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 Dextran-induced release of histamine from rat mast cells was inhibited equally in complete and glucose-free Tyrode solution by doxantrazole (0.03-3 micronmol/l), theophylline (0.1-3 mmol/l) and dicumarol (0.01-10 micronmol/litre). 2 Doxantrazole (3 micronmol/l), theophylline (3 mmol/l) and dicumarol (10 micronmol/l) did not reduce the adenosine 5'-triphosphate (ATP) content of mast cells in glucose-free medium. Higher concentrations of dicumarol (56-100 micronmol/l) markedly reduced the cellular ATP content. This reduction was reversed by glucose. 3 Papaverine was a more potent inhibitor of histamine release from mast cells incubated in glucose-free solution than in complete Tyrode solution (dose-ratio = 20). Like antimycin A (L MICRONMOL/L), PAPAVERINE (3 MICRONMOL/L) CAUSED A DEPLETION OF MAST CELL ATP that was greater in the absence (85%) than in the presence (25%) of extracellular glucose. 4 These results suggest that dicumarol, like doxantrazole and theophylline, inhibits histamine release without affecting mast cell energy metabolism. In contrast, papaverine probably inhibits release by depleting ATP that is required for exocytosis. 5 Inhibition of histamine release by dibutyryl cyclic adenosine 3,5'-monophosphate (1-3 mmol/l) was significantly greater when cells were incubated in complete rather than in glucose-free medium.
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PMID:The relationship between energy metabolism and the action of inhibitors of histamine release. 7 78

In mice a single injection of 4 mg of Dextran sulphate within a few days produces an enlargement of area draining lymph nodes and activates basophils/mast cells. This activation is manifested by many-fold increase of mast cell number per lymph node, degranulation of mast cells and appearance of young, immature mast cells capable to synthetize new granules. In contrast to the lymph nodes, the Dextran-injected connective tissue mast cells remained unchanged. This suggest that Dextran sulphate directly activates lymph node mast cells, probably by activation of T-cell suppressor or macrophages.
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PMID:Murine lymph nodes in response to the local administration of dextran sulphate. 215 45

The catalytic activity of human tryptase, a mast cell neutral endoprotease, is expressed when the enzyme is in its tetrameric form, but is lost under physiologic conditions concomitant with a quaternary structural alteration involving conversion to a monomeric form. The associated changes in the CD spectra noted in the current study indicate accompanying alterations in the secondary structure of the protein. In particular, the progressive disappearance of the negative minimum centered at 228 nm suggests an effect on beta-sheet structure, which may be important for monomer-monomer interaction and/or stabilization of catalytic activity. Dextran sulfate, like heparin, stabilizes the catalytic activity and quaternary structure of tryptase and also maintains the native secondary structure of the enzyme at and beyond a temperature of 40 degrees C. Dextran sulfate-stabilized tryptase therefore was used as an immunogen to which were produced three murine mAb (B2, C11, and G4) recognizing the catalytically active form of the enzyme. Inactive tryptase bound to plastic microtiter wells was not recognized by any of the newly made antibodies, whereas inactive tryptase in solution was recognized by G4, which when biotinylated, could be used as a detector antibody in a sandwich ELISA for tryptase. Each of the newly made mAb recognized the catalytically active form of tryptase. Thus, alterations in epitopes, perhaps reflecting tertiary structural alterations as well as changes in secondary and quaternary conformations, occur with tryptase inactivation. A pragmatic result of these newly generated antibodies is the affinity purification to homogeneity of active tryptase by sequential chromatography with B2 coupled to CH-Sepharose and heparin-agarose. Tryptase purified by this technique had a specific activity with p-tosyl-L-arginine methyl ester of 117 +/- 9 U/mg and had 3.9 +/- 0.3 active sites per molecule of active enzyme (134,000 m.w.) as titrated with p-nitrophenyl-p'-guanidinobenzoate. The spectral and immunologic data in the current study are consistent with concerted conformational alterations in the secondary and tertiary as well as quaternary structures of tryptase associated with loss of catalytic activity. Failure to reverse any of these alterations with dextran sulfate suggests that the pathway of tetramer assembly in vivo is more complicated than simple subunit association.
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PMID:Immunologic and physicochemical evidence for conformational changes occurring on conversion of human mast cell tryptase from active tetramer to inactive monomer. Production of monoclonal antibodies recognizing active tryptase. 217 9

Cardiac output (CO) and blood flow to major organs were investigated in pentobarbital-anesthetized rats using 85Sr and 141Ce labelled microspheres (MS) of 15 microns diameter injected into the left ventricle. Changes in organ blood flow and CO were measured after intraventricular dextran (3.4 mumol/kg/min) and intravenous neurotensin (NT) at two different rates, 2.5 nmol/kg/min and 0.125 nmol/kg/min. Dextran, known to give anaphylactoid response in rats, reduced the mean arterial pressure (MAP) from 118 +/- 17 to 55 +/- 8 mmHg (p less than 0.001) concomitant with a 56% decline in CO and significant decreases in blood flow to most organs. At 2.5 nmol/kg/min, NT caused a pattern of changes in MAP, CO and organ blood flow similar to that obtained with dextran, and thus consistent with an indirect response via mast cell stimulation. NT injected at 0.125 nmol/kg/min resulted in a significant increase (30%) in blood flow to the small intestine (p less than 0.01) without changes in MAP or CO. Vascular resistance decreased by 30% in the small intestine (p less than 0.01) and by 20% in the large intestine (p less than 0.05). The results show that circulating NT, at concentrations below those eliciting hypotension, enhances intestinal blood flow without significant changes in other organs.
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PMID:Neurotensin-induced increase in intestinal blood flow in the anesthetized rat. 618 52

Human skin tryptase, a serine proteinase stored within mast cell secretory granules, rapidly loses enzymatic activity in solutions of physiological salt concentration, pH, and temperature. The inactivation of tryptase can be slowed and even reversed by addition of heparin, a highly sulfated glycosaminoglycan also found in the secretory granules. These properties may be relevant to tryptase regulation after secretion from mast cells. To further characterize the molecular changes underlying the functional instability of tryptase, circular dichroism (CD) and analytical ultracentrifugation were used to investigate structural changes during spontaneous inactivation. The CD spectra of active and spontaneously inactivated tryptase are different, particularly in the region around 230 nm where active tryptase displays a distinct negative peak. This peak is also observed in the CD spectrum of bovine chymotrypsin but not in trypsin, elastase, or chymotrypsinogen. Loss of activity resulting from spontaneous inactivation was accompanied by a diminution of the 230-nm signal. The kinetics for the signal loss appeared to be first-order and closely paralleled the rate of enzymatic activity loss. Dextran sulfate, a highly sulfated polysaccharide, was capable of reactivating tryptase and restoring the CD signal. After 2 h of decay (> 90% loss of activity), addition of dextran sulfate resulted in an almost immediate return of the CD signal to that of active tryptase. The return of the CD signal appeared to be more rapid than the return of enzymatic activity, thereby suggesting the presence of an unidentified step which is rate-limiting for activity return (and loss) and subsequent (prior) to the CD change accompanying activity loss. Ultracentrifugation analysis of tryptase showed a marked change in its association state upon inactivation. Sedimentation equilibrium under stabilizing conditions demonstrated the presence of a single species with the molecular weight of a tetramer. After spontaneous inactivation, a mixture of species was evident, which was characterized as monomers and tetramers in equilibrium. These results demonstrate that spontaneous inactivation of tryptase is associated with reversible conformational changes and that a consequence of inactivation is the formation of a destabilized tetrameric form. Although the molecular mechanism initiating these changes remains unclear, possible insights into the process are discussed on the basis of the similarity between the CD spectra of tryptase and chymotrypsin.
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PMID:Structural changes associated with the spontaneous inactivation of the serine proteinase human tryptase. 765 17

To determine the role of heparin in mast cell exocytosis, we studied the effect of heparin on histamine release induced by compound 48/80 or calcium ionophore A23187 in canine mastocytoma cells (BR). Heparin caused concentration-dependent inhibition of compound 48/80-induced histamine release from mast cells (n = 4; P < 0.05) with a mean inhibitory concentration of 0.14 +/- 0.01 U/ml (mean +/- SE). Mean maximal inhibition was 69.3 +/- 2.0%. In contrast, heparin had no effect on calcium ionophore A23187-induced histamine release. Although benzyl alcohol, a preservative of pharmaceutical heparin, had no effect, purified heparin produced a similar inhibitory effect on compound 48/80-induced histamine release (n = 4; P < 0.05). The inhibitory effect of heparin on histamine release was rapid and was eliminated by washing cells. Dextran sulfate, a polysaccharide with negative charge density, produced a similar inhibitory effect on compound 48/80-induced histamine release (n = 4; P < 0.05). We conclude that heparin inhibits compound 48/80-induced exocytosis in mast cells probably by its negative charge density.
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PMID:Heparin inhibits histamine release from canine mast cells. 768 86

Heparin from degranulating mast cells influences a wide range of cellular and humoral reactions associated with allergic inflammation and asthma. Agents that inhibit mast cell degranulation may therefore compromise the moderating effects of heparin in the tissues and result in worsening inflammation and other associated pathology. This study measures heparin release from allergen-challenged human lung tissue and compares the effect of the mast cell stabilizing beta 2-agonists, salbutamol and fenoterol, and a non-beta 2-agonist, sodium cromoglycate, on the release of heparin. Pieces of lung tissue 2 to 3 mm3 were sensitized with high titer Dermatoaphagoides pteronyssinus-specific IgE serum and challenged with D. pteronyssinus allergen, with and without prior addition of salbutamol, fenoterol, or sodium cromoglycate. Dextran sulfate was added to the mixture to prevent the binding of heparin to tissue proteins. Heparin was released together with histamine after challenge. The mean and 95% confidence interval of prechallenge and postchallenge heparin concentrations in the lung tissue filtrates were 0.10 IU/ml (0.07, 0.12) and 0.24 IU/ml (0.17, 0.30), respectively (P < 0.001). Addition of the beta 2-agonists produced a mean inhibition of released heparin of 71% (50, 92), and 73% (55, 91), respectively. Sodium cromoglycate gave a 35% (20, 51) inhibition that was significantly less than that produced by the beta 2-agonists (P < 0.01). The beta 2-agonists salbutamol and fenoterol strongly inhibited heparin release from mast cells. The therapeutic use of mast cell stabilizing agents may therefore be potentially detrimental to the control of allergic inflammation and other associated pathologies.
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PMID:Effect of salbutamol, fenoterol, and sodium cromoglycate on the release of heparin from sensitized human lung fragments challenged with Dermatophagoides pteronyssinus allergen. 768 96

