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)

1. Intravenous administration of substance P (SP) or of the NK1 selective agonist [beta-Ala4, Sar9, Met (O2)11] SP-(4-11) increased vascular permeability in the urinary bladder of urethane-anaesthetized rats, providing evidence for an NK1 receptor-mediated inflammatory response. 2. BW 755C, a dual inhibitor of arachidonate cyclo-oxygenase and lipoxygenase, significantly reduced the plasma extravasation induced by SP, but did not modify the effect of [beta-Ala4, Sar9, Met (O2)11] SP-(4-11). 3. SP-induced microvascular leakage was also inhibited by systemic pretreatment with indomethacin or with the prostaglandin receptor antagonist SC-19220, while it was unaffected by the selective 5-lipoxygenase inhibitor BW A4C or the leukotriene antagonist FPL 55712. 4. Pretreatment of rats with the mast cell degranulating agent compound 48/80 significantly attenuated the inflammatory effect of SP. Indomethacin administration to 48/80-pretreated animals failed to produce further inhibition. 5. These findings indicate that intravascular SP promotes plasma exudation in rat urinary bladder through an NK1-mediated effect on venular permeability and the release of cyclo-oxygenase metabolites of arachidonic acid. The latter effect largely derives from the interaction of the neuropeptide with mast cells.
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PMID:Microvascular leakage induced by substance P in rat urinary bladder: involvement of cyclo-oxygenase metabolites of arachidonic acid. 138 Sep 64

Plasma exudation characterizes the early phase of acute inflammation. The possible role of mast cells and their mediators in this event in immune complex-induced injury was studied. Dye exudation was assessed from 5 min to 2 hr after initiating reverse passive Arthus reaction in mast cell-deficient mice, WBB6F1-W/Wv (W/Wv), and their normal congenic controls, WBB6F1-+/+ (+/+). The response to antibody (10, 30 and 100 micrograms/site, i.d.) was dose- and time-dependent in both groups of mice. At the lower doses of antibody, 10 and 30 micrograms/site, exudation was significantly less (30% and 40%, respectively) in W/Wv as compared to +/+ mice between 15 to 45 min. With 100 micrograms of antibody/site, significant differences between W/Wv and +/+ mice were noted only at 15 and 30 min. The deficit in permeability changes in W/Wv mice was reversed by local mast cell reconstitution. In +/+ mice, pyrilamine and methysergide pretreatment reduced vascular permeability to the same extent by 70, 60 and 35% when stimulated for 30 min with 10, 30 and 100 micrograms of antibody/site, respectively. An equivalent inhibition was observed with the 5-lipoxygenase inhibitor A-63162. None of the inhibitors decreased plasma permeation in W/Wv mice. These results indicate that the mast cell mediators histamine and serotonin regulate vascular permeability early during an immune complex-mediated inflammation. The data also suggest the involvement of leukotrienes and the importance of mast cells in their synthesis. The profile of inhibition in +/+ mice agrees well with the difference in exudation observed between normal and mast cell-deficient mice.
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PMID:Mast cell mediators regulate vascular permeability changes in Arthus reaction. 138 83

Sch 40120 (10-(3-chlorophenyl)-6,8,9,10-tetrahydrobenzo[b] [1,8]naphthyridin-5(7H)-one) is an inhibitor of the 5-lipoxygenase enzyme in rat neutrophils, human neutrophils and the the MC9 murine mast cell clone with IC50 values of 8, 4 and 7 microM, respectively. The drug was examined for its effects on acute inflammatory responses in the paw and pleural cavity of rats. The drug suppressed paw inflammation triggered by a reverse passive Arthus reaction or a subplantar injection of the polysaccharide carrageenan with p.o. ED50 values of 0.2 and 1.5 mg/kg, respectively. In reverse passive Arthus reaction and carrageenan pleurisy models, Sch 40120 was found to suppress both the cellular and fluid components of the acute inflammation. The p.o. ED50 values for inhibition of cells and fluid in pleurisy models were in the range of 0.1 to 0.7 mg/kg. When applied locally to the ears of mice, the drug blocked an arachidonic acid-induced and leukotriene-mediated ear inflammation with an ED50 of 0.072 mg/ear. These findings suggest that Sch 40120 is a potent anti-inflammatory agent that may be particularly useful in the treatment of inflammatory diseases such as psoriasis in which leukotrienes appear to be major mediators of the pathological symptoms that characterize the disease state.
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PMID:Actions of a 5-lipoxygenase inhibitor, Sch 40120, on acute inflammatory responses. 138 87

Stimulation of peritoneal cells from BALB/c, CBA/J or WBB6F1(-)+/+ mice with IgE/antigen caused the release of mast cell granules and leukotriene C4. No leukotriene formation was observed with peritoneal cells from mast cell-deficient WBB6F1-W/Wv mice. Mast cells (greater than 98% purity), separated on metrizamide gradients, did not synthesize detectable amounts of leukotriene C4 when challenged immediately after purification. Co-culture of the mast cells with 3T3 fibroblasts restored the capability of the mast cells to produce leukotrienes. Addition of IL-3 during culture enhanced the synthesis of this eicosanoid. The 5-lipoxygenase inhibitor A-63162 blocked the leukotriene formation. Western blot analysis confirmed the presence of 5-lipoxygenase in connective tissue mast cells. These experiments demonstrate that mouse peritoneal (connective tissue) mast cells can produce significant amounts of leukotrienes.
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PMID:Leukotriene formation by mouse connective tissue mast cells. 141 79

During anaphylaxis the sensitized liver can have substantial capacity for leukotriene production. However, the intrahepatic cellular source for these potent eicosanoid mediators has been unclear so far. We therefore analyzed the appropriate role of resident liver cells in organ-specific generation of leukotrienes by immunohistochemical localization of 5-lipoxygenase, by measurement of cysteinyl leukotriene production in animals or isolated livers and by histochemical monitoring of mast cells in rat, guinea pig and mouse livers, respectively. During anaphylaxis in vivo, these species all generated large amounts of leukotrienes. Immunohistochemistry with rat liver demonstrated resident mast cells as the predominant cell type in liver containing 5-lipoxygenase. Rat and guinea pig livers contained numerous mast cells and produced substantial amounts of leukotrienes on antigen challenge; in contrast, mouse livers neither showed detectable mast cells nor generated leukotrienes when stimulated analogously. Infusion of histamine or serotonin (1 mmol/L each) or of the degranulating substance P (8 mumol/L) did not elicit leukotriene generation in rat livers. Furthermore, substantial degranulation of liver mast cells by compound 48/80 (0.5 mg/kg body mass) was paralleled by only modest leukotriene formation (63 +/- 10 pmol in bile/kg body mass/30 min). These results indicate that during anaphylaxis mast cells are the main intrahepatic cells initiating leukotriene production and that such leukotriene generation is likely to be independent of mast cell degranulation or the release of histamine or serotonin.
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PMID:Resident mast cells are the main initiators of anaphylactic leukotriene production in the liver. 144

Immune injury of the basement membrane occurs in various human diseases. In the present study, an antibody specific for the basement membrane of mouse skin was injected i.d. into mast cell-deficient WBB6F1-W/Wv mice and their congenic controls, WBB6F1-(+/+). Vascular permeability changes, oedema and fibrin deposition were assessed. Plasma permeation, evaluated by dye exudation, was time and dose dependent in both groups of animals, but significantly less in WBB6F1-W/Wv than in normal mice. At 30 min, the time of maximum in congenic controls, extravasation of the dye was 60% less in mast cell-deficient than in WBB6F1-(+/+) mice. Pyrilamine decreased exudation by 40% in normal but not in WBB6F1-W/Wv mice, indicating that the mast cell mediator histamine contributes to the increase in vascular permeability. Mast cell deficiency also markedly reduced fibrin deposition as assessed by direct immunostaining. Oedema, measured as skin thickness, was 60% less in WBB6F1-W/Wv mice than in their congenic controls. A 5-lipoxygenase blocker inhibited plasma exudation and oedema in normal but not in WBB6F1-W/Wv mice. This indicates that leukotrienes are involved in these processes and that mast cells are important for their production. Local mast cell reconstitution restored dye extravasation and oedema to normal levels as well as the effect of the 5-lipoxygenase inhibitor. These findings show that mast cells and their mediators participate in these inflammatory processes which were initiated by the deposition of IgG on the skin basement membrane.
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PMID:Role of mast cells in plasma permeation due to immune injury of the skin basement membrane. 147 86

