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)

To investigate the direct effect of leukocyte adherence to microvessel walls on microvessel permeability, we developed a method to measure changes in hydraulic conductivity (L(p)) before and after leukocyte adhesion in individually perfused venular microvessels in frog mesentery. In 19 microvessels that were initially free of leukocyte sticking or rolling along the vessel wall, control L(p) was measured first with Ringer-albumin perfusate. Blood flow was then restored in each vessel with a reduced flow rate in the range of 30-116 microm/s to facilitate leukocyte adhesion. Each vessel was recannulated in 45 min. The mean number of leukocytes adhering to the vessel wall was 237 +/- 22 leukocytes/mm(2). At the same time, L(p) increased to 4.7 +/- 0.5 times the control value. Superfusion of isoproterenol (10 microM) after leukocyte adhesion brought the increased L(p) back to 1.1 +/- 0.2 times the control in 5-10 min (n = 9). Superfusing isoproterenol before leukocyte adhesion prevented the increase in L(p) (n = 6). However, the number of leukocytes adhering to the vessel wall was not significantly affected. These results demonstrated that leukocyte adhesion caused an increase in microvessel permeability that could be prevented or restored by increasing cAMP levels in endothelial cells using isoproterenol. Thus cAMP-dependent mechanisms that regulate inflammatory agent-induced increases in permeability also modulate leukocyte adhesion-induced increases in permeability but act independently of mechanisms that regulate leukocyte adhesion to the microvessel wall. Application of ketotifen, a mast cell stabilizer, and desferrioxamine mesylate, an iron-chelating reagent, attenuated the increase in L(p) induced by leukocyte adhesion, suggesting the involvement of oxidants and the activation of mast cells in leukocyte adhesion-induced permeability increase. Furthermore, with the use of an in vivo silver stain technique, the locations of the adherent leukocytes on the microvessel wall were identified quantitatively in intact microvessels.
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PMID:Leukocyte adhesion and microvessel permeability. 1077 50

The present study presents a mode of action profile of RLX (6, 7, 8, 9, 10, 12-hexahydro-azepino-[2, 1-b]-quinazoline-12-one) a bronchodilator obtained by the chemical modification in the molecule of alkaloid vasicine (Ex: Adhatoda vesica). The effect of RLX (p.o.) was observed on: (a) mast cell degranulation, (b) release of histamine and prostaglandin E (PGE), (c) 45Ca uptake and (d) activities of cAMP phosphodiesterase (PDEase) and lipoxygenase enzymes in mesenteries/peritoneal mast cells/lung tissue homogenates in rats under systemic anaphylaxis. RLX (10 and 20 mg/kg) inhibited antigen-induced mast cell degranulation and released of histamine from target tissues. An increased outflow of PGE (lungs) and an inhibited 45Ca uptake (peritoneal mast cells) were noted. Lung PDEase and lipoxygenase activities were decreased. These results suggested that RLX could be acting like disodium cromoglycate and aminophyline with additional attributes its oral efficacy and long duration of action.
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PMID:Mechanism of action of 6, 7, 8, 9, 10, 12-hexahydro-azepino-[2, 1-b] quinazolin-12-one-(RLX)--a novel bronchodilator. 1091 99

We examined the effect of sulfapyridine on mast cell-mediated immediate-type allergic reactions. Sulfapyridine (1 and 10 microg/kg) significantly inhibited systemic allergic reaction induced by compound 48/80 in rats. Sulfapyridine (1 and 10 microg/kg) also inhibited significantly local mast cell-mediated immediate-type allergic reactions activated by anti-dinitrophenyl (DNP) IgE. Moreover, sulfapyridine inhibited histamine release dose-dependently in the rat peritoneal mast cells (RPMC) activated by compound 48/80 or anti-DNP IgE. When sulfapyridine was added, the level of cAMP in RPMC, transiently and significantly increased about 4-fold compared with that of basal cells. These results indicate that sulfapyridine inhibits mast cell-mediated immediate-type allergic reactions in vivo and in vitro.
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PMID:Inhibitory effect of mast cell-mediated immediate-type allergic reactions by sulfapyridine. 1095 30

The digitalic glicoside ouabain induces potentiation of rat mast cell histamine release in response to several stimuli, which is mediated by Na+/Ca2+ exchanger. In this work, we studied the effect of ouabain on cytosolic calcium, intracellular pH and histamine release with Ca2+ ionophore A23187 in conditions designed to maximize ouabain-induced potentiation of rat mast cells response. The effect of protein kinase C (PKC), cAMP and phosphatase inhibition was also tested. Ouabain induced an enhancement in histamine release, cytosolic calcium and intracellular pH. The adenylate cyclase activator forskolin reduced the effect of ouabain on histamine release and intracellular pH, but enhanced the effect on cytosolic calcium. PKC activator PMA enhanced the effect of ouabain on histamine release and cytosolic calcium, without affecting intracellular pH. A PKC inhibitor, GF-109203X, reduced ouabain-induced enhancement of histamine release and intracellular pH, but increased the enhancement on cytosolic calcium. Finally, inhibition of protein phosphatases 1 and 2A with okadaic acid, increased the effect of ouabain on histamine release and intracellular pH, but reduced cytosolic calcium in presence of ouabain. This result suggest that ouabain-induced potentiation of rat mast cell histamine release with A23187 is modulated by kinases, and this modulation may be carried out by changes in intracellular alkalinization. However, the mechanism underlying cellular alkalinization remains to be elucidated.
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PMID:Ouabain-induced enhancement of rat mast cells response. Modulation by protein phosphorylation and intracellular pH. 1151 27

