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)

Release of inflammatory mediators by mast cells can be modulated by certain cytokines and by nitric oxide. An in vitro platelet aggregation bioassay was used to assess the effects of interleukin-1 beta (IL-1 beta) on the release of platelet-activating factor and nitric oxide from resting or ionophore-activated peritoneal mast cells (PMC) from rat. PMC spontaneously released a substance that inhibits thrombin-stimulated platelet aggregation. The activity of this substance is abolished by addition of hemoglobin to the platelet suspension and augmented by preincubation of the PMC with L-arginine, suggesting that it is nitric oxide. Within minutes, IL-1 beta concentration-dependently (1 pg/ml-100 ng/ml) enhanced the release from activated PMC of nitric oxide, as measured by its ability to inhibit thrombin-induced platelet aggregation, and as confirmed with a biochemical assay for nitrite. This action of IL-1 beta was inhibited by pretreatment of PMC with a calmodulin antagonist (calmidazolium), an IL-1 receptor antagonist, or either of two nitric oxide synthase inhibitors (L-NAME and LY-83583). IL-1 beta also inhibited the release of platelet-activating factor from PMC through a nitric-oxide-dependent mechanism. These results demonstrate that IL-1 beta is a potent and rapid-acting modulator of mast cell reactivity, stimulating nitric oxide release while inhibiting the production of platelet-activating factor.
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PMID:Modulation of rat mast cell reactivity by IL-1 beta. Divergent effects on nitric oxide and platelet-activating factor release. 839 60

We describe the case of a 69-year-old man with systemic mastocytosis and severe osteopetrosis who carries a somatic activating mutation in the c-kit proto-oncogene. The patient initially presented with urticaria pigmentosa, progressing to systemic mast cell disease with severe anemia due to bone marrow involvement, chronic diarrhea, and hepatosplenomegaly. Direct sequencing using amplimers from reverse transcriptase-polymerase chain reactions (RT-PCR) from skin mast cell-derived RNA revealed a point mutation in the c-kit proto-oncogene at position 2468, introducing a new recognition site for the restriction endonuclease HinfI. Treatment with interferon-alpha 2a, prednisone, and erythropoietin was initiated. Subsequently, clinical symptoms improved significantly and hemoglobin levels are now stable at 13 g/dl.
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PMID:c-kit mutation and osteopetrosis-like osteopathy in a patient with systemic mast cell disease. 979 83

We investigated the effect of sodium nitroprusside (SNP), a donor of nitric oxide, on the formation of platelet-activating factor (PAF) and uterine contractility in mouse uterine horns from mice treated with estrogen. Because the major pathway of PAF synthesis is the remodeling pathway in uterine tissue, we evaluated the incorporation of 14C-acetate into PAF-like molecules. Our results showed that SNP (100-300 mumol/L) caused a transient increase in the synthesis of PAF, which remained cell-associated. The addition of SNP (100-300 mumol/L) to a mouse uterine horn in an isolated organ bath preparation evoked a transient increase in contractility, which was inhibited by hemoglobin (2 micrograms/mL), a nitric oxide scavenger, but not by methylene blue (10 mumol/L), a guanylate cyclase inhibitor. The pharmacological characteristics of the contractions evoked by SNP resembled those evoked after mast cell activation, in that they were blocked by ritodrine (a beta 2 adrenergic agonist, 0.1 mumol/L); indomethacin (a cyclooxygenase inhibitor, 10 mumol/L); ketotifen (a mast cell stabilizer, 1.0 mumol/L); cromolyn sodium (a mast cell stabilizer, 100 mumol/L); pyrilamine (an H1 antagonist, 10 mumol/L); and ketanserine (5HT2 antagonist, 0.1 mumol/L). These data demonstrate that nitric oxide generated from SNP stimulated the synthesis of PAF and evoked contractility in uterine horns from mice treated with estrogen. This result suggests the possibility that these tissue conditions might be favorable for the generation of peroxynitrites, possible mediators of both effects. It is also shown that the contractility evoked by the addition of SNP was not due to production of PAF, because its antagonist, WEB 2086 (10-30 mumol/L, a concentration that blocked contractions evoked by PAF 1 nmol/L), had no effect on the SNP-evoked contractions.
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PMID:Nitroprusside stimulates contractility and the synthesis of 14C-acetylated PAF-like substances in estrogen primed-mouse uterine horns. 1036 96

We investigated the contribution of mast cell chymase in mast cell-dependent angiogenesis using the hamster sponge-implant model, where angiogenesis in the granulation tissue surrounding the subcutaneously implanted sponge was evaluated by measuring the hemoglobin content. Daily local injection of compound 48/80 (3-100 microg/site/day), a potent mast cell activator, induced formation of granulomas and angiogenesis in time- and dose-dependent manners. This angiogenic response was inhibited by chymase inhibitors including chymostatin (> or = 1 nmol/site/day), soybean trypsin inhibitor (SBTI; > or = 1.4 nmol/site/day) and lima bean trypsin inhibitor (LBTI; > or = 3.3 nmol/site/day), but not by a tryptase inhibitor like leupeptin (> or = 700 nmol/site/day). Although pyrilamine (> or = 2,580 nmol/site/day), a histamine H1 receptor antagonist, and protamine (300 microg/site/day) also inhibited angiogenesis, these effects were much less pronounced than those by chymase inhibitors. Furthermore, antigen-induced angiogenesis in hamsters pre-sensitized with ovalbumin was also inhibited by the chymase inhibitors by 60-70%. Our results suggest that chymase is a major mediator in mast cell-mediated angiogenesis.
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PMID:Chymase mediates mast cell-induced angiogenesis in hamster sponge granulomas. 1094 Mar 72

Olopatadine is a human conjunctival mast cell stabilizer with antihistaminic activity. Ketotifen is an older molecule that possesses antihistaminic activity and is reported to have additional pharmacological properties. The interactions of these two compounds with model membranes (i.e., monolayers of 1-stearoyl-2-oleoyl-sn-glycerophosphocholine at the argon-buffer interface), and natural (i.e., erythrocyte) membranes were compared in an effort to understand the differences in their biological activities. Drug-lipid interaction with monolayers was determined by monitoring the surface pressure as a function of the drug concentration in the aqueous phase supporting the monolayer. Drug interaction with erythrocyte membranes was determined by monitoring changes in the permeability of the membranes to hemoglobin and 6-carboxyfluorescein as a function of drug concentration in the medium. Olopatadine and ketotifen are both intrinsically surface active and both interact with phospholipid monolayers. However, in both the presence and absence of lipid monolayers, the changes in surface pressure induced by olopatadine are lower than those caused by ketotifen. The effects of these two drugs on cell membranes were dramatically different. Exposure of bovine erythrocytes to increasing concentrations of ketotifen (1-10 mM) resulted in complete hemolysis of the cells, whereas olopatadine (1-10 mM) caused only minimal hemolysis (< 8%). Consistent results were obtained in experiments measuring the leakage of 6-carboxyfluorescein from erythrocyte ghosts as a more sensitive marker of membrane perturbation. Olopatadine treatment (0.1-10 mM) minimally perturbed the cell membrane while ketotifen (1-10 mM) caused a concentration dependent release of the fluorescent marker. These data demonstrate fundamental differences between the two drugs in their effects on cell membranes. Moreover, the differences are consistent with the surface activities of the two compounds measured in monolayers and with reported differences in their pharmacological activities. These findings offer an explanation for the biphasic non-specific cytotoxic effect of ketotifen on histamine release from mast cells and may account for the nonlytic mast cell stabilizing activity of olopatadine.
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PMID:A comparison of the effects of olopatadine and ketotifen on model membranes. 1105 42

Parallel isofocusing studies established that carboxypeptidase A removal of the His-146 (HC3) and Tyr-145 (HC2) residues of beta heme subunits affected the assembly properties of both Des beta(A) and Des beta(S) with alpha heme chains, albeit to differing degrees. Indeed, the rate of Des beta(A) oligomer dissociation (k1), as determined by visible spectroscopy, was 4.3-fold faster than that of its native beta(A) counterpart. Furthermore, Soret spectral studies have affirmed distinct rates of normal (HbA), sickle (HbS), and Des HbA hemoglobin assembly (k'2) from their alpha and beta [Des beta(A)] heme-containing monomers. Matching kinetic analysis of Des beta(A) and Des beta(S) chain assembly (with an identical a chain) revealed 4.6- and 7.8-fold faster combination rates than those seen for beta(A) and beta(S) chains, respectively. This 3-fold disparity in rates strongly supports the critical role of the beta-6 (A3) residue, and its amino-terminal region, in a chain partner recognition and subsequent human hemoglobin assembly.
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PMID:Carboxyl-terminal modification alters the subunit interactions and assembly pathways of normal and sickle hemoglobins. 1189 Feb 1

Modified hemoglobins are being considered as possible "blood substitutes." Experiments were performed to determine whether diaspirin cross-linked hemoglobin (DBBF-Hb) produces epithelial damage and whether this is reduced by selenium (Se). Anesthetized Sprague-Dawley rats, half of which received 2 x 10(-6) g/ml Se, daily for 3 weeks, in their drinking water, were injected with a 5 ml bolus of 10 mg/ml DBBF-Hb. Control animals received saline (5 animals per group). After 30 minutes, the intestine was perfusion-fixed for light and electron microscopy. Eighty villi per rat were assigned an epithelial integrity index (E.I.), ranging from 1 (intact) to 3 (some cell-cell and cell-basement membrane separation). In non-Se rats, E.I. was significantly compromised by DBBF-Hb, compared to HBS-BSA (2.47+/-0.57 (SD) vs. 1.36+/-0.49, p<0.001). In Se rats, neither injection with DBBF-Hb or HBS-BSA caused epithelial damage (1.03+/-0.17 vs. 1.07+/-0.26). Mast cell degranulation per villus (MCD) was measured in 60 villi per rat. In non-Se rats, MCD was significantly greater after DBBF-Hb than after HBS-BSA injection (1.83+/-1.42 vs. 0.2+/-0.4). Supplementary Se did not reduce this effect. In fact, MCD was significantly increased in both sets of rats compared to their non-Se counterparts (3.27+/-2.40 and 1.48+/-1.70 for DBBF-Hb and HBS-BSA, respectively). Since mast cell mediators damage cells, Se must protect the mucosal epithelium in some way.
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PMID:Selenium reduces hemoglobin-induced epithelial damage to intestinal mucosa. 1200 Feb 23