Immunologic basement membrane injury occurs in certain human diseases. We investigated the role of mast cells in the initiation of inflammation induced by selective deposition of antibody on the basement membrane in the skin. Intradermal injection of the antibody into mast cell-deficient WBB6F1-W/Wv mice and their congenic controls, WBB6F1-+/+, caused C (C3) deposition and tissue damage preferentially at the dermo-epidermal junction (basement membrane). Damage occurred earlier and was more extensive in normal than in WBB6F1-W/Wv mice. Hemorrhage in WBB6F1-W/Wv was reduced by 50%. In both groups of mice, a dose- and time-dependent neutrophil infiltration reached maximum at 8 h. At the peak, neutrophil accumulation in WBB6F1-W/Wv was only 50% of that in normal mice. Mast cell reconstitution of WBB6F1-W/Wv mice normalized the inflammatory response. Pretreatment with a 5-lipoxygenase inhibitor, A-63162, reduced neutrophil infiltration by 60% in normal but not in WBB6F1-W/Wv mice. Mast cell repletion restored the effect of A-63162. The results indicate that mast cells are important for the initiation of inflammation induced by the deposition of antibody on the basement membrane and the production of leukotrienes participating in neutrophil elicitation.
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PMID:Mast cells enhance the antibody-mediated injury of skin basement membrane in mice. 152 88

Airway damage secondary to eosinophil activation is thought to contribute to the development of asthma. Using the fluorescent dye FURA-2 to measure the concentration of cytosolic calcium, we found that supernatants from anti-IgE-stimulated human lung mast cells increased cytosolic calcium in human eosinophils. We then examined the major mast cell mediators (histamine, PGD2, platelet-activating factor (PAF), eosinophil chemotactic factor of anaphylaxis (ECF-A), leukotriene (LT)C4 and LTB4) for their ability to increase cytosolic calcium in eosinophils. We found that both PAF (5 x 10(-9) to 5 x 10(-6) M) and PGD2 (two of five donors responsive at 1 x 10(-9) M) were potent stimuli for calcium mobilization. LTB4 (10(-8), 10(-7) M) and histamine were also active, although higher concentrations of histamine were required to see a response (3 x 10(-7) to 10(-5) M). LTC4, val-ECF-A, and ala-ECF-A were inactive. The effects of PGD2 and histamine were specific for eosinophils, although LTB4 and PAF increased calcium in both neutrophils and eosinophils. The histamine-induced increase in intracellular calcium was not blocked by the H1 or H2 antagonists pyrilamine or cimetidine (10(-4) M), respectively; however, the response to 10(-6) M histamine was completely blocked by the specific H3 antagonist thioperamide (10(-6) M). To evaluate the relative contribution of these stimulatory mast cell mediators on the calcium mobilizing activity in supernatants from anti-IgE-stimulated human lung mast cell (HLMC), we examined the effect of supernatants from HLMC pretreated with indomethacin and/or the 5-lipoxygenase pathway inhibitor MK886. These supernatants were added to FURA-2-loaded eosinophils that had been preincubated with thioperamide and/or the PAF antagonist WEB-2086. We found that the increase in eosinophil calcium in response to supernatants from anti-IgE-stimulated-HLMC was totally inhibited only when the mast cells were challenged in the presence of indomethacin and MK886, and the eosinophils were preincubated with thioperamide. WEB-2086 had little effect. When we examined the effect of these mediators on eosinophil secretory function, we found that PGD2 (not histamine) primed eosinophils for enhanced release of LTC4 in response to the calcium ionophore A23187. We conclude that the activation of eosinophils by PGD2 and other mast cell products may contribute to airways inflammation that is characteristic of asthma.
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PMID:Mast cell mediators prostaglandin-D2 and histamine activate human eosinophils. 158 43

The response to antigen (trinitro-phenyl-haptenized ovalbumin) and the modulatory role of several antiallergic drugs was studied in isolated hearts from actively sensitized rats. Antigen induced a triphasic effect on coronary flow (CF) and left ventricular pressure (LVP) characterized by short-term increase (0-1.5 min = phase 1) and a severe decrease (1.5-7.5 min = phase 2) followed by a less pronounced long-lasting decrease (7.5- greater than 20 min = phase 3). The first phase was accompanied with a substantial release of 5-hydroxytryptamine (5-HT), histamine, and leukotrienes measured in cardiac effluents. The histamine2 (H2)-receptor antagonist cimetidine (60 microM) reversed the antigen-induced increase in CF to a decrease. In contrast, H1-receptor blockade by mepyramine (6 microM) had no effect. Methysergide (10 microM) and ketotifen (0.1 microM) evoked a mild suppression during all three phases. Indomethacin (10 microM) was almost inactive while tolfenamic acid (1 microM) was slightly active in this respect during phase 2. Addition of the 5-lipoxygenase inhibitor AA 861 (1 microM) resulted in complete suppression of the antigen-induced decrease in CF. The leukotriene antagonist FPL 55712 (5 and 50 nM) evoked a dose-dependent suppression with respect to the anaphylactic phases 2 and 3. A similar reduction was obtained with sodium cromoglycate (1 mM). AA 861, FPL 55712, and sodium cromoglycate also suppressed the antigen-induced decrease in LVP. The antigen-induced histamine release was not affected by the aforementioned drugs. Our results provide evidence that H2-receptor blockade during cardiac anaphylaxis enhances coronary constriction and may be detrimental in this condition. On the other hand, leukotriene antagonists and 5-lipoxygenase inhibitors may exert beneficial effects during cardiac anaphylaxis. Further experiments in this area are needed to clarify the precise role of mast cell-generated mediators in cardiac anaphylaxis possibly leading to new therapeutic approaches in this life-threatening disorder.
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PMID:Characterization and modulation of antigen-induced effects in isolated rat heart. 172 33

Immune complex-induced injury is an important pathogenic factor in antibody-mediated nephritis, systemic lupus erythematosus, rheumatoid arthritis, and other diseases. In this study we investigated the role mast cells in immune complex-mediated injury in mouse skin. Reverse Arthus reaction was induced in mast cell-deficient WBB6F1-W/Wv mice and their congenic controls (WBB6F1(-)+/+). Serial skin sections were evaluated for neutrophil infiltration, edema, and hemorrhage. In WBB6F1-W/Wv mice the neutrophil influx was only 40% and edema 60% of that in congenic controls. Hemorrhage was also significantly reduced in the mast cell-deficient mice. After mast cell reconstitution, the magnitude of the reaction in WBB6F1-W/Wv was equivalent to that in WBB6F1(-)+/+ mice. Mast cell release in reverse Arthus reaction was evaluated by measuring fluorescence intensity after avidin-FITC staining of mast cell granules. There was a 70% decrease in fluorescence intensity. The 5-lipoxygenase inhibitor A-63162 significantly decreased neutrophil accumulation (40%), edema (60%), and hemorrhage in WBB6F1(-)+/+, but not in mast cell-deficient mice. Mast cell reconstitution of WBB6F1-W/Wv mice restored the effect of A-63162. The results indicate that mast cells and their mediators, including leukotrienes, make an important contribution to reverse Arthus reaction.
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PMID:Augmentation of reverse arthus reaction by mast cells in mice. 183 74


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