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)

In the lung, the contraction of smooth muscle, or bronchospasm, is generally caused by an immunologic insult resulting in mast cell degranulation and the release of histamine, slow reacting substances, and other mediators of inflammation (1). Although the immediate response is bronchospasm, continued activation of this sequence of events results in a chronic inflammatory disease. In the uterus, numerous conditions can result in smooth muscle contraction. One major pathophysiological syndrome associated with increased uterine tone and severe rhythmic contraction is primary dysmenorrhea (2). In this disease state, prostaglandins have been shown to play a major role in these contractions (3,4), and inhibitors of cyclooxygenase have proven beneficial in clinical practice (5). Both dysmenorrhea and cervical ripening have been likened to inflammatory reactions due to varying degrees of vasodilation, invasion by inflammatory cells, proliferation of fibroblasts and smooth muscle contraction (6,7). Metabolism of arachidonic acid (AA) via cyclooxygenase to prostaglandins and thromboxanes and via lipoxygenase to hydroxyeicosatetraenoic acids (HETEs) and leukotrienes is an integral part of both the acute and chronic inflammatory reaction in the lung or uterus. The material reviewed here examines the effect of endogenous leukotrienes on both the lung and uterus and suggests that other smooth muscles and pathophysiological states may be more involved with the lipoxygenase pathway of AA metabolism than previously believed.
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PMID:Smooth muscle contraction as a model to study the mediator role of endogenous lipoxygenase products of arachidonic acid. 642 Jun 33

Mediators released from human basophils and mast cells in response to immunologic and other stimuli are felt to be important in the pathophysiology of several nasal and pulmonary disease processes. Recently, we have developed techniques to purify these cells, thus allowing precise ultrastructural, biochemical and pharmacological studies of mediator release. Previous literature has emphasized the similarities of the two cell types including their metachromatic staining and IgE-mediated release of mediators. However, we now appreciate that several differences exist between the two cell types. At the ultrastructural level, basophil release is characterized by individual granules emptying to the cell exterior, while mast cell granules fuse intracellularly and release their contents through cytoplasmic channels. Functionally, basophils are 10- to 30-fold more sensitive than mast cells to anti-IgE, but the kinetics of release are less rapid. Basophil, but not mast cell, release is (I) inhibited by histamine H2 agonists and glucocorticoids; (II) enhanced by PgD2 and (III) modulated by arachidonic acid lipoxygenase metabolites. Significant quantities of slow-reacting substance of anaphylaxis, PgD2 and platelet-activating factor are generated by mast cells. Basophils produce little or none of these mediators. Studies with these purified, relevant human cell types should provide important insights into the cellular basis of hypersensitivity states and their control.
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PMID:Purified human basophils and mast cells: current concepts of mediator release. 657 86

Highly purified porcine phospholipase A2 induced noncytotoxic rat cell degranulation, as indicated by release of histamine without release of the cytoplasmic marker lactate dehydrogenase. Ultrastructural studies using transmission, scanning, and freeze fracture electron microscopic techniques indicated that phospholipase A2-induced degranulation was comparable to that caused by other mast cell secretagogues. Secretory changes noted were fusion of perigranular and plasma membranes, formation of vacuoles containing less electron-dense granules, and exocytosis of the altered granules through pores in the plasma membrane, without alteration in other intracellular organelles. The earliest consistent feature of the exocytotic process (within 1 minute) was the formation of plasma membrane bulges overlying cytoplasmic granules, with depletion of intramembranous particles from the bulges and a reduction in surface microridges. Phospholipase A2-induced mast cell degranulation was blocked by the phospholipase inhibitor 4-bromophenacyl bromide and by eicosa-5,8,11,14-tetraynoic acid (ETYA) but not by indomethacin. Since ETYA inhibits both the cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism and indomethacin only the cyclooxygenase pathway, these findings are compatible with the mediation of phospholipase A2-induced mast cell degranulation by a lipoxygenase product of the released arachidonic acid ETYA, however, may inhibit phospholipase activity directly and thus affect degranulation by phospholipase A2 in this way. These studies indicate that phospholipase A2 can induce mast cell degranulation and provides evidence that is compatible with, but not proof of, mediation of this process by a lipoxygenase product of arachidonic acid metabolism.
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PMID:Phospholipase A2-induced rat mast cell secretion. Role of arachidonic acid metabolites. 681 79