Mast cell activation requires Cl(-) flux, which maintains the driving force for entry of extracellular calcium and initiates release of mediators such as histamine. However, chloride channel expression in mast cells has been poorly understood. For the first time, reverse transcriptase-polymerase chain reaction shows that rat-cultured mast cells (RCMC) and peritoneal mast cells (PMC) contain mRNA for the cystic fibrosis transmembrane conductance regulator (CFTR), an important chloride channel. Immunostaining with an anti-CFTR antibody indicates expression of CFTR in PMC and RCMC. Mast cell CFTR is a functional Cl(-) channel because it is capable of mediating Cl(-) flux in response to elevated cAMP. An inhibitor of CFTR-dependent Cl(-) flux, diphenylamine-2-carboxylate down-regulates mast cell mediator release. These results show that rat mast cells express a functional CFTR, which might be important in mediator release.
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PMID:Expression and functional characterization of CFTR in mast cells. 1178 80

Mast cells are implicated in the pathogenesis of a broad spectrum of immunological disorders. These cells release inflammatory mediators in response to a number of stimuli, including IgE-Ag complexes. The degranulation of mast cells is modified by PGs. To begin to delineate the pathway(s) used by PGs to regulate mast cell function, we examined bone marrow-derived mast cells (BMMC) cultured from mice deficient in the EP(1), EP(2), EP(3), and EP(4) receptors for PGE(2). Although BMMCs express all four of these PGE(2) receptors, potentiation of Ag-stimulated degranulation and IL-6 cytokine production by PGE(2) is dependent on the EP(3) receptor. Consistent with the coupling of this receptor to G(alphai), PGE(2) activation of the EP(3) receptor leads to both inhibition of adenylate cyclase and increased intracellular Ca(2+). The magnitude of increase in intracellular Ca(2+) induced by EP(3) activation is similar to that observed after activation of cells with IgE and Ag. Although PGE alone is not sufficient to initiate BMMC degranulation, stimulation of cells with PGE along with PMA induces degranulation. These actions are mediated by the EP(3) receptor through signals involving Ca(2+) mobilization and/or decreased cAMP levels. Accordingly, these studies identify PGE(2)/EP(3) as a proinflammatory signaling pathway that promotes mast cell activation.
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PMID:Receptors and signaling mechanisms required for prostaglandin E2-mediated regulation of mast cell degranulation and IL-6 production. 1237 Mar 97

Prostaglandin D2 (PGD2) is a mast cell-derived mediator that seems to play a role in asthma and allergic diseases. It is the only primary prostanoid to activate human eosinophils, which it accomplishes through the DP2 receptor/chemoattractant receptor-homologous molecule expressed on T helper cell type 2 (Th2) cells (CRTH2). In addition, PGD2 has both pro- and anti-inflammatory effects via the adenylyl cyclase-coupled DP1 receptor. To attempt to identify potent and selective DP2 receptor agonists we compared the abilities of a series of PGD2 analogs to activate eosinophils via the DP2 receptor with their abilities to stimulate adenylyl cyclase in platelets via the DP1 receptor. All of the PGD2 analogs tested stimulated CD11b expression and actin polymerization with a rank order of potency of 15R-methyl-PGD2 > PGD2 > 17-phenyl-18,19,20-trinor-PGD2 > 15S-methyl-PGD2 approximately equal16,16-dimethyl-PGD2 > 11-keto-fluprostenol. Surprisingly, 15R-methyl-PGD2, which has the unnatural R-configuration at carbon 15, was about 5 times more potent than PGD2 and about 75 times more potent than 15S-methyl-PGD2. 15R-methyl-PGD2 (EC50 value of 1.7 nM) was also much more potent as an eosinophil chemoattractant than PGD2 (EC50 value of 10 nM) and 15S-methyl-PGD2 (EC50 value of 128 nM). Cross-desensitization experiments indicated that 15R-methyl-PGD2 acts through the DP2 receptor. None of the PGD2 analogs tested elevated platelet cAMP by more than 20% of the maximal level in response to PGD2. However, in contrast to eosinophils, the most active was 15S-methyl-PGD2. In conclusion, 15R-methyl-PGD2 is the most potent known DP2 receptor agonist, and because of its selectivity and resistance to metabolism, should be a useful tool in probing the physiological role of this receptor in inflammatory diseases.
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PMID:15R-methyl-prostaglandin D2 is a potent and selective CRTH2/DP2 receptor agonist in human eosinophils. 1249 Jun 11

