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)

Prostaglandin (PG) D2 and histamine concentrations have been measured in blood draining cold-challenged forearm skin in patients with cold urticaria. Local venous concentrations of both histamine and PGD2 rose in four patients who developed a whealing response. Plasma histamine concentration increased from a mean resting value of 0.24 +/- 0.09 (SD) ng/ml to peak values of 16.9 to 96.6 ng/ml. Resting concentrations of PGD2 were below the limit of detection (5 pg/ml) in three patients and 62 and 27 pg/ml in the fourth. Peak plasma PGD2 concentration after challenge ranged from 166 to 279 pg/ml. Time course of histamine and PGD2 release was similar with peak concentrations at 6 and 10 minutes, respectively. The maximum clinical response occurred between 10 and 20 minutes after challenge. Our findings demonstrate that PGD2 is produced in association with mast cell degranulation in man, but the amount, relative to histamine, is low. Despite its high potency in production of inflammatory effects, PGD2 probably has only minor direct effects in cold urticaria, although it may act to potentiate other mediators.
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PMID:Prostaglandin D2 and histamine release in cold urticaria. 242 56

Cells dispersed from human foreskin were passively sensitized with IgE and then depleted or enriched in mast cells by density gradient centrifugation. Arachidonic acid metabolism was initially studied by radio-high-performance liquid chromatography analysis of incubation media from cells that had been prelabeled with [3H] arachidonic acid. In subsequent experiments with unlabeled cells the eicosanoids were quantified by radioimmunoassay. Prostaglandin (PG)D2 was the major cyclooxygenase product released from purified mast cells challenged with anti-IgE or A23187. In density gradient studies there was a significant correlation between PGD2 and histamine release (r = 0.52, p less than 0.01) and between PGD2 release and the numbers of mast cells (r = 0.42, p less than 0.02). There was no correlation with the total numbers of nucleated cells. Other cyclooxygenase products were also detected, the formation of 6-keto-PGF1 alpha and PGE2 being principally associated with gradient fractions containing endothelial cells. Leukotriene (LT)C4 was the major lipoxygenase product detected, reaching a maximum of 3.87 +/- 0.56 ng/10(6) mast cells upon activation with anti-IgE compared with 35.37 +/- 7.22 ng/10(6) mast cells of PGD2. When normalized to histamine release and expressed in molar terms, skin mast cells released approximately 20-fold more PGD2 than LTC4. Thus, the cutaneous mast cell is one likely source of the PGD2 and LTC4 released during cutaneous immediate hypersensitivity reactions.
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PMID:The IgE- and calcium-dependent release of eicosanoids and histamine from human purified cutaneous mast cells. 250 19

The findings reported here demonstrate that PGE2 can exert both anti- and pro-inflammatory activities in one and the same tissue, as exemplified by inhibition of mediator release and enhancement of mediator action. Furthermore, the complete reversal of indomethacin potentiation of allergic inflammation by addition of PGE2 in low concentration advocates a regulatory function of the endogenous and locally formed PGE2. In the present in vivo model for mast cell-dependent inflammation the influence of PGE2 was mainly on the release of mediators. However, factors such as the degree of local blood flow, or the state of the tissue and the site of prostaglandin production, may in other instances shift the Yin-Yang balance in favour of PGE2 action at the target level for released mediators. Finally, it was noted that the cheek pouch mast cells, in addition to their pivotal role in the initiation of inflammatory reactions, have a predominant periarteriolar distribution that promotes oriented and, in terms of covered area, efficient migration of recruited leukocytes. Whether this previously unrecognized organization is specific for the hamster cheek pouch or exemplifies a more general phenomenon is presently not known.
Adv Prostaglandin Thromboxane Leukot Res 1989
PMID:Dual action of prostaglandin E2 in allergic inflammation. 252 34

The experiments discussed above indicate that during immediate hypersensitivity reactions, macrophages are stimulated by mast cells to synthesize PGE2 and 6-keto-PGF1 alpha but not LTC4. The arachidonic acid utilized for these products is mobilized from the macrophages itself and not shuttled from the mast cells. The stimulus for the involvement of the macrophage does not appear to be a direct cell interaction between the two cell types or a soluble factor released by the mast cells. Since the profile of eicosanoids produced by macrophages when exposed to mast cell granules is similar to that observed in the contribution of macrophages to immediate hypersensitivity reactions, mast cell granules appear to be responsible for the recruitment of macrophages to this reaction.
Adv Prostaglandin Thromboxane Leukot Res 1987
PMID:Nature of the mast cell-macrophage interaction in immediate hypersensitivity. 295 44

Prostaglandin (PG) D2 has been shown to be transformed by human 11-ketoreductase to 9 alpha,11 beta-PGF2, a biologically active metabolite that is produced in vivo. During the course of developing a mass spectrometric assay for 9 alpha,11 beta-PGF2, several compounds with characteristics similar to PGF2 were detected in both plasma and urine of normal humans by selected ion monitoring. Analysis of pooled plasma obtained from patients with mastocytosis during severe episodes of systemic mast cell activation associated with the release of markedly increased quantities of PGD2 was revealing in that all of these compounds were present in approximately 800-fold greater abundance compared to levels found in normal plasma, suggesting that these compounds arose from PGD2 metabolism. Complete electron impact mass spectra were obtained of these compounds in both plasma and urine; these spectra established that they were all isometric forms of PGF2. Approximately 16 isomeric PGF2 compounds were identified. Treatment with butylboronic acid indicated that the C-9 and C-11 hydroxyls were trans in approximately one-third of the compounds and cis in approximately two-thirds. Preliminary experiments suggest that PGD2 is a very labile compound in vivo and undergoes extensive isomerization, after which reduction by 11-ketoreductase yields a family of more stable isomeric PGF2 compounds. Elucidating the profile of biological activity of these compounds and their mechanism of formation will contribute importantly to our understanding of the biological consequences of PGD2 release in vivo. These results also bring into question the reliability of assays for PGF2 alpha and its metabolites in human biological fluids as a specific index of endogenous PGF2 alpha biosynthesis, as these assays may also measure in part isomeric PGF2 compounds arising from PGD2 metabolism.
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PMID:Isomeric prostaglandin F2 compounds arising from prostaglandin D2: a family of icosanoids produced in vivo in humans. 342 30

