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)

Treatment for 24 h in vitro with dexamethasone inhibited the antigen-induced contractile response in guinea pig tracheal rings and parenchymal strips without inhibiting the contractile response of the tissues to either methacholine or histamine, respectively. Antigen-induced histamine release was inhibited by approximately 50% in both tissues by prior treatment with dexamethasone. Dexamethasone treatment also inhibited the release of immunoreactive sulfidopeptide leukotriene from parenchymal strips. In tracheal rings, dexamethasone treatment reduced spontaneous release of all cyclooxygenase metabolites (PGE2, PGF2 alpha, TXB2, PGD2, and 6-k-PGF1 alpha were tested), with the exception of PGD2, and also inhibited the antigen-induced release of all cyclooxygenase metabolites studied. Dexamethasone-treatment did not inhibit the spontaneous release of cyclooxygenase metabolites in the guinea pig lung strips, and only modestly inhibited the antigen-induced release of PGE2, PGF2 alpha, and PGD2. The results suggest that the inhibition of contractile response of guinea pig lung strips and airway tissue to antigen by dexamethasone is the result of a reduced release of inflammatory mediators. The inhibition by dexamethasone of antigen-induced release of mast cell mediators from guinea pig lung parenchyma contrasts with results previously obtained with human parenchymal lung tissue.
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PMID:Dexamethasone inhibits the antigen-induced contractile activity and release of inflammatory mediators in isolated guinea pig lung tissue. 310 4

Although a great deal has been learned about the mediators produced by mast cells, the ultimate biologic function(s) of mast cell remains a mystery. Histamine, LTC4, PAF, and possibly tryptase (C3a generation) all enhance vasopermeability. Mediators with anticoagulant activities such as heparin and tryptase (fibrinogenolysis) and antithrombotic activity, PGD2, would appear to facilitate dispersion in tissues of the plasma ultrafiltrate brought there by the subgroup of mediators that enhance vasopermeability. In contrast, PAF causes platelet aggregation and chymase may cause arteriolar vasoconstriction (decreasing the volume of plasma reaching venules) by generation of angiotensin II. Assessment of any differential production of mediators by different types of mast cells will be of obvious importance in sorting out the physiologic responses to mast cell activation as well as the pathophysiology of allergic reactions.
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PMID:Mediators of human mast cells and human mast cell subsets. 310 66

PGD2 undergoes extensive isomerization in vivo followed by metabolism by 11-ketoreductase to yield a family of biologically active isomeric PGF2 compounds, including 9, alpha 11 beta-PGF2. Because immunologically activated human mast cells produce substantial quantities of PGD2 and eosinophils accumulate around mast cells at sites of immediate hypersensitivity reactions, the ability of eosinophils to metabolize PGD2 was investigated. Purified human circulating eosinophils from four different donors transformed PGD2 to 9, alpha 11 beta-PGF2 and 12-epi-9 alpha, 11 beta-PGF2 in a time- and concentration-dependent manner. The formation of these compounds increased rapidly during the first 30 min of incubation of eosinophils with PGD2 and tended to plateau at approximately 2 h. Detection and quantification of the formation of 9 beta,11 beta-PGF2 and its 12-epi isomer was accomplished by a negative ion chemical ionization gas chromatography/mass spectrometry assay. On one occasion, eosinophils from one donor also transformed PGD2 to two additional isomeric PGF2 compounds, the stereochemical structures of which were not identified. The ability of eosinophils to produce PGD2 was then investigated. After stimulation with 2 microM A23187, the major cyclooxygenase product formed was thromboxane B2 (2247 pg/10(6) eosinophils) whereas only small quantities of PGD2 were produced (50 pg/10(6) eosinophils). Inasmuch as PGF2 compounds can exert biologic actions that differ from those of PGD2, this ability of eosinophils to transform PGD2 to PGF2 compounds could alter the local biologic effects of PGD2 released from adjacent mast cells and thus may represent a physiologically relevant mast cell-eosinophil interaction.
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PMID:Transformation of prostaglandin D2 to isomeric prostaglandin F2 compounds by human eosinophils. A potential mast cell-eosinophil interaction. 313 58

Bronchial asthma is a multifactorial disease characterized by reversible bronchoconstriction, airway hyperreactivity, oedema and excessive mucus production. Present therapy directed against specific mediators has not been overwhelmingly successful. Even though there exists a multiplicity of purported mediators, perhaps the key to better therapy is a vigorous understanding of the arachidonic acid cascade and investigations to modulate specific products of these pathways. Within the cyclooxygenase pathway an interesting scenario might be to effectively antagonize the potent bronchoconstrictive effects of prostaglandin (PG)D2 and its recently identified predominant metabolite, an 11-hydroxyl epimer, 9 alpha,11 beta-PGF2. PGD2 is the major cyclooxygenase product released from sensitized human lung and bronchoalveolar lavage (BAL) mast cells; it possesses a myriad of biological actions relevant to the pathogenesis of asthma. While no specific antagonists of PGD2 or 9 alpha,11 beta-PGF2 have been identified, some preliminary studies have suggested that, perhaps, PGD2 may be interacting, at least in part, with thromboxane receptors. In addition, peroxidation of arachidonic acid catalyzed by 5-lipoxygenase produces the leukotrienes, which are extremely potent bronchoconstrictors as well as oedema and mucus secretagogues. Leukotrienes are primary mast cell mediators which may be the vital link to both early (acute) and late (chronic) asthmatic attacks. Research seeking leukotriene antagonists has been intensive. Leading clinical candidates have emerged from Smith Kline and French, Lilly, Merck-Frosst, ICI-Stuart and other groups. However, we must await the outcome of ongoing clinical trials in asthmatics to determine just how important the leukotrienes really are in the pathogenesis of asthma, allergy and inflammation. Thus, modulation of the effects of products of arachidonic acid metabolism may provide a new and more specific treatment for bronchial asthma.
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PMID:Modulation of arachidonic acid metabolites as potential therapy of asthma. 314 Jun 17

In summary, mast cell activation is associated with the release of chemotactic factors, enzymes, proteoglycans, and vasoactive mediators. The vasoactive mediators include the leukotrienes, prostaglandin PGD2, adenosine, PAF, and histamine. Their effects are associated with an early phase reaction. This early reaction in the airways is manifested by cough, wheeze, mucous secretion, and a short-lived bronchospastic response. The release of chemotactic factors perhaps including PAF, eosinophil-directed and neutrophil-directed mediators would be associated with the influx into the airway of a variety of leukocytes although neutrophils and eosinophils predominate. The eosinophil contains a variety of toxic materials including a major basic protein known to kill tracheal epithelial cells. The eosinophil also generates PAF and leukotrienes. It could, therefore, be responsible for a self-sustaining tissue damaging inflammatory infiltrate. And finally, there are the neutral protease enzymes whose function remains unknown. It is tempting to speculate that the vasoactive mediators cause an early phase reaction while the enzymes and chemotactic factors set up the inflammation associated with a late phase response. The clinical pertinence to this has been demonstrated by researchers who studied nonspecific bronchial reactivity in patients who have early phase reactions only as compared with those who have both early and late phase reactions to antigen bronchoprovocation. These individuals with only an early phase reaction following antigen bronchoprovocation have a lesser degree of sensitivity to histamine, ie, it requires more histamine to cause bronchoconstriction, and there is no change in their histamine threshold after their early phase response.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Basic mechanisms in asthma. 316 72

