 59

Prostaglandin D2 (PGD2) synthesis in activated mast cells occurs in two phases, an early phase that is dependent on prostaglandin synthase 1 and a delayed phase that is dependent on activation-induced prostaglandin synthase 2 gene expression. Early phase PGD2 synthesis in activated mast cells also requires the activity of a secretory phospholipase A2 (PLA2). It has been thought that the secretory PLA2 expressed in mast cells is group IIa PLA2, encoded by the Pla2 g2a gene. However, activated bone marrow-derived mast cells prepared from Pla2 g2a+/+ mice and mast cells prepared from mice with a mutation in the Pla2 g2a gene both demonstrate early phase PGD2 synthesis. Moreover, mast cells from both murine strains secrete PLA2 activity following activation. Northern and reverse transcriptase/polymerase chain reaction analyses demonstrate that mast cells from Pla2 g2a+/+ and Pla2 g2a-/- mice do not express group IIa PLA2 message. Instead, Northern and reverse transcriptase/polymerase chain reaction analyses demonstrate that both Pla2 g2a+/+ and Pla2 g2a-/- mast cells express mRNA for group V PLA2, encoded by the Pla2gV gene. An antisense oligonucleotide directed against group V PLA2 is also able to inhibit both the early phase of PGD2 production and the secretion of PLA2 activity by activated mast cells. Our data suggest that (i) group IIa PLA2 does not play a significant role in murine mast cell prostaglandin synthesis, (ii) group V PLA2 mediates early mast cell PGD2 production and transcellular PGE2 production in murine mast cells, and (iii) much of the data, based on studies with chemical inhibitors and antibodies, suggesting that group IIa PLA2 is responsible for arachidonic acid mobilization needs to be reevaluated.
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PMID:Analysis of the secretory phospholipase A2 that mediates prostaglandin production in mast cells. 915 7

The purpose of this study was to determine the effects of mast cell coculture on human orbital fibroblasts. Thyroid-associated ophthalmopathy is characterized by infiltration of lymphocytes and mast cells and connective tissue activation in the orbit, leading to a disordered accumulation of hyaluronan and intense inflammation. Here, we report that HMC-1, an established human mast cell line, can activate human orbital fibroblasts to produce increased levels of prostaglandin E2 (PGE2) and hyaluronan when cocultured. HMC-1 cells up-regulate, in these fibroblasts, the expression of PG endoperoxide H synthase-2 (EC 1.14.99.1, PGHS-2), the inflammatory cyclooxygenase. This induction, at a pretranslational level, underlies the increase in PGE2 synthesis. The up-regulation can be attenuated with dexamethasone (10 nM), and the increase in PGE2 production can be inhibited by SC 58125, a specific PGHS-2 inhibitor. Moreover, anti-interleukin-4 receptor antibodies can block prostanoid production in the fibroblasts elicited by HMC-1 cells, suggesting that this cytokine might represent a molecular conduit for mast cell/fibroblast cross-talk. HMC-1 cells also increased hyaluronan synthesis, as was evidenced by a 2-fold increase in [3H]glucosamine incorporation into the macromolecule. To our knowledge, these findings are the first demonstrating the ability of mast cells to activate orbital fibroblasts, and the findings suggest a potential role for these cell-cell interactions in the pathogenesis of thyroid-associated ophthalmopathy.
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PMID:HMC-1 mast cells activate human orbital fibroblasts in coculture: evidence for up-regulation of prostaglandin E2 and hyaluronan synthesis. 1043 7

The production of prostaglandin D2 (PGD2) by rat peritoneal mast cells incubated with N-acetyl glucosamine (GlcNAc) oligomer-specific Datura stramonium agglutinin (DSA) for 10 min in the presence of 0.3 mM Ca2+ was examined. Previously, our group reported that the incubation of rat mast cells with DSA (5 - 100 microg/ml) under similar conditions resulted in a calcium influx and histamine release via a pertussis toxin-sensitive G-protein pathway of the mast cells, and the histamine release was inhibited by haptenic sugar chitooligosaccharides or GlcNAc-specific lectin wheat germ agglutinin (WGA) (K. Matsuda et al., Jpn J Pharmacol 66, 195 - 204 (1994)). DSA (5 - 100 microg/ml) dose-dependently stimulated the mast cells to generate PGD2. Chitooligosaccharides (1% w/v) and WGA (100 microg/ml) inhibited the production of PGD2 induced by 100 microg/ml of DSA, suggesting that the effect of DSA is sugar-specific. A prostaglandin G/H synthase inhibitor NS-398 (N-[cyclohexyloxy-4-nitrophenyl] methanesulfonamide) (10 microM) inhibited the formation of PGD2 induced by DSA (20 microg/ml). These results suggest that the binding of DSA to the corresponding sugar residues on the mast cell surface mediates the signaling of the prostaglandin G/H synthase pathway.
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PMID:Prostaglandin D2 generation by rat peritoneal mast cells stimulated with Datura stramonium agglutinin and its inhibition by haptenic sugar and wheat germ agglutinin. 1239 30

The discovery of an inducible form of prostaglandin synthase initiated a reexamination of the biochemical pathways for ligand-induced prostaglandin synthesis. As a result, new pharmaceutical agents with potential activity against pain, fever, chronic and acute inflammation, cardiovascular disorders, and colon cancer have been developed and are currently under intense investigation. Careful biochemical and pharmacologic studies of the differences between the constitutive and inducible prostaglandin synthase enzymes have suggested a previously unexpected mechanism for some of the therapeutic effects of aspirin. Identification of a new phospholipase, and recognition of its role in mast cell prostaglandin production and in transcellular prostaglandin synthesis, have identified additional potential targets for pharmacologic intervention in inflammation and other prostaglandin-mediated disorders.
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PMID:Recent progress in the cellular and molecular biology of prostaglandin synthesis. 2123 25


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