Prostaglandin (PG) D2, the predominant prostanoid released from activated mast cells in humans is initially metabolized by reduction of the C-11 keto function to yield 9 alpha,11 beta-PGF2. In this study the airways effects of 9 alpha,11 beta-PGF2 were compared with those of its epimer 9 alpha,11 alpha-PGF2 (PGF2 alpha) and PGD2. 9 alpha,11 beta-PGF2 was a potent contractile agonist of isolated guinea pig trachea and 4-mm human airways in vitro; the potencies of the PGs relative to PGD2 (= 1.00) being 0.65 (NS) and 4.08 (P less than 0.001) for 9 alpha,11 beta-PGF2, and 0.52 (P less than 0.01) and 2.40 (P less than 0.001) for PGF2 alpha, respectively. When inhaled by asthmatic subjects, 9 alpha,11 beta-PGF2 was a potent bronchoconstrictor agent, being approximately equipotent with PGD2 and 28-32 times more potent than histamine (P less than 0.01). These studies suggest that 9 alpha,11 beta-PGF2 is at least equipotent with PGD2 as a bronchoconstrictor agonist, and in being a major metabolite of PGD2, could contribute to the bronchoconstrictor effect of this mast cell-derived mediator in asthma.
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PMID:9 alpha,11 beta-prostaglandin F2, a novel metabolite of prostaglandin D2 is a potent contractile agonist of human and guinea pig airways. 346 18

6,9-deepoxy- 6,9-(phenylimino)-delta 6,8-Prostaglandin I1 (U-60,257), a prostaglandin analogue known to inhibit leukotriene formation in a number of cell systems, potentiates mast cell release of prostaglandin D2 from human dispersed lung cells activated with ionophore A23187. Over the same concentration range of 30-300 microM there was a related inhibition of ionophore-induced generation of thromboxane B2 (r = 0.93, P less than 0.01). As both prostaglandin D2 and thromboxane A2 are potent bronchoconstrictors, these observations may be relevant to the potential of this drug in the treatment of asthma.
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PMID:6,9-deepoxy-6,9-(phenylimino)-delta 6,8-Prostaglandin I1, (U-60,257) stimulates prostaglandin D2 and inhibits thromboxane B2 release from ionophore challenged human dispersed lung cells. 643 67

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

Prostaglandin (PG) D2, the major cyclooxygenase metabolite generated from immunologically stimulated mast cells, is thought to contribute to the pathogenesis of allergic diseases due to its various inflammatory effects. However, since no DP receptor antagonist has been developed as an antiallergic drug, the role of PGD2 in the pathogenesis of allergic diseases remains uncertain. Here, we report the in vivo efficacy of our newly established DP receptor antagonist, S-5751 [((Z)-7-[(1R,2R,3S,5S)-2-(5-hydroxy benzo[b]thiophen-3-ylcarbonylamino)-10-norpinan-3-yl]hept-5- enoic acid)], using various allergic inflammation guinea pig models. In allergic rhinitis models, oral administration of S-5751 dramatically inhibited not only early nasal responses, as assessed by sneezing, mucosal plasma exudation, and nasal blockage, but also late responses such as mucosal plasma exudation and eosinophil infiltration. Even when S-5751 was administered after recovery from the early responses, these late phase responses were almost completely suppressed. In addition, S-5751 alleviated allergen-induced plasma exudation in the conjunctiva in an allergic conjunctivitis model and antigen-induced eosinophil infiltration into the lung in an asthma model. These findings provide evidence for the crucial role of PGD2 as a mediator of allergic inflammation in guinea pigs and suggest that DP receptor antagonists may be useful in the treatment of allergic diseases triggered by mast cell activation.
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PMID:Prevention of allergic inflammation by a novel prostaglandin receptor antagonist, S-5751. 1145 1

Allergic inflammations feature an accumulation of T helper 2 (Th2) cells, eosinophils, and basophils into the inflamed sites and are often triggered by antigen-IgE mediated activation of mast cells that secret a variety of mediators. Therefore, the mast cell is known as a conductor cell in allergic inflammations. Prostaglandin (PG) D(2) is the major prostanoid secreted from the activated mast cell and has long been implicated in allergic diseases. The involvement of PGD(2) in allergic inflammation has been corroborated by several studies. Two PGD(2) receptors are known as the DP receptor and CRTH2. CRTH2 differs from DP in its signal pathways: CRTH2 is coupled with Gi-type G protein and DP is coupled with Gs-type G protein. It was reported that DP-deficient mice subjected to ovalbumin-induced asthma model systems showed suppressed allergic reactions. Functions of CRTH2 in vivo have not been clear, but CRTH2 mediates PGD(2)-dependent cell migration and the activation of Th2 cells, eosinophils, and basophils. Therefore, the CRTH2 signal seems to promote allergic disease. The findings from these in vivo and vitro studies suggest that PGD(2) secreted from activated mast cells may be involved in the formation and/or maintenance of allergic inflammations through its dual receptor systems.
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PMID:[Prostaglandin D2 in allergy: PGD2 has dual receptor systems]. 1469 54


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