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PubMed1983

Platelet activation by endogenous 5-hydroxytryptamine and histamine released by mast cell degranulation with compound 48/80 in the rat.

The intravenous injection of the mast cell degranulator C 48/80 (1 mg/kg) in rats did not produce thrombocytopenia nor circulating platelet aggregates but sensitized the platelets to aggregate upon turbulence challenge. Such turbulence-induced platelet aggregation was not accompanied by formation of thromboxane B2. Electron microscopy revealed absence of platelet degranulation. Turbulence-induced platelet aggregation was completely prevented by pre-treatment of the rats with cyproheptadine, dipyridamole and VK 774, partially with ketanserin (5HT2-receptor antagonist), but not with methysergide (antiserotonergic drug), pyrilamine (antihistaminic drug), suprofen, aspirin (cyclo-oxygenase inhibitors), phentolamine, propranolol, flunarizine, lidoflazine, oxycoumarin or Trasylol. Combined treatment with the anti-histaminic drug pyrilamine and the 5HT2-receptor antagonist ketanserin resulted in a dose-related inhibition for ketanserin of the turbulence-induced platelet aggregation. These experiments point to an interaction between histamine and 5-hydroxytryptamine in the platelet activation by mast cell released mediators.

Animals↗
PubMed1999

Participation of xanthine-xanthine oxidase system and neutrophils in development of acute gastric mucosal lesions in rats with a single treatment of compound 48/80, a mast cell degranulator.

The participation of xanthine-xanthine oxidase and neutrophils in the development of acute gastric mucosal lesions was examined in rats injected once with compound 48/80, a mast cell degranulator. Gastric mucosal lesions appeared 0.5 hr after compound 48/80 injection and developed at 3 hr. The formation of gastric mucosal lesions at 0.5 hr after compound 48/80 injection was prevented by pretreatment with anti-neutrophil antiserum and NPC 14686, an antiinflammatory agent, but not with allopurinol, a xanthine oxidase inhibitor. The development of gastric mucosal lesions at 3 hr after compound 48/80 injection was prevented by pretreatment with anti-neutrophil antiserum, NPC 14686, or allopurinol. Increases in the activities of gastric mucosal xanthine oxidase and myeloperoxidase, an index of neutrophil infiltration, and the content of lipid peroxide occurred 0.5 hr after compound 48/80 injection, and these increases were enhanced at 3 hr. The increases in gastric mucosal myeloperoxidase activity and lipid peroxide content at 0.5 hr after compound 48/80 injection were attenuated by pretreatment with anti-neutrophil antiserum and NPC 14686, while only the increase in gastric mucosal xanthine oxidase activity at the same time point was arrested by allopurinol pretreatment. The increases in gastric mucosal xanthine oxidase and myeloperoxidase activities and lipid peroxide content at 3 hr after compound 48/80 treatment were attenuated by pretreatment with anti-neutrophil antiserum, NPC 14686, or allopurinol. When compound 48/80-injected rats were treated with allopurinol at 0.5 hr after compound 48/80 injection, the progression of gastric mucosal lesions at 3 hr after the injection was almost completely prevented with inhibition of the increases in gastric mucosal xanthine oxidase and myeloperoxidase activities and lipid peroxide content. These results indicate that in rats with a single compound 48/80 treatment neutrophils infiltrated into the gastric mucosa participated in the development of acute gastric mucosal lesions and that the xanthine-xanthine oxidase system in the gastric mucosa participated in the progression rather than the formation of the gastric mucosal lesions.

Acute Disease↗
PubMed2002

Evidence for involvement of mast cell degranulation and subsequent stimulation of histamine H1 and H2 receptors in radiographic contrast media-increased vascular permeability in rats.

In the present study, the effects of systemic injection of radiographic contrast media (RCM) on vascular permeability was examined in various tissues of rats and the involvement of mast cell histamine in the RCM-induced vascular hyperpermeability subsequently determined. Both ionic (amidotrizoate) and non-ionic RCM (iohexol) enhanced vascular permeability specifically in lungs, as assessed by the extravasation of Evans blue (EB) dye. Another ionic RCM, ioxaglate, also markedly increased pulmonary vascular permeability and decreased pulmonary histamine content, whereby the extent of the reduction correlated well with the vascular hyperpermeability. Depletion of mast cells by prior treatment with compound 48/80 markedly attenuated the ioxaglate-induced enhancement of EB extravasation. The ioxaglate-increased extravasation was also inhibited by the mast cell stabilizer sodium cromoglicate and histamine H(1) and H(2) receptor antagonists. In isolated rat pulmonary mast cells, ioxaglate induced the concentration-dependent release of beta-hexosaminidase, an index of mast cell degranulation. The present findings thus show clearly that RCM causes the degradation of pulmonary mast cells and the resultant release of histamine that in turn increases vascular permeability by stimulating histamine H(1) and H(2) receptors.

Animals↗
PubMed2001

Impact of MK-886 on H2O2 generation by human neutrophils and cell degranulation.

Metabolic inhibitors can clearly affect different aspects of the functional activity of cells. This property was studied in the present work with respect to MK-886, a well-known inhibitor of the 5'-lipoxygenase-activating protein. It was found that this inhibitor in a micromolar concentration range (2-20 microM) induced in a dose-dependent manner H2O2 generation by human neutrophils and the release of lysozyme from the cells. The MK-886-induced activation of neutrophils was accompanied by a significant decrease in N-(1-pyrene)maleimide-accessible SH-groups in the cells. According to its activity, MK-886 can be considered an agonist that causes up-regulation of inherent neutrophil functions. In summary, the results indicate that during the application of MK-886 as a 5;-lipoxygenase inhibitor in neutrophils, the impact of the compound on the functional activity of the cells should be taken into consideration.

Cell Degranulation↗
PubMed2003

Exogenous administration of gangliosides inhibits Fc epsilon RI-mediated mast cell degranulation by decreasing the activity of phospholipase C gamma.

Gangliosides released from tumor cells, as well as administered exogenously, suppress the immune responses by largely unknown mechanisms. We show here that a pretreatment of rat basophilic leukemia cells with isolated brain gangliosides inhibited the release of preformed secretory mediators from cells activated via FcepsilonRI but not Thy-1 glycoprotein. Exogenously administered gangliosides also affected the cell-substrate adhesion and the levels of polymeric filamentous actin in Ag-activated cells. Although the production of phosphoinositides was also decreased, enzymatic activity of phosphatidylinositol 3-kinase was not inhibited. Gangliosides had no or only marginal effect on the association of aggregated FcepsilonRI with glycosphingolipid-enriched membranes and on tyrosine phosphorylation of FcepsilonRI and the linker for activation of T cells. Though pretreatment with gangliosides did not inhibit the association of linker for activation of T cells with phospholipase C (PLC)gamma1 and PLCgamma2, tyrosine phosphorylation of these enzymes, as well as their enzymatic activities and association with detergent-insoluble signaling assemblies were reduced. This resulted in a decreased production of inositol 1,4,5-trisphosphate and an inhibition of Ca(2+) mobilization. The combined data support the concept that exogenously administered gangliosides interfere with those properties of glycosphingolipid-enriched membranes that are important for the formation of plasma membrane-associated signaling assemblies containing PLCgamma but not for initial tyrosine phosphorylation of FcepsilonRI subunits.

Animals↗
PubMed2003

Cloning and characterization analysis of the genes encoding precursor of mast cell degranulating peptide from 2 honeybee and 3 wasp species.

The precursors of mast cell degranulating peptide (MCDP) genes were amplified by RT-PCR from the total RNA of venom gland of two honeybee species, Apis mellifera ligustica, Apis cerana cerana, and three wasp species, Vespa magnifica, Vespa velutina nigrothorax and Polistes hebraeus, respectively. Their PCR products were ligated into pGEM T-easy vector and the nucleotide sequences were analyzed. The length of five fragments was the same, it was 341 bp containing an ORF of 153 bp coding the precursor of MCDP and 188 bp 3' noncoding region. They have more than 90% homologues with each other in nucleotide sequences. The precursors of MCDP of A. cerana cerana, V. magnifica, V. velutina nigrothorax and P. hebraeus shared 96%, 100%, 94% and 98% homology with A. mellifera ligustica, respectively. The two species of wasps, V. magnifica and V. velutina nigrothorax, contained the same MCDP as A. mellifera ligustica, though they belong to different families with quite different biological properties, while A. cerana cerana contained the different MCDP in their venom as A. mellifera ligustica though they belong to the same genus. The fifth amino acid residue of MCDP in A. cerana cerana and P. hebraeus is arginine, replacing the cysteine, an important disulfide bridges element, in the position as in A. mellifera ligustica.