Human LDLs oxidized with Cu2+ are known to promote leukocyte-endothelial cell adhesion (LECA) and albumin leakage in postcapillary venules. The objective of this study was to compare the ability of LDL oxidized with Cu2+ (Cu-LDL), phospholipase A2 plus lipoxygenase (PLA2-LDL), horseradish peroxidase plus H2O2 (HRP-LDL), or -OCl (-OCl-LDL) to promote (1)neutrophil-endothelial cell adhesion (NECA) in vitro and (2)LECA and albumin leakage in rat mesenteric venules. In vitro adhesion assays revealed that only Cu-LDL elicited a dose-dependent NECA response, whereas PLA2-LDL but not normal (N-LDL), HRP-LDL, or -OCl-LDL increased NECA at the highest concentration studied (670 micrograms/mL). The magnitude of the NECA responses elicited by the different forms of oxidized LDL was related to the degree of lipid peroxidation but unrelated to the level of protein oxidation. Local intra-arterial infusion of Cu-LDL, PLA2-LDL, or -OCl-LDL but not N-LDL elicited significant increases in leukocyte adherence and emigration, mast cell degranulation, and albumin leakage in rat mesenteric venules. The LECA induced by all forms of oxidized LDL was not accompanied by significant alterations of venular shear rate.
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PMID:Oxidized LDL-induced microvascular dysfunction. Dependence on oxidation procedure. 748 57

This study was initiated to test the hypothesis that histamine can act as an endothelium-derived contracting factor in bovine isolated intrapulmonary vein. The effects of calcium ionophore, calcimycin (A23187), on isometric tension were compared in unstimulated rings of intrapulmonary vein with and without endothelium. A23187 (0.1-10 microM) induced concentration-related contraction when endothelium was present. Destruction of endothelium markedly inhibited A23187-induced contraction. Methylene blue, hemoglobin or NG-methyl-L-arginine significantly enhanced A23187-induced contraction only in venous rings with endothelium consistent with attenuation of the contraction by the concomitant release of endothelium-derived relaxing factor (nitric oxide) [EDRF(NO)]. Histamine H1 receptor antagonists inhibited, and iproniazid enhanced, contraction elicited by A23187. A23187 induced release of greater amounts of histamine from venous rings with than without endothelium. A23187-induced contraction was not mimicked by the mast cell activator, compound 48/80, and was not inhibited by preexposure to compound 48/80 or in the presence of cromolyn or doxantrazole. A23187-induced contraction was not inhibited by pretreatment with indomethacin, phentolamine, lipoxygenase inhibitors or superoxide dismutase. The results indicate that A23187 induces endothelium-dependent contraction in bovine intrapulmonary vein and support histamine as one major mediator involved. The association of destruction of endothelium with an inhibition of both A23187-induced contraction and histamine release is consistent with the endothelium as a source for histamine which can exert a local vasoconstrictor effect in bovine intrapulmonary vein.
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PMID:Evidence that histamine is involved as a mediator of endothelium-dependent contraction induced by A23187 in bovine intrapulmonary vein. 752 73

Colonic smooth muscle function may be altered in food protein hypersensitivity reactions and could contribute to the clinical manifestation of diarrhea. To characterize such functional changes and elucidate the mediators and mechanisms involved. Hooded-Lister rats were sensitized by intraperitoneal injection of egg albumin (10 micrograms), and controls were sham sensitized with saline. Fourteen days later the contractility of longitudinally oriented distal colonic segments (mucosa intact) were studied in standard tissue baths in response to antigen (Ag) or other agents. After Ag exposure, a contractile response was documented in animals that were sensitized [specific immunoglobulin E (IgE) antibody levels > or = 1:64] and was specific for the sensitizing Ag. Mast cell involvement was suggested by a significant reduction in the number of granulated mucosal mast cells in sensitized tissues after Ag challenge and in the magnitude of the Ag-induced contractile response in the presence of mast cell stabilizers. The antigen-induced response was significantly and independently inhibited by both cyclooxygenase and lipoxygenase enzyme inhibitors and by leukotriene D4 and platelet activating factor receptor antagonists. The Ag-induced response was resistant to histamine and the 5-hydroxytryptamine antagonists, atropine and tetrodotoxin. These results suggest that the food protein-induced contraction of colonic longitudinal smooth muscle in the sensitized rat is due to IgE-mediated mast cell activation with the subsequent production and release of membrane-derived mediators that, in vitro, act directly on the smooth muscle.
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PMID:Intestinal anaphylaxis: mediation of the response of colonic longitudinal muscle in rat. 776 60

1. Eosinophil accumulation and plasma extravasation are features of type I allergic responses. In an attempt to characterize the mediators of these responses, we have examined the local accumulation of 111In-eosinophils and leakage of 125I-human serum albumin (125I-HSA) during passive cutaneous anaphylaxis (PCA) reactions and in response to defined inflammatory mediators in the guinea-pig. Animals were passively sensitized by intradermal injection of anti-bovine gamma globulin antibody (50 microliters, 1/50 dilution). After 20-24 h, animals were injected intravenously with 111In-eosinophils and 125I-HSA for the measurement of cell accumulation and plasma leakage, respectively. 2. When injected into sensitized sites, antigen caused a dose-related increase in the accumulation of 111In-eosinophils and plasma leakage in guinea-pig skin. Time course experiments over 24 h revealed that the maximal rate of 111In-eosinophil accumulation occurred over the first 90 min, with little accumulation at later time points. Plasma leakage was completed within the first 30 min after challenge. Responses to the mast cell degranulator, compound 48/80, exhibited very similar responses to the PCA reaction. 3. Co-injection of antigen with the PAF antagonist, WEB 2086 (10(-7) mol/site) or the 5-lipoxygenase inhibitor, PF 5901 (10(-7) mol/site) did not significantly alter the accumulation of 111In-eosinophils or plasma leakage, whereas these drug doses abolished responses to exogenous PAF (10(-9) mol/site) and arachidonic acid (AA, 3 x 10(-8) mol/site), respectively. The H1 receptor antagonist chlorpheniramine (2.5 x 10(-8) mol/site) did not reduce antigen-induced 111In-eosinophil accumulation. Drug combinations were also injected with antigen into sensitized sites, but were unable to reduce "'In-eosinophil accumulation.4. These results indicate that anaphylactic eosinophil accumulation in this model involves mediators other than histamine, PAF or lipoxygenase products. This is in contrast to plasma leakage in this reaction, which can be abolished by a combination of antagonists blocking these mediators.
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PMID:Investigation of the endogenous chemoattractants involved in 111In-eosinophil accumulation in passive cutaneous anaphylactic reactions in the guinea-pig. 781 29

We previously demonstrated that tracheal hyperreactivity (in vitro) and altered lung functions (in vivo) were induced during a delayed-type hypersensitivity (DTH) reaction in murine lungs. These alterations were transferable with T cells, suggesting that this animal model could be used as a model for cellular IgE-independent immunity. In the present study we demonstrated that depletion of T suppressor/cytotoxic cells failed to abolish the ability of transferred cells to induce hyperresponsiveness. Depletion of T helper cells partially inhibited the induction of hyperreactivity. Depletion of 14-30+ cells (the monoclonal antibody 14-30 reacts with a common isotype of T cell-derived antigen binding molecules [TABM] that can arm mast cells) completely abolished the ability to transfer hyperreactivity. The cromoglycate-like antiasthmatic drug nedocromil, which stabilizes mast cells, inhibited the induction of T cell-mediated hyperresponsiveness. Moreover, in mast cell-deficient mice, T cell-mediated hyperresponsiveness can be less induced compared with normal littermates. These experiments indicate that mast cells play at least a partial role in the induction of airway hyperresponsiveness in this model. Dexamethasone, a well-known inhibitor of phospholipase A2, inhibited the T cell-mediated hyperresponsiveness, whereas the cyclooxygenase inhibitor suprofen did not. This indicated that arachidonic acid metabolites, but not cyclooxygenase products, play a role in the induction of T cell-mediated hyperreactivity. Pretreatment with the lipoxygenase inhibitor AA-861 significantly inhibited the induction of tracheal hyperreactivity. Platelet-activating factor appeared not to be involved in the induction of hyperresponsiveness in this model, because the platelet-activating factor antagonist WEB 2170 failed to abolish the induction of T cell-mediated hyperreactivity. Intravenous injection of purified mast cell-arming TABM, followed by intranasal hapten challenge 30 min later, resulted in increased vascular permeability 2 h after challenge, which is characteristic of the early initiating phase of DTH. In addition, tracheal hyperreactivity (in vitro) and altered lung functions (in vivo) were observed 2 h after challenge. From these data we conclude that airway hyperreactivity and altered lung functions are induced by early steps in the cellular cascade of DTH.
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PMID:T cell-derived antigen binding molecules play a role in the induction of airway hyperresponsiveness. 795 11

The term ocular allergy encompasses a group of diseases in which there is a high frequency of atopy, ocular itching, stringy discharge and a papillary conjunctival reaction. Conditions confined to the lids and conjunctiva (e.g. seasonal allergic conjunctivitis) have a good prognosis but those involving the cornea may result in visual impairment (e.g. atopic keratoconjunctivitis). Mast cell and eosinophil mechanisms are important in al the ocular allergies, but T cell inflammation is prominent only in vernal keratoconjunctivitis, atopic keratoconjunctivitis and giant papillary conjunctivitis. Therapy involves the use of antigen avoidance (where possible), nonspecific medical therapy (e.g. cold compresses, artificial tears), specific medical therapy and, in certain situations, immunotherapy and surgery. Topical antihistamines (often in combination with a vasoconstrictor) and oral antihistamines are widely used in perennial and seasonal conjunctivitis. Levocabastine is a new preparation which is more rapid and potent. Mast cell inhibitors [e.g. sodium cromoglycate (cromolyn sodium)] have a proven track record as safe and effective therapy for all ocular allergic diseases and the newer, more potent nedocromil and lodoxamide are now available. Topical steroids are only indicated in sight-threatening disease due to their serious adverse effects and other therapy should be continued to minimise the dose required. There is a lack of intermediate potency and high potency but safe topical preparations. A number of future possibilities exist, some of which have been partially explored. Cyclo-oxygenase inhibitors have proved of limited use, but inhibitors of lipoxygenase and kinin pathways are awaited. Although results with HEPP have been disappointing, other modulators of mast cell function (e.g. picumast, beta-agonists and phosphodiesterase inhibitors) may prove useful in the future. So far, results with topical cyclosporin in serious disease are very encouraging. Future developments in the manipulation of eosinophilic products, cytokines and adhesion molecules may also be relevant. However, the current situation for those with serious ocular allergy remains a disturbing dependence upon topical steroids, with all the attendant risks.
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PMID:Therapeutic options in ocular allergic disease. 852 55

We have recently reported that the 5-lipoxygenase (5-LO) inhibitor, zileuton, alters lung inflammation produced by segmental antigen challenge in ragweed-allergic human subjects. Specifically, zileuton inhibited the urinary excretion of leukotriene E4 produced by antigen challenge, and the significant increase in bronchoalveolar lavage (BAL) eosinophils observed in subjects on placebo was not seen in subjects on zileuton. In this manuscript, we report additional data obtained during that study which provide information about mechanisms important during IgE-mediated inflammatory reactions in the lung. Three different areas are addressed: 1) the time to recovery of the lung from an IgE-mediated inflammatory response; 2) mechanisms related to the generation of cyclooxygenase products in the lung after antigen challenge and the effect of 5-LO inhibition on the production of cyclooxygenase metabolites; and 3) mechanisms responsible for the production of peptide leukotrienes in the lung and lung injury (as shown by albumin influx into the alveolar air space) 24 h after antigen challenge. We observed the following: 1) a significant BAL eosinophilia and basophilia remained 31 days (range 21-48) after segmental antigen challenge and bronchoalveolar lavage; 2) a decreased quantity of BAL cyclooxygenase products, as well as lipoxygenase products, in the presence of 5-LO inhibition; and 3) correlative analyses which suggest that while eosinophils appear most important for the production of peptide leukotrienes and lung injury 24 h after antigen challenge in subjects taking placebo, other effector mechanisms, perhaps those involving basophils and the initial mast cell triggering event, appear to gain in importance when the IgE-mediated inflammatory reaction is blunted by 5-LO inhibition.
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PMID:Insights into IgE-mediated lung inflammation derived from a study employing a 5-lipoxygenase inhibitor. 858 68


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