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)

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

Human dispersed lung cells containing 5-10% mast cells synthesised and released large quantities of prostaglandin D2 (PGD2) and thromboxane B2 (TXB2), with either IgE-dependent activation or ionophore A23187 challenge. The generation of these prostanoids and the release of histamine was related to the strength of activation stimulus. After activation the release of histamine and PGD2 proceeded in parallel, and the significant correlation between the release of these mediators suggests a common mast cell origin. This hypothesis is supported by cell enrichment experiments using Percoll density gradients. Prostaglandin D2 and histamine release was always associated with those fractions containing mast cells, whereas the generation of TXB2 was mainly associated with cells of the monocyte-macrophage series. The putative 5-lipoxygenase inhibitor 6,9-deepoxy-6, 9-(phenylimino)- 6,8-prostaglandin I1 (U-60,257, Piriprost) had complex inhibitory and potentiating effects on immunoreactive leukotriene C4 generation from ionophore activated human lung cells. The drug also had a surprising potentiating action on PGD2 release, while simultaneously inhibiting the generation of TXB2. The release of prostanoids from human lung cells is discussed in relation to the putative role of prostaglandins in asthma, with particular emphasis on the pharmacological actions of PGD2 on human airway function in vivo.
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PMID:The generation of prostaglandins by human lung and their effects on airway function in man. 351 76

This study was undertaken to determine if a plasma protease such as thrombin, a highly specific procoagulant enzyme that has numerous effects on platelets, endothelial cells, and smooth muscle cells, could mediate mast cell activation processes. Our results indicate that at near physiologic levels, thrombin can rapidly trigger mast cell degranulation without activating the 5-lipoxygenase system.
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PMID:Thrombin-induced degranulation of cultured bone marrow-derived mast cells. 620 76

Guinea pig lung mast cells can be isolated and purified to high purity. This has given us the opportunity to study in greater detail mediator release from these cells. Both immunologic (ovalbumin sensitized) and nonimmunologic (calcium ionophore, CaI) stimuli caused a dose-dependent release of histamine and pLT from monodispersed lung cells and highly purified lung mast cells. Examination of the time release curve for pLT revealed a 5-min lag in the release of this mediator and a peak release at 60 min after challenge with antigen. Verification of pLT release was obtained by use of the 5-lipoxygenase inhibitor A64077 (Zileuton). Pretreatment of lung mast cells with the 5-lipoxygenase inhibitor prevented release of pLT by either antigen or CaI but had no appreciable effect on histamine release (HR). The pulmonary mast cell appears to be an important contributor to pLT release in the guinea pig lung.
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PMID:Peptidoleukotriene (pLT) release from guinea pig lung mast cells. 751 58

1. The sensory neuropeptide substance P (SP), when released from sensory nerves, has been implicated in the development of neurogenic inflammation. In the present study, using an in vivo model system, we have characterized and investigated the mechanisms underlying SP-induced leukocyte accumulation and oedema formation in the guinea-pig. 2. Intradermally injected SP (i.d., 10(-13) - 10(-9) mol per site), induced a dose- and time-dependent accumulation of 111In-neutrophils, 111In-eosinophils and oedema formation as measured by the local accumulation of i.v. injected 125I-albumin. The leukocyte accumulation evoked by SP was significant at 10(-10) and 10(-9) mol per site, whereas oedema formation was significant at the lowest dose tested (10(-13) mol per site). 3. The NK1 receptor antagonists, CP-96,345 (1 mg kg-1, i.v.) and RP-67,580 (10 micrograms per site, i.d.), significantly attenuated the oedema formation induced by the lower doses of SP. Oedema formation and leukocyte accumulation induced by 10(-9) mol per site SP were unaffected by either antagonist. 4. SP-elicited responses were not significantly affected by the platelet activating factor (PAF) receptor antagonist, UK-74,505 (2.5 mg kg-1, i.v.) or the H1 histamine receptor antagonist, chlorpheniramine (10(-8) mol per site, i.d.). However, the 111In-eosinophil accumulation, but not the 111In-neutrophil accumulation or oedema formation, induced by SP was significantly inhibited by the specific 5-lipoxygenase (5-LO) inhibitor, ZM-230,487 (10(-8) mol per site, i.d.). 5. The accumulation of both 111 In-neutrophils and 111 In-eosinophils induced by SP was abolished in guinea-pigs treated i.v. with an anti-CD18 monoclonal antibody 6.5E F(ab')2 (2.5 mg kg-1). The oedema response was unaffected in these animals.6. These results suggest that SP-induced inflammatory events may be mediated via two mechanisms involving NK1 receptor-dependent and independent pathways. Oedema formation induced by the lower doses of SP may be mediated via the direct activation of NK1 receptors whilst, at higher doses, oedema formation and leukocyte accumulation may be mediated via the release of secondary mediators, possibly mast cell derived, with 5-LO products playing an important role in the leukocyte infiltration. The leukocyte accumulation, but not the oedema induced by SP, is dependent on the expression of the CD18antigen on leukocytes.
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PMID:Substance P-induced inflammatory responses in guinea-pig skin: the effect of specific NK1 receptor antagonists and the role of endogenous mediators. 754 89

