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PubMed1989

Solid phase synthesis and biological activity of mast cell degranulating (MCD) peptide: a component of bee venom.

Mast cell degranulating (MCD) peptide, a 22 amino acid residue basic peptide from bee venom, was synthesized by stepwise solid phase synthesis on a benzhydrylamine resin support. N alpha-t-butyloxycarbonyl and benzyl type side chain protection was used. The two disulfide bridges were formed selectively by using S-acetamidomethyl protection for the cysteine residues in position 5 and 19 and S-methylbenzyl protection for the cysteine residues in positions 3 and 15. Crude synthetic MCD peptide was obtained following deprotection and cleavage from the resin by the low/high HF method. The peptide was isolated in pure form by ion exchange chromatography and gel filtration. The final product has physical, chemical, and biological properties identical with those reported for the natural product. The synthetic strategy utilized for MCD peptide will facilitate the availability of structurally similar analogs for evaluating antihistaminic and anti-inflammatory activities.

Animals↗
PubMedDate not supplied

Effect of brain mast cells degranulation on the corticosterone response to stimulation of central opioid receptors in rats.

The influence of brain mast cells degranulation, exerted by compound 48/80 given intracerebroventricularly, on the opioid-induced stimulation of the pituitary-adrenal axis, measured indirectly through corticosterone secretion, was investigated in conscious rats. The mu- and delta-opioid receptor agonists Leu-enkephalinamide, morphine and beta-endorphin, given intracerebroventricularly, dose-dependently increased the serum corticosterone levels. The effect of Leu-enkephalinamide was not changed by pretreatment with the histamine H1- and H2-receptor antagonists mepyramine and cimetidine. When Leu-enkephalinamide, morphine and beta-endorphin were given 3 hr after compound 48/80, the serum corticosterone levels were higher than after either one of these drugs given separately, which suggests an independent mechanism of action. In rats pretreated 24 hr earlier with compound 48/80, i.e., when brain mast cells were completely degranulated, the stimulating effect of morphine was almost abolished and the effects of Leu-enkephalinamide and beta-endorphin were considerably reduced. Since the histamine levels in the whole brain and thalamus were elevated 3 and 24 hr after administration of compound 48/80, these results suggest that factors other than histamine depletion from brain mast cells by compound 48/80 may be responsible for the dramatic impairment of the stimulating effect of morphine, Leu-enkephalinamide and beta-endorphin on the pituitary-adrenal axis.

Animals↗
PubMed2003

Chlorine inhalation produces nasal congestion in allergic rhinitics without mast cell degranulation.

Seasonal allergic rhinitic (SAR) subjects are more sensitive to nasal irritants than nonrhinitic (NR) subjects; however, the mechanism underlying this difference is unclear. This study sought to determine whether irritant-induced nasal congestion involves mast cell degranulation. Eight SAR and eight NR subjects were exposed to both 1.0 parts per million chlorine and filtered air in separate visits; exposures were via nasal mask and lasted 15 min. Rhinomanometry was performed before, immediately after and 15 min after exposure. Following > or = 2 weeks, exposures and symptom reporting were repeated with nasal lavage, rather than rhinomanometry, pre- and postexposure. A separate substudy using rye grass antigen provided a positive control. Mast cell tryptase was measured in nasal lavage fluid from both substudies using an automated fluoroenzyme immunoassay. Chlorine provocation significantly increased nasal airway resistance in SAR but not NR subjects. Conversely, tryptase levels in nasal lavage fluid were unaffected. Nasal allergen challenge significantly increased both nasal obstruction and nasal lavage tryptase in SAR subjects. Irritant-induced nasal congestion is more pronounced among seasonal allergic rhinitic than nonrhinitic subjects. However, unlike nasal allergen challenge, the mechanism of response to chlorine does not appear to involve mast cell degranulation.

Administration, Inhalation↗
PubMed1990

Studies on inhibitors of rat mast cell degranulation produced by microorganisms. I. Screening of microorganisms, and isolation and physico-chemical properties of eurocidins C, D and E.

Microorganisms producing anti-inflammatory substances were screened by the inhibitory effect on mast cell degranulation. Three new compounds related to pentaene macrolide eurocidins, eurocidins C, D and E, have been isolated from the culture broth of Streptoverticillium eurocidicum IFO 13491 as the inhibitors. Their molecular weights and molecular formulae were estimated as 781.89 and C39H59NO15 for eurocidin C, 795.92 and C40H61NO15 for eurocidin D, and 779.92 and C40H61NO14 for eurocidin E, respectively.

Animals↗
PubMed1999

Neurotensin mediates rat bladder mast cell degranulation triggered by acute psychological stress.

OBJECTIVES: An increased number of activated mast cells have been documented in interstitial cystitis (IC), a painful bladder disorder occurring primarily in women and exacerbated by stress. Mast cells in the bladder and in the intestine are often found in juxtaposition to neurons, where they are activated by neuropeptides and neurotransmitters as well as by acute psychological stress. This work was undertaken to investigate whether the neuropeptide neurotensin (NT) is involved in the activation of bladder mast cells by acute psychological stress. METHODS: Male 300-g Sprague-Dawley rats were either kept on the bench in a quiet procedure room or stressed by confining them one at a time for 30 minutes in a clear Plexiglas immobilizer and then killed with carbon dioxide. The bladder was removed and fixed with 4% paraformaldehyde. Frozen sections were either stained with acidified toluidine blue or processed for NT immunocytochemical analysis. An immunosorbent assay was used to also measure NT in bladder homogenate before and after stress. RESULTS: Bladder mast cell activation in control rats was 37.3 +/- 1.4%, as judged by extrusion of granule contents. Degranulation in stressed animals increased to 75.3 +/- 5.5% (P = 0.0003). Treatment of the animals neonatally with capsaicin decreased mast cell degranulation to 48.9 +/- 7.5% (P = 0.008), a 35.1% inhibition. Intraperitoneal administration of the nonpeptide NT receptor antagonist SR48692 sixty minutes before stress decreased bladder mast cell degranulation to 25.2 +/- 3.6% (P = 0.00007), a 66.5% inhibition. This value is 32.5% below control levels, indicating that NT is involved in basal mast cell degranulation. Stress also reduced the total bladder NT content. CONCLUSIONS: The present results indicate that NT mediates the effect of acute, nontraumatic psychological stress on bladder mast cell degranulation. They further suggest that NT receptor antagonists may be useful in subpopulations of patients with IC in whom symptoms worsen under stress.

Acute Disease↗
PubMed1996

Transgenic mice expressing the human high-affinity immunoglobulin (Ig) E receptor alpha chain respond to human IgE in mast cell degranulation and in allergic reactions.

The high-affinity receptor for immunoglobulin (Ig) E (Fc epsilon RI) on mast cells and basophils plays a key role in IgE-mediated allergies. Fc epsilon RI is composed of one alpha, one beta, and two gamma chains, which are all required for cell surface expression of Fc epsilon RI, but only the alpha chain is involved in the binding to IgE. Fc epsilon RI-IgