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)

Mast cells are secretory cells strategically located in the vicinity of blood vessels where they can readily initiate and modulate various inflammatory processes, including plasma exudation and leukocyte infiltration. We have previously shown that 50% of the neutrophil influx during immune complex peritonitis in mice is due to mast cells. Eicosanoids are important mediators of various inflammatory processes including neutrophil infiltration. The possibility that mast cells are essential for the production of leukotrienes (LT) involved in the elicitation of neutrophils in immune complex peritonitis was investigated in mast cell-deficient, WBB6F1-W/WV, and normal, WBB6F(1-)+/+, mice. The time course and amounts of immunoreactive PGE2, 6-keto-PGF1 alpha, and TX3B2 released into the peritoneal exudates were similar in both sets of mice. LTB4 and LTC4 levels, however, were twofold higher in +/+ than in W/WV mice 2 h after stimulation. HPLC analysis of the peritoneal exudate confirmed the presence of leukotrienes. The 5-lipoxygenase inhibitor A-63162 blocked leukotriene production in a dose-dependent manner in both sets of mice. However, this compound caused a significant reduction (60%) of neutrophil infiltration only in WBB6F(1-)+/+ but not in the mast cell-deficient mice. Mast cell reconstitution of WBB6F1-W/WV mice restored the effect of A-63162 on PMN recruitment. These data suggest that mast cells in the vicinity of blood vessels are important for the synthesis of leukotrienes responsible for PMN recruitment.
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PMID:Mast cells are critical for the production of leukotrienes responsible for neutrophil recruitment in immune complex-induced peritonitis in mice. 188 Apr 19

The extent of ethanol-induced acute gastric lesions, gastric leukotriene C4 (LTC4) levels, and the number of gastric mucosal mast cells were examined in mast cell-deficient W/Wv mice, normal litter-mate +/+ mice, and bone marrow-reconstituted W/Wv mice. After administration of ethanol, +/+ mice developed gastric lesions and elevation of gastric LTC4 levels in a dose dependent manner. In mast cell-deficient W/Wv mice, the extent of gastric lesions was far less than that of +/+ mice and the level of gastric LTC4 was not significantly altered. This difference was not due to anemia because blood-transfused non-anemic W/Wv mice were still resistant to ethanol-induced gastric lesions. When W/Wv mice were reconstituted with +/+ bone marrow cells, their natural resistance against ethanol-induced gastric lesions was abrogated. The extent of gastric lesions of bone marrow-reconstituted W/Wv mice paralleled with the increase in number of gastric mucosal mast cells and also with the level of gastric LTC4. Furthermore, ethanol-induced gastric lesions in bone marrow-reconstituted W/Wv mice was inhibited by pretreatment with 5-lipoxygenase inhibitor, AA-861, in a dose dependent manner. These results suggest that LTC4 may, even if it is not a prerequisite factor for ethanol induced acute gastric lesions, act as the amplitier in the sequential events of the pathogenesis.
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PMID:Natural resistance of W/Wv mice to ethanol-induced gastric lesions and its abrogation by bone marrow grafting: possible role of mast cells and LTC4. 188 87

The extent of acute gastric lesions produced by intragastric administration of ethanol in mice paralleled gastric leukotriene (LT) C4 levels. Furthermore, an inverse dose-response relationship was observed between the extent of gastric lesions and the number of mast cells in the gastric mucosa. When mice were pretreated with the 5-lipoxygenase inhibitor, AA-861, both the extent of ethanol-induced gastric lesions and the level of gastric LTC4 decreased dose-dependently. In contrast, when mice were pretreated with the LTC4 receptor antagonist, FPL-55712, the extent of ethanol-induced gastric lesions was depressed without significant reduction of gastric LTC4 level. These results indicate that both production of LTC4 and also subsequent binding of LTC4 to the receptors is important for the pathogenesis of gastric lesions and suggest that mast cell-derived LTC4 plays a major role in the development of ethanol-induced gastric lesions.
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PMID:The possible role of LTC4 in the pathogenesis of ethanol-induced gastric lesions in mice and their prevention by 5-lipoxygenase inhibitor AA-861, and leukotriene receptor antagonist FPL-55712. 190 Oct 44