Amino Acid Sequence↗
PubMed2002

Endothelin-1 induces mucosal mast cell degranulation and tissue injury via ETA receptors.

The effects of endothelin-1 (ET-1) on mucosal mast cells are of special interest, since they may be an important component of the tissue response that occurs during ischaemic preconditioning or ischaemia/re-oxygenation injuries. Increasing doses of ET-1 were administered intravenously to anaesthetized rats. In a second series of experiments, animals were pretreated with the ET(A) receptor antagonists BQ-610 or ETR-P1/fl peptide, or with the ET(B) receptor antagonist IRL-1038. Intestinal perfusion changes were recorded, and the proportion of degranulated mast cells and the degree of mucosal damage were determined in ileal biopsies. ET-1 induced dose-dependent alterations in the haemodynamic and morphological parameters, and caused significant mast cell degranulation. These changes were inhibited significantly by pretreatment with the ET(A) receptor antagonists, but not with the ET(B) receptor antagonist. We conclude that a cross-talk exists between endothelial cell-derived humoral mediators and the intestinal mast cell system.

Analysis of Variance↗
PubMed1991

The intracerebroventricularly administered mast cells degranulator compound 48/80 increases the pituitary-adrenocortical activity in rats.

The effect of brain mast cells degranulation by compound 48/80 on the pituitary-adrenocortical activity, measured indirectly through corticosterone secretion, and the involvement of a histaminergic mechanism in that stimulation was investigated in conscious rats. All the drugs were given intracerebroventricularly (icv), histamine antagonists 15 min prior to compound 48/80. Compound 48/80 induced a significant dose- and time-related increase in the serum corticosterone levels. That increase, measured 1 h after administration of compound 48/80, was moderately diminished by icv pretreatment of rats with mepyramine and cimetidine, histamine H1- and H2-receptor antagonists. Three hours after administration of compound 48/80 mast cells of the thalamus and the hypothalamus were completely degranulated. At the same time the thalamus and the whole brain histamine levels were substantially higher than in the saline-treated control rats. The above results suggest that histamine liberated from the brain mast cells and central histamine receptors play a moderate role in increasing the pituitary-adrenocortical activity by compound 48/80.

Adrenal Cortex↗
PubMed1993

Acute effects of in vitro mast cell degranulation on human lung muscarinic receptors.

Allergic asthmatic patients have baseline airway cholinergic hyperresponsiveness that rapidly increases after antigen inhalation and mediator release. We therefore examined whether anaphylaxis of human lung tissue (exposure to mast cell mediators) acutely modulated the human lung muscarinic receptor system in ways that might account for these increased in vivo cholinergic airway responses. Fresh thoracotomy peripheral lung samples from 24 patients were incubated with (anaphylaxis) or without (control) anti-IgE (1:100) for up to 90 min. The average percentage of histamine released ranged from 20 to 30% in anaphylaxis and 3 to 5% in control samples, with > 80% of total histamine released by 15 to 30 min. Lung fragments were quick frozen at various times after anti-IgE for analyses of muscarinic receptor binding parameters. Antagonist Kd (dissociation constant) and receptor concentration values were determined using [3H]quinuclidinyl benzilate, and agonist IC50 values were determined using carbachol. In comparison with time 0, neither anaphylaxis nor control samples had differences in receptor binding parameters with time. There were also no differences between anaphylaxis and control lung samples at any time point, and ratios of log control binding parameter/log anaphylaxis binding parameter ranged from 0.96 to 1.04. Thus, anaphylaxis of lung does not lead to acute changes in antagonist or agonist affinity for muscarinic receptors or changes in receptor concentration. Therefore, under the conditions studied, lung mast cell degranulation does not appear to acutely alter the human lung muscarinic receptor system in ways that might account for the increased in vivo lung cholinergic hyperresponsiveness found in allergic asthmatic patients.

Adult↗
PubMed1990

Rat paw oedema and mast cell degranulation caused by two phospholipase A2 enzymes isolated from Trimeresurus mucrosquamatus venom.

Two phospholipase A2 (PLA2) enzymes, TMVPLA2 I and TMVPLA2 II, isolated from Trimeresurus mucrosquamatus venom (TMV) induce rat hind-paw oedema in a dose-dependent manner. This response is suppressed by pretreatment with diphenhydramine, methysergide or compound 48/80, which reduces tissue histamine content. In isolated mast cells, TMVPLA2 I and TMVPLA2 II cause concentration-, time- and calcium-dependent release of histamine and beta-glucuronidase. This effect is inhibited by disodium cromoglycate, mepacrine, nordihydroguaiaretic acid, piriprost and BW 755C, but not by aspirin or indomethacin. These observations indicate that the mast cell plays a predominant role in TMVPLA2 I- and TMVPLA2 II-induced paw oedema, and that venom PLA2 enzyme needs an intact lipoxygenase pathway to induce mast cell degranulation.

Animals↗
PubMed2005

Effect of gefarnate on acute gastric mucosal lesion progression in rats treated with compound 48/80, a mast cell degranulator, in comparison with that of teprenone.

We have reported that teprenone (geranylgeranylacetone), an anti-ulcer drug, prevents acute gastric mucosal lesion progression in rats treated once with compound 48/80 (C48/80), a mast cell degranulator, possibly by suppressing mucus depletion, neutrophil infiltration, and oxidative stress in the gastric mucosa. Herein, we examined the preventive effect of gefarnate (geranyl farnesylacetate), an anti-ulcer drug, on acute gastric mucosal lesion progression in rats treated once with C48/80 (0.75 mg/kg, i.p.) in comparison with that of teprenone, because the chemical structure and anti-ulcer action of gefarnate are similar to those of teprenone. Gefarnate (50, 100 or 200 mg/kg) administered orally at 0.5 h after C48/80 treatment, at which time gastric mucosal lesions appeared, reduced progressive gastric mucosal lesions at 3 h dose-dependently. At 3 h after C48/80 treatment, the gastric mucosa had decreased adherent mucus and hexosamine contents and increased myeloperoxdiase (an index of neutrophil infiltration) and xanthine oxidase activities and thiobarbituric acid reactive substances (an index of lipid peroxidation) content. Post-administered gefarnate attenuated all these changes dose-dependently. These preventive effects of gefarnate were similar to those of teprenone at a dose of 200 mg/kg. Post-administered gefarnate did not affect the increases in serum serotonin and histamine concentrations and the decrease in gastric mucosal blood flow at 3 h after C48/80 treatment like teprenone. These results indicate that orally administered gefarnate prevents acute gastric mucosal lesion progression in C48/80-treated rats possibly by suppressing mucus depletion, neutrophil infiltration, and oxidative stress in the gastric mucosa like teprenone.

Animals↗
PubMed1994

The anaphylaxis hypothesis of sudden infant death syndrome (SIDS): mast cell degranulation in cot death revealed by elevated concentrations of tryptase in serum.

A series of cases of sudden unexpected post-neonatal deaths from two centres in the UK have been investigated for evidence of mast cell activation using the biochemical markers tryptase and 9 alpha,11 beta-PGF2. Tryptase was selected as a possible marker because it is a component of mast cell secretory granules and, unlike histamine, it is not released from basophils. The prostaglandin 9 alpha,11 beta-PGF2 is an initial and pharmacologically active metabolite of PGD2, the major mast cell-derived cyclooxygenase product. This prostaglandin was chosen to serve as a marker of newly generated mediator release. In the study, unexplained infant deaths were associated with a higher concentration of tryptase in serum compared with cases of unexpected, but subsequently explained death. However, 9 alpha,11 beta-PGF2 was found to be an unsuitable post mortem marker in this situation. These results provide direct evidence that mast cell degranulation, possibly as a result of anaphylaxis, may be occurring around the time of death in some cases of cot death.

Anaphylaxis↗
PubMed1999

Von Willebrand factor receptor GPIb alpha is expressed by human factor XIIIa-positive dermal dendrocytes and is upregulated by mast cell degranulation.