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

Recent evidence suggests that mast cell derived mediators other than histamine are likely to be involved in the pathogenesis of physical urticarias. Much of the work has been performed in idiopathic cold contact urticaria where the presence of neutrophil and eosinophil chemotactic factors, and platelet activating factor-like lipid substances have been previously demonstrated. Now, an increase in prostaglandin D2 measured by GC-MS has been demonstrated in venous blood draining the cold challenged area. This appeared a few minutes later than histamine, but then both substances paralleled the onset, development and subsidence of the urticarial reaction. There appeared to be no quantitative relationship between histamine and PGD2 release. A similar rise in histamine and PGD2 occurred on heat challenge of a subject with the rare localized form of heat urticaria. This rise of both substances was considerably reduced after combined treatment with induction of tolerance and oral indomethacin. The concentrations of PGD2 measured suggested that it plays an indirect role.
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PMID:[New pharmacologic developments in physical urticaria--therapeutic consequences]. 347 18

Mediators released from mast cells and secondary effector cells in the airways contribute to bronchoconstriction of allergic asthma. This study investigates methods for defining the effect of two inflammatory mediators on airway calibre in asthma. In an initial study on three asthmatic subjects, subconstrictor (subthreshold) concentrations of two mast cell derived mediators, histamine and prostaglandin (PG) D2, produced similar displacement to the left of a histamine concentration-specific airways conductance (sGaw) response curve. With both agonists enhancement of histamine-induced bronchoconstriction was greater at low histamine concentrations. Since potentiation of histamine-induced bronchoconstriction was independent of the class of subconstrictor agent given, it is likely to represent a physiological rather than a pharmacological interaction. During provoked asthma different constrictor mediators are likely to be released simultaneously into the airways. A method was therefore devised to investigate the combined effect of equiconstrictor concentrations of two mediators on airway calibre. Two pairs of inhaled bronchoconstrictor agonists were chosen for study: adenosine with methacholine and PGD2 with histamine. For each agonist, concentration-sGaw response curves were constructed, from which were derived the provocation concentrations of agonist causing a 25% fall in sGaw from baseline (PC25) and required to further this to 50% (PC50-25). On separate days, eight subjects received paired inhalations of methacholine-adenosine, methacholine-methacholine and adenosine-adenosine. The concentration used for the first inhalation was the PC25 value and for the second inhalation the PC50-25 value. Before, immediately after the first inhalation, and at regular intervals after the second inhalation, sGaw was followed for 30 min.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The combined effects of two pairs of mediators, adenosine with methacholine and prostaglandin D2 with histamine, on airway calibre in asthma. 353 Jun 10

The immediate and late asthmatic reactions provoked by inhaled allergens have provided useful models enabling the dissection of individual inflammatory cells and their mediators that may contribute to the pathogenesis of asthma. The immediate reaction is considered to be mast cell-mediated on the basis that about 50% of the response is inhibitable by potent and selective H1-receptor antagonists such as terfenadine and astemizole. Additional inhibition (approximately 30%) by the potent cyclooxygenase inhibitor flurbiprofen implies an important role for prostanoids in the immediate response, the most likely mast cell-derived product being prostaglandin (PG) D2. In man, PGD2 is selectively metabolised to 9 alpha 11 beta-PGF2, a unique prostaglandin which shares with PGD2 contractile properties on guinea-pig and human airways smooth muscle. The inability of piriprost, a potent leukotriene synthesis inhibitor, to influence the allergen-provoked immediate reaction raises the possibility that sulphidopeptide leukotrienes play a minor role in this response. The late asthmatic reaction is considered to resemble clinical asthma since it is accompanied by increased responsiveness of the airways to a wide range of stimuli. The late reaction in man is inhibited by nedocromil sodium (4 mg) but only marginally attenuated by salbutamol (200 micrograms) if both drugs are administered prior to allergen challenge. Since salbutamol, in the dose administered, is a potent mast cell-stabilising agent, these findings must question the obligatory role of mast cell mediator release in the pathogenesis of the late response.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Primary and secondary effector cells in the pathogenesis of bronchial asthma. 355 30


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