A cloned murine mast cell line designated MC9 expresses a 5-lipoxygenase activity when stimulated with the ionophore A23187. Upon addition of 0.5 microM ionophore, MC9 cells produce 270 +/- 43 pmoles 5-HETE, 74 +/- 40 pmoles 5,12 diHETEs and 65 +/- 31 pmoles LTC4/10(6) cells from 37 microM exogenously added [1-14C]arachidonic acid in two minutes. 5-HETE and 5,12-diHETES, including LTB4 were identified by GC/MS whereas LTC4 was confirmed by HPLC mobility, bio-assay, RIA and enzymatic transformation. The principal cyclooxygenase products were PGD2 and TxB2 (8.5 +/- 2.4 and 5.4 +/- 1.2 pmoles/10(6) cells respectively). Prostanoids were identified by comigration with authentic standards on two-dimensional thin layer chromatograms. Production of arachidonic acid lipoxygenase metabolites stimulated with ionophore proved relatively insensitive to removal of extracellular Ca+2 and chelation by EGTA. In addition, MC9 5-lipoxygenase required only low micromolar amounts of exogenous arachidonic acid for maximal activity. Whereas production of arachidonic acid metabolites lasted only two to five minutes, histamine release stimulated with ionophore was not initiated until 5 minutes (12 +/- 3% cellular histamine) and continued for 30 minutes (37 +/- 7% cellular histamine). Although these cells metabolize arachidonic acid differently from the classic peritoneal-derived mast cell, they resemble subpopulations found in certain tissues (such as mucosa) and should be useful in understanding the biochemistry of mast cell mediator release.
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PMID:Ionophore-stimulated lipoxygenase activity and histamine release in a cloned murine mast cell, MC9. 240 98

Mucosal mast cells constitute the subclass of IgE-FcR-bearing cells for which the murine bone marrow derived mast cell (BMMC) is an in vitro model. BMMC can be induced by an IgE-dependent mechanism to biosynthesize prostaglandin D2, several 5-lipoxygenase products, and an alkyl-ether phospholipid metabolite, as well as to degranulate. By introduction of selective enzyme inhibitors, it was determined that the bioavailability of each mediator class occurred without regulatory effects on the others. Additionally, since BMMC divide in culture, cell responsiveness for secretion of each mediator class was shown to be independent of the state of proliferation by employing three different nontoxic inhibitors of cell division.
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PMID:Pharmacologic regulation of mediator generation and release from the murine bone marrow derived mast cell. 240 10

We investigated the release of the 5-lipoxygenase derivatives of arachidonic acid (AA) in purified human basophils and compared them with similar results obtained in the human lung mast cell. We have shown that purified basophils (average purity = 51 +/- 6%) challenged with 0.1 microgram/ml anti-IgE released histamine (35 +/- 9%), and LTC4 (32 +/- 10 ng/10(6) cells) but failed to release measurable quantities of immunoreactive LTB4. In contrast, the non-specific stimulus, A23187, caused the release of histamine and both LTC4 (279 +/- 95 ng/10(6) cells) and LTB4 (148 +/- 41 ng/10(6) cells). Closer analysis of the data revealed an inverse relationship between the levels of LTB4 released and the purity of the basophils, strongly suggesting that the contaminating monocytes were responsible for LTB4 synthesis. Purified human lung mast cells have been shown to release 6 ng of immunoreactive LTB4/10(6) cells, indicating that basophils release significantly less LTB4 following an IgE-mediated challenge. In a series of experiments using highly purified basophils prelabeled with [3H]AA, we demonstrated that exposure to 0.1 microgram/ml anti-IgE led to the release of [3H]LTC4, with no detectable [3H]LTB4, whereas exposure to 1.0 micrograms/ml A23187 caused the release of [3H]LTC4 and smaller quantities of [3H]LTB4, [3H]LTD4, and [3H]LTE4. We failed to detect any [3H]LTB4 in the cell pellet following challenge with either anti-IgE or A23187, indicating that LTB4 was not synthesized and retained within the cell pellet. Finally, we found that exogenously added [3H]LTB4 was not metabolized, either by basophils alone or by basophils stimulated with anti-IgE (0.1 microgram/ml).
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PMID:Purified human basophils do not generate LTB4. 244 28