Chymase, a major product of mast cell activation, is secreted as a fully active enzyme. We have prepared recombinant human prochymase and have investigated the conditions under which it may be activated by dipeptidyl peptidase I (DPP I). The gene for human chymase was cloned in a baculovirus vector and expressed in High Five insect cells, and the recombinant protein purified by heparin-agarose and gel-filtration chromatography. The purified prochymase was homogeneous by SDS/PAGE with the same molecular mass as native human chymase, and its identity confirmed by N-terminal sequence analysis and Western blotting with chymase-specific antibodies. Treatment with DPP I to remove the N-terminal dipeptide prosequence resulted in enzymatically active chymase, with substrate and inhibitor profiles very similar to those of the native human enzyme. The activation of prochymase by DPP I was strongly inhibited by heparin (IC50 = 0.5 microg ml[-1]) and histamine (IC50 = 2 mM), though these mast cell products had little effect on the action of DPP I towards a low molecular-mass substrate. The pH optimum of DPP I was also higher and narrower with prochymase. The inhibitory action of heparin was lost at NaCl or KCl concentrations sufficient to elute prochymase from a heparin agarose column. Dextran sulphate was as inhibitory as heparin, whereas chondroitin sulphate C was more than 10-fold less effective. Our findings suggest that the activation of prochymase might be restricted to the early stages of vesicle maturation, when the pH is close to neutrality and the histamine and heparin concentrations are low.
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PMID:The conversion of recombinant human mast cell prochymase to enzymatically active chymase by dipeptidyl peptidase I is inhibited by heparin and histamine. 957 89

Polyethylene glycol (PEG)-conjugated Hb (PEG-Hb) is being considered as a blood substitute. Previously, we showed that PEG-Hb extravasates rapidly from the intestinal mucosa and causes transient epithelial sloughing, resulting in temporary unimpeded passage of material between the intestinal lumen and the microcirculation. The present study quantifies the time course of factors related to this disturbance. Anesthetized Sprague-Dawley rats (350-450 g) were injected with a bolus of PEG-Hb (10 mg/ml) in saline. Control animals received saline, alone or with Dextran 70 (5 mg/ml). After 2, 8, 15, 60, or 90 min, the small intestine was perfusion fixed for microscopy (4 animals for each time point). Epithelial cell detachment and mucosal mast cell degranulation peaked at 2 and 8-15 min, respectively, but by 90 min were back to normal. Goblet cell secretion increased with time up to 8-15 min, after which it leveled off. Mean interstitial width was significantly greater 8 min after injection than for controls and continued to increase with time. In capillaries, endothelial fenestral diaphragms were replaced by thick, amorphous structures. Mesenteric mast cell degranulation was significantly greater 60-90 min after injection compared with controls. We propose that these results are consistent with intravascular injection of PEG-Hb invoking a transient inflammatory response in the intestine.
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PMID:Ultrastructural effects of intravascularly injected polyethylene glycol-hemoglobin in intestinal mucosa. 968 51

This study investigates the role of mast cells in the hypotension induced by antigen-mediated anaphylaxis, compound 48/80 and dextran in mast cell-deficient white spotting (Ws/Ws) and normal wild type (+/+) rats. Rats were sensitized with 10 microg of intraperitoneal ovalbumin in saline or saline alone (sham-sensitized). Sensitized rats, both Ws/Ws and +/+ but not sham-sensitized rats, challenged intravenously with ovalbumin exhibited hypotensive responses. There was no evidence of mast cell activation in rat mesentery 20 min after intravenous antigen challenge in sensitized +/+ rats. Hypotension induced by intravenous injection of dextran (Dextran-162, 6%, 2 ml kg(-1)) or compound 48/80 (1 mg kg(-1)) occurred in +/+ rats, but not in Ws/Ws rats, and was inhibited by pretreatment with a combination of chlorpheniramine and cimetidine. Taken together, these data indicate that the hypotensive response induced by antigen-mediated anaphylaxis is independent of mast cell activation, whereas mast cell amines play the main role in the hypotensive response induced by dextran or compound 48/80.
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PMID:Absence of mast cell involvement in active systemic anaphylaxis in rats. 1171 Oct 48


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