To study cytokine regulation of the 5-lipoxygenase (5-LO)/leukotriene (LT) synthase pathway we have developed mouse bone marrow-derived mast cells (BMMC) that minimally express each protein of the pathway by using a novel culture system, lacking interleukin (IL)-3. When mouse bone marrow cells were cultured for 5 weeks with 100 ng/ml c-kit ligand (KL) and 10 units/ml IL-10, a population of > 95% mast cells was obtained. These cells generated 8.3 +/- 4.5 ng of LTC4/10(6) cells and 8.1 +/- 2.4 ng of prostaglandin (PG) D2/10(6) cells after IgE-dependent activation. When these BMMC were cultured for 2-5 weeks more with 100 units/ml IL-3 in the continued presence of KL and IL-10, the IgE-dependent generation of LTC4 and PGD2 increased to 212 +/- 36 and 25.5 +/- 8.6 ng/10(6) cells, respectively. The dramatic increase in the IgE-dependent generation of LTC4 in response to IL-3 was accompanied by a concomitant increase in expression of 5-LO and 5-LO-activating protein and preceded the increased expression of cytosolic phospholipase A2 and LTC4 synthase. The recognition that IL-3 up-regulates the expression of each protein of the 5-LO pathway for the generation of LTC4 contrasts with our recent finding that KL up-regulates the expression of cytosolic phospholipase A2, prostaglandin endoperoxide synthase-1, and hematopoietic PGD2 synthase and increases the IgE-dependent generation of PGD2 in BMMC developed from bone marrow with IL-3. Thus, developmentally segregated regulation of the prostanoid and cysteinyl leukotriene pathways in lineage-related committed mast cell progenitors reveals the pleiotropism of this effector cell of allergic inflammation, a cytokine/growth factor basis for preferential expression of pathways of eicosanoid biosynthesis, and the particular role of IL-3 in regulating the expression of the proteins of the 5-LO/LTC4 synthase pathway.
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PMID:Interleukin-3 regulates development of the 5-lipoxygenase/leukotriene C4 synthase pathway in mouse mast cells. 755 81