Intravital microscopy of the hamster cheek pouch was adopted to serve as a model for quantitative studies of microvascular dynamics and parallel measurements of histamine release during immediate-type mast cell-dependent reactions. Topical challenge with specific antigen in the cheek pouch of immunized hamsters caused an acute inflammatory reaction, including leakage of plasma, vasodilation, and accumulation of leukocytes. Several lines of evidence indicated that the response was due to activation of mast cells: 1) an almost identical inflammatory reaction was seen after challenge with the mast cell secretagogue compound 48/80; 2) both antigen and compound 48/80 evoked distinct mast cell degranulatio and histamine release; 3) blockage of histamine 1-receptors reduced the plasma leakage response (but not leukocyte accumulation) to antigen and compound 48/80 in a very similar manner. In addition, fluorescein-labelled antigen bound specifically to mast cells in cheek pouches of immunized animals, suggesting involvement of mast cell-fixed antigen-specific antibodies, possibly immunoglobulin E. It is suggested that vasodilating prostaglandins exert both pro- and anti-inflammatory actions in vivo, and that they modulate acute allergic inflammation by i) inhibition of inflammatory mediator release, most likely unrelated to prostanoid-induced vasodilation, but caused by cAMP elevation in the mediator-secreting cells, and ii) enhancement of the target action of individual inflammatory mediators (i.e. plasma leakage and leukocyte emigration), most likely as a direct consequence of prostaglandin-induced vasodilation. This view is based on the following observations in the hamster cheek pouch: 1) Inhibition of prostaglandin synthesis with two different nonsteroidal anti-inflammatory drugs (NSAIDs) greatly potentiated plasma leakage, leukocyte emigration and histamine release after challenge with antigen or compound 48/80. The enhanced antigen-induced extravasation of plasma and leukocytes was significantly reduced by 5-lipoxygenase inhibitors, but was unaffected by PAF-receptor antagonism. 2) All aspects of NSAID-induced potentiation, including the increased histamine release, were effectively prevented by topically applied prostaglandin E2 (PGE2, 30 nM), which per se caused a five-fold increase in arteriolar blood flow. Moreover, PGE2 as well as prostaglandin I2 (PGI2) in vasodilating concentrations suppressed the antigen-induced plasma leakage also in the absence of NSAID treatment. 3) In contrast to the mast cell-dependent reactions, the inflammatory effects of individual mediators histamine, leukotrienes B4 and C4) were not influenced by NSAID treatment, and were markedly enhanced by both PGE2 and PGI2.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Intravital microscopic studies on acute mast cell-dependent inflammation. 247 89

Leukotrienes (LT) C4, D4, and E4 are major contributors to the pathobiology of human bronchial asthma. Therefore, it is likely that compounds that antagonize the action or inhibit the formation of LTs will be useful therapeutic agents. We have studied the effects of LT antagonists, 5-lipoxygenase inhibitors and selected standards in a model of LT-mediated allergic bronchospasm in guinea pigs. Sensitized animals were pretreated with mepyramine, indomethacin and propranolol to eliminate the influence of histamine, prostaglandins, thromboxanes and circulating catecholamines. In these animals, inhalation of antigen resulted in a bronchospasm consistent with a LT-mediated response that was slow in onset, of long duration and was inhibited by the selective LTD4, antagonists FPL-55712, LY-171,883 and ICI-198,615. ICI-198,615 was approximately 50-times more potent than FPL-55712 by the intravenous and intratracheal routes. However, of thirteen compounds known to inhibit 5-lipoxygenase and LT biosynthesis in vitro only phenidone, piriprost and AA-861 were active in this in vivo model. The allergic bronchospasm was inhibited by bronchodilators (e.g. PGE2, aminophylline and forskolin) and by some mast cell stabilizers, but was otherwise insensitive to other pharmacological classes of compounds including calcium channel blockers and antagonists of serotonin, acetylcholine and platelet-activating factor. This model seems useful and reasonably selective for the evaluation of new antianaphylactic compounds that are LT antagonists. The inactivity of many 5-lipoxygenase inhibitors in this model suggests they do not inhibit LT formation in vivo.
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PMID:The effect of leukotriene antagonists, lipoxygenase inhibitors and selected standards on leukotriene-mediated allergic bronchospasm in guinea pigs. 257 32