Three "blood substitutes," a diaspirin cross-linked human hemoglobin (DBBF-Hb), a bovine polymerized hemoglobin (PolyHbBv), and a human polymerized hemoglobin (O-R-PolyHbA(0)), that have undergone clinical trials are used in this study. Previously, we showed in the rat that coadministration of sodium selenite (Na(2)SeO(3)) and DBBF-Hb significantly decreased mesenteric venular leakage and epithelial disruption produced by DBBF-Hb alone but did not reduce mast cell degranulation unless given orally. The purpose of this study was to determine whether Na(2)SeO(3) produced similar beneficial responses when used with PolyHbBv and O-R-PolyHbA(0). In anesthetized Sprague-Dawley rats, the mesenteric microvasculature was perfused with PolyHbBv or O-R-PolyHbA(0), with and without Na(2)SeO(3) in the perfusate and suffusate, for 10 min, followed by FITC-albumin for 3 min, and then fixed for microscopy. Na(2)SeO(3) did not reduce leak number or area in preparations perfused with PolyHbBv and only reduced leak number (but not significantly) in preparations perfused with O-R-PolyHbA(0). Na(2)SeO(3) significantly increased mesenteric mast cell degranulation and impaired epithelial integrity in animals treated with PolyHbBv. In vitro, Na(2)SeO(3) significantly reduced the oxidation rate of DBBF-Hb in the presence of oxidants, had little effect on PolyHbBv, and increased the oxidation rate of O-R-PolyHbA(0). These results suggest that Na(2)SeO(3) moderates hemoglobin-induced damage, at least partly, through its redox interactions with the heme sites in the hemoglobin molecules studied and that accessibility of the heme site to Na(2)SeO(3) governs those interactions.
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PMID:Differential effects of sodium selenite in reducing tissue damage caused by three hemoglobin-based oxygen carriers. 1455 84

Documentation concerning the pathogenesis of gastric hemorrhagic ulcer in Salmonella typhimurium (Salmonella typhi)-infective disease is lacking. This research first proposed that alterations of mast cell histamine release, gastric acid back-diffusion and mucosal microvascular permeability are important in modulating gastric ulcer and hemorrhage in Salmonella typhi-infected rats. Additionally, effects of several histamine-related drugs on this ulcer model were evaluated. Male Wistar rats were deprived food for 36 h. Live cultures of Salmonella typhi (OU 5045, 1 x 10(10) CFU in 1.0 mL of sterilized phosphate buffer saline) were challenged, intrajejunally to rats just before withdrawal of food. Control rats received the same volume of sterilized vehicle only. Rat stomachs were irrigated for 3 h with either normal saline or simulated gastric juice. Gastric acid back-diffusion, mucosal histamine concentration, microvascular permeability as well as luminal hemoglobin content and ulcer areas were determined. Severe gastric hemorrhage and mucosal ulcerations, particularly in acidic stomachs, were observed in Salmonella typhi-infected rats. A positive correlation of histamine to gastric hemorrhage and ulcer was found in those rats with Salmonella typhi-infection. This hemorrhagic ulcer in Salmonella typhi-infected rats was effectively ameliorated by intraperitoneal ketotifen, diphenhydramine and ranitidine but was worsen by exogenous histamine or diamine oxidase. In conclusion, enhancement of acid back-diffusion, mast cell histamine release and microvascular permeability is important in modulating gastric hemorrhage and ulcer in Salmonella typhi-infected rats.
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PMID:Role of histamine and acid back-diffusion in modulation of gastric microvascular permeability and hemorrhagic ulcers in Salmonella typhimurium-infected rats. 1496 97

Studies were carried out to evaluate the impact of a high-fat dietary regimen on aortic wall thickness, peripheral blood leukocyte profile, and plasma cholesterol and triglyceride levels in the mast cell-deficient Sl/Sl(d) mouse. The results demonstrated that the mean aortic wall thickness of Sl/Sl(d) mice was significantly higher than their normal littermates, and were increased in both genotypes after a 17-day high-fat regimen. In comparison with normal littermates, Sl/Sl(d) genotypes had elevated levels of plasma triglycerides with normal levels of plasma cholesterol, and the high-fat diet markedly lowered the triglyceride levels. Total peripheral blood leukocytes, the monocyte and granulocyte counts, and hemoglobin levels were significantly lower in Sl/Sl(d) mice, although the number of lymphocytes, eosinophils and basophils were the same in both genotypes. Interestingly, the high-fat diet regimen elevated leukocyte counts and the number of monocytes and granulocytes in Sl/Sl(d) mice.
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PMID:Deranged aortic intima-media thickness, plasma triglycerides and granulopoiesis in Sl/Sl(d) mice. 1577 49


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