GPIb alpha, a glycoprotein component of the GPIb-IX-V complex, serves as a platelet membrane receptor that mediates adhesion to von Willebrand factor normally present in the vascular subendothelium. Recent data have demonstrated that GPIb alpha is not restricted to platelets, but is also expressed by endothelium in vitro. In this study, we describe the expression and distribution of GPIb alpha in normal adult and neonatal human skin. GPIb alpha is present, as detected by immunohistochemistry, on endothelial cells and on highly dendritic cells localized within the perivascular space, dermal-epidermal junction, and reticular dermis. By dual-labeling immunofluorescence and confocal microscopy, GPIb alpha-positive cells within the dermal interstitium are demonstrated to represent factor XIIIa-positive dermal dendrocytes. In organ cultures of neonatal human foreskin, mast cell degranulation induced by either substance P or compound 48/80 resulted in transiently increased GPIb alpha expression by dermal dendrocytes. Because the GPIb-IX-V complex plays a part in regulating hemostasis and may be important for cellular interactions with extracellular matrix molecules, these data provide additional insight into the potential function of FXIIIa-positive dermal dendrocytes in skin remodeling and repair.

Adult↗
PubMed2004

Excavation of lead compounds that inhibit mast cell degranulation by combinatorial chemistry and activity-guided.

An allergic reaction ensues after antigen binds to mast cell or basophil high affinity IgE receptor, Fc epsilonRI, resulting in degranulation of various inflammatory mediators that produce various allergic symptoms. In this study, i) we isolated the active component for the inhibition of mast cell degranulation from the extract of leaves of Castanea crenata and identified it as quercetin; ii) we established the total synthesis procedure of quercetin; iii) using quercetin as positive control, we excavated some lead compounds that possess inhibitory activities for mast cell degranulation by screening the chemical libraries of 1,3-oxazolidine derivatives prepared by solid phase combinatorial chemistry. Some of 1,3-oxazolidine compounds possessing acetyl and 3',4'-dichlorophenyl group displayed strong inhibitory activities on Fc epsilonRI-mediated mast cell degranulation, suggesting that they can be used as lead compounds for the development of anti-allergic agents.

Animals↗
PubMed1990

Long-term enhancement of synaptic transmission by synthetic mast cell degranulating peptide and its localization of binding sites in hippocampus.

A bee venom, mast-cell-degranulating (MCD) peptide, was synthesized by stepwise formation of the two disulfide bridges. This synthetic MCD peptide induced long-term potentiation (LTP) in the CA1 region of a hippocampus slice at concentrations ranging from 10(-7) to 10(-5) M. The potentiating effect of MCD was not lost by biotinylation of its N-terminus, and thus it became possible to investigate localization of its binding site at a cellular level in the hippocampus slice at a LTP-inducible concentration (1 microM). We found that even after brief application of N-biotinyl-MCD (1 microM) to perfusate, its presence was observed in pyramidal cell bodies in the CA1 and CA3 regions, but not in granule cells in the dentate gyrus of the hippocampus slice. This observation does not coincide with the localization of its high-affinity binding sites revealed by 125I-MCD binding, suggestive that another type(s) of MCD binding site, such as low-affinity binding sites, are present in the hippocampus.

Animals↗
PubMed1981

Glycosphingolipid clustering and mast cell degranulation.

It was shown using spin-labelled probes that challenge of sensitized rat peritoneal mast cells results in clustering of sphingolipids located in the outer leaflet of the plasma membrane bilayer. This clustering is partially inhibited by antiallergic drugs of the chromone type. It is hypothesized that the sphingolipid clustering may be involved in the Ca++ gate mechanism which is associated with anaphylactically-induced mast cell degranulation.

Animals↗
PubMed1987

The influence of the sesquiterpene lactones from Geigeria on mast cell degranulation.

The sesquiterpene lactones isolated from Geigeria were found to be incapable of inducing rat peritoneal mast cell degranulation at levels of 0.3-1.6 mM. The sulphydryl reagent, N-ethylmaleimide, too was unable to trigger mast cell secretion. Instead, it was observed that these compounds inhibited the release of histamine induced by Compound 48/80. Pretreatment of the lactones and N-ethylmaleimide with the amino acid, L-cysteine, reduced their inhibition ability of histamine release to a considerable extent, but not completely. Geigerin(V), which lacks an alpha-methylene group and the chemically prepared cysteine-adduct of dihydrogriesenin(I), were also capable of inhibiting mast cell secretion by Compound 48/80, but to a lesser extent.

Alkylation↗