Metabolism of arachidonic acid was studied in the unique human mast cell line HMC-1. By HPLC and/or gas chromatography mass spectrometry (GC-MS), 19 oxygenated metabolites were identified, including monohydroxy acids, leukotrienes, prostaglandins, and thromboxane. Intact cells incubated with the calcium ionophore A23187 and arachidonic acid expressed 5-lipoxygenase activity and produced 5-hydroxyeicosatetraenoic acid (5-HETE) as the major metabolite (745 pmol/10(7) cells) followed by leukotriene (LT) C4 (245 pmol/10(7) cells) and 11-trans-LTC4 (74 pmol/10(7) cells). Low but clearly detectable levels of LTB4 were also observed. The total amounts of 5-LO products were comparable to those obtained with RBL-1 cells and corresponded to approx. 30% of the levels obtained with isolated human polymorphonuclear leukocytes. Time-course experiments revealed that HMC-1 cells contained the enzyme activities required to metabolize LTC4 into LTD4 and further into LTE4. The profile of prostanoids included, prostaglandin (PG) E2, PGF2 alpha, and PGD2, whereas 6-keto-PGF1 alpha, reflecting prostacyclin formation, could not be detected. Furthermore, we were able to unambiguously establish that HMC-1 cells could produce substantial amounts of thromboxane (TX) A2, measured as TXB2 (0.1-2.2 nmol/10(7) cells). Generation of TXA2 in such quantities, exceeding those of LTC4, suggests that mast cells may be an important source of thromboxane and points to a possible role for these cells in hemostasis and thrombosis. After approx. 10 passages in culture, 5-lipoxygenase activity in HMC-1 cells drastically declined concomitantly with changes in growth behavior and cell morphology. Analysis by Northern and Western blots revealed that loss of 5-lipoxygenase activity correlated well with a reduced 5-lipoxygenase gene expression at both a transcriptional and translational level. This loss of enzyme activity and gene expression may be related to a genetic abnormality propagated in HMC-1 cells, i.e., a 10;16 translocation, which thus involves the chromosome containing the 5-lipoxygenase gene.
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PMID:Arachidonic acid metabolism in the human mast cell line HMC-1: 5-lipoxygenase gene expression and biosynthesis of thromboxane. 759 81

The antiinflammatory activity of rolipram, a selective inhibitor of the cyclic AMP-specific phosphodiesterase (PDE IV), was studied. Rolipram did not inhibit 5-lipoxygenase activity but did inhibit human monocyte production of leukotriene B4 (LTB4, IC50 3.5 microM). Likewise, murine mast cell release of leukotriene C4 and histamine was inhibited. In vivo, rolipram inhibited arachidonic acid-induced inflammation in the mouse, while the low Km-cyclic-GMP PDE inhibitor, zaprinast, did not inhibit. Rolipram had a modest effect on LTB4 production in the mouse, but markedly reduced LTB4-induced PMN infiltration. Beta-adrenergic receptor activation of adenylate cyclase was important for rolipram antiinflammatory activity since beta blockade abrogated arachidonic acid-induced inflammation. Thus, the antiinflammatory profile of rolipram is novel and may result from inhibition of PMN function and perhaps vasoactive amine release and leukotriene biosynthesis. These actions may be dependent upon endogenous beta-adrenergic activity and are likely mediated through inhibition of PDE IV.
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PMID:Effect of selective phosphodiesterase type IV inhibitor, rolipram, on fluid and cellular phases of inflammatory response. 768 37

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

It has been proposed that a primary detector mechanism for tissue infection or injury may be the mast cell that releases agents that recruit leukocytes to the appropriate site at risk. The objective of this study was to evaluate the early mechanisms involved in mast cell-induced leukocyte recruitment. We used intravital microscopy to visualize leukocyte-rolling flux and adhesion in single 25 to 40 microns venules in mesenteric preparations that were treated with the mast cell-degranulating agent, compound 48/80 (CMP 48/80). Superfusion of the rat mesentery with CMP 48/80 caused a dose-dependent rise in the number of rolling and adherent cells, events significantly reduced by: 1) mast cell stabilizers, ketotifen, or cromolyn, and 2) chronic treatment with CMP 48/80 to deplete mast cell constituents. The increase in leukocyte flux associated with CMP 48/80 was blocked by diphenhydramine (H1-receptor antagonist) and an anti-P-selectin Ab (PB1.3), but not by the 5-lipoxygenase inhibitor, MK 886. The reduction in the flux of rolling leukocytes translated into fewer adherent leukocytes with diphenhydramine or PB1.3. The CMP 48/80-induced rise in leukocyte adhesion, but not leukocyte flux, was reduced by the platelet-activating factor (PAF)-receptor antagonist (WEB 2086) and an anti-CD18 Ab (CL26). MK 886 did not prevent the increased leukocyte adhesion. In vitro data revealed that mast cell-derived PAF induced essentially all of the leukocyte adhesion to endothelium or protein-coated plastic. These data suggest that mast cell degranulation induces P-selectin-dependent leukocyte rolling and CD18-dependent leukocyte adhesion via histamine and PAF, respectively.
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PMID:Mechanisms underlying acute mast cell-induced leukocyte rolling and adhesion in vivo. 781 84


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