1 The principal aim of the present study was to determine whether long-term treatment of human lung mast cells (HLMC) with the clinically-relevant beta(2)-adrenoceptor agonists, salbutamol and terbutaline, leads to desensitization of beta(2)-adrenoceptor-mediated responses in these cells. 2 The non-selective beta-adrenoceptor agonist, isoprenaline, and the selective beta(2)-adrenoceptor agonists, salbutamol and terbutaline, inhibited the IgE-mediated release of histamine from HLMC. Salbutamol (pD(2); 7.7+/-0.3) and terbutaline (pD(2); 7.3+/-0.2) were roughly equipotent as inhibitors of histamine release although both agonists were less potent than isoprenaline (pD(2); 8.6+/-0.2). 3 Isoprenaline (10(-5) M), salbutamol (10(-5) M) and terbutaline (10(-5) M) enhanced total cell cAMP levels in HLMC over basal by 361+/-90, 150+/-38 and 165+/-35%, respectively. 4 Long-term exposure (24 h) of HLMC to either salbutamol (10(-7) M) or terbutaline (10(-7) M) led to a subsequent reduction in the effectiveness of salbutamol and terbutaline (both 10(-9)-10(-4) M) to inhibit histamine release. However, salbutamol was significantly (P<0.05) more effective than terbutaline at promoting the functional desensitization. 5 Radioligand binding studies, using iodinated cyanopindolol, were performed to determine beta(2)-adrenoceptor density in cell membranes after pretreatment (24 h) of cells with either salbutamol (10(-6) M) or terbutaline (10(-6) M). Both agonists reduced beta(2)-adrenoceptor density in membranes to about the same extent (approximately 25% reduction) but these changes in receptor density were not statistically significant (P>0.05). 6 These data indicate that long-term exposure of mast cells to salbutamol causes greater levels of desensitization to beta(2)-adrenoceptor-mediated responses in HLMC than terbutaline. These findings may have wider clinical significance in the context of asthma treatment as compromised mast cell inhibition could result following long-term exposure of mast cells to short-acting bronchodilators.
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PMID:Desensitization of beta2-adrenoceptor-mediated responses by short-acting beta2-adrenoceptor agonists in human lung mast cells. 1256 76

In an air pouch-type carrageenin-induced inflammation model in rats, the selective cyclooxygenase (COX)-2 inhibitor NS-398 dose dependently inhibited the granulation tissue formation, angiogenesis and the level of vascular endothelial growth factor (VEGF) in the granulation tissue. In culture of the minced granulation tissue, PGE2 induced VEGF production in a concentration-dependent manner. Histamine also induced VEGF production in the granulation tissue in vitro. The H2 receptor antagonist cimetidine, the cAMP antagonist Rp-cAMP and the protein kinase A inhibitor H-89 suppressed the histamine-induced VEGF production in the granulation tissue. However, the H1 receptor antagonist pyrilamine maleate, the H3 receptor antagonist thioperamide, the protein kinase C inhibitors Ro 31-8425 and calphostin C or the tyrosine kinase inhibitor genistein showed no effect. Subcutaneous implantation of a cotton thread in the dorsum of histidine decarboxylase-deficient (HDC-/-) mice, but not in mast cell-deficient (WBB6F1-W/Wv) mice, induced less angiogenesis with lower levels of VEGF in the granulation tissue than in their corresponding wild-type (HDC+/+ and WBB6F1(-)+/+) mice. In HDC-/- mice, the topical injection of histamine or the H2 receptor agonist dimaprit rescued the defective angiogenesis and granulation tissue formation. In addition, cimetidine but not pyrilamine maleate and thioperamide inhibited the histamine-induced angiogenesis in the granulation tissue in HDC-/- mice. These findings suggest that PGE2 and histamine augment angiogenesis in the inflammatory granulation tissue by inducing VEGF production, and histamine induces VEGF production possibly through the H2 receptor--cAMP--protein kinase A pathway.
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PMID:Regulation by prostaglandin E2 and histamine of angiogenesis in inflammatory granulation tissue. 1277 86

Mast cells play a major role in the initiation of inflammation and allergic reactions. As cell numbers are tightly controlled by the interplay of factors affecting cell proliferation, development, and death the regulation of mast cell number may be important. Melanocyte-stimulating hormone inhibits most forms of inflammation by an unknown mechanism. In the present study, we have found that the alpha-melanocyte-stimulating hormone (alpha-MSH) inhibited endotoxin-mediated nuclear transcription factor kappaB (NF-kappaB) activation in different cells correlated with the expression of alpha-MSH receptors. We have also found for the first time that it induces cell death alone or in endotoxin-stimulated mast cells. alpha-MSH-mediated apoptosis was not observed in NF-kappaB overexpressed cells. The inhibitory effect of alpha-MSH was mediated through generation of cAMP, as inhibitors of adenylate cyclase and of protein kinase A reversed its inhibitory effect. Overall, our results suggest that NF-kappaB is the key molecule involved in alpha-MSH-mediated cell death and this may help to regulate mast cell-mediated inflammation.
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PMID:alpha-Melanocyte-stimulating hormone induces cell death in mast cells: involvement of NF-kappaB. 1291 31


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