Leukotrienes are synthesised from arachidonic acid via the 5-lipoxygenase pathway in neutrophils, eosinophils, monocytes/macrophages, basophils and certain mast cell populations. Their synthesis is closely regulated by several known factors and the cells which contain 5-lipoxygenase do not all possess the capability to synthesise all of the leukotrienes. Neutrophils produce leukotriene B4, which attracts other neutrophils, whereas the leukotriene C4, produced by eosinophils, increases the contractile activity of smooth muscle. Monocytes/macrophages are able to produce both of these leukotrienes. Receptor sites for leukotriene B4 have been identified on monocytes and neutrophils and receptors for leukotriene D4, a cleavage product of leukotriene C4, have been defined in pulmonary tissue. In animals, sulphidopeptide leukotrienes have been shown to cause potent vasoconstriction resulting in increased blood pressure and increased vascular permeability leading to hypovolaemia. These leukotrienes also depress renal (in animals) and pulmonary (in animals and humans) function, the latter probably as a result of effects on peripheral rather than central airways. In patients with mild asthma, however, there is no differential activity of this type. The sulphidopeptide leukotrienes caused wheal and flare when administered intradermally in healthy volunteers, which was of considerably longer duration than that induced by prostaglandin D2. Conversely, leukotriene B4 caused accumulation of neutrophils in the absence of wheal and flare. Studies into the effects of dietary fish oil showed that 2 constituents, docosahexanoic acid and eicosapentaenoic acid (EPA), inhibit the conversion of arachidonic acid by cyclo-oxygenase, but not by 5-lipoxygenase. Furthermore, 5-lipoxygenase converts EPA to a pentene series of leukotrienes and the sulphidopeptide derivatives possess similar activity to their tetrameric counterparts.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The role of arachidonic acid metabolites in local and systemic inflammatory processes. 303 59

In order to identify regulatory steps in leukotriene synthesis, the biochemical characteristics of a 5-lipoxygenase activity in the 100,000 xg supernatant from sonicates of cells of an IL-3 dependent murine mast cell clone, MC-9 were determined. Principal products from exogenous 14C-arachidonic acid were identified as leukotriene B4, diastereomeric 5,12-dihydroxy-eicosatetraenoic acids (5,12 diHETEs) 5-hydroperoxy and hydroxyeicosatetraenoic acids (5-HPETE and 5-HETE) as well as a novel metabolite 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE). The crude lipoxygenase activity had a pH optimum of 6.9 and was highly dependent upon added Ca++. The effective Ca++ concentration for 50 per cent activation (EC50) was 3 microM. Activity was also stimulated by ATP (EC50 = 160 microM). The cytosolic 5-lipoxygenase activity exhibited a biphasic concentration dependence for arachidonic acid with maximum product formation occurring at 35 microM (ca. 20 nmole/mg/4 min). The lipoxygenase activity exhibited apparent lag phase kinetics which were more pronounced at low protein concentrations (0.3 mg/ml). In addition, the lag phase was greatly accentuated by the addition of a hydroperoxide scavenging system consisting of glutathione (1 mM) plus glutathione peroxidase (0.4 unit/ml). In contrast, addition of any of several hydroperoxides, i.e. 5-,8-,9- or 15-HPETE (EC50 ca. 1 microM), but not the corresponding alcohols (5-HETE and 15-HETE), shortened the lag phase. These results show that the 5-lipoxygenase requires hydroperoxide for activation and that cellular level of hydroperoxides may be an important factor regulating leukotriene synthesis.
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PMID:Modulation of the 5-lipoxygenase activity of MC-9 mast cells: activation by hydroperoxides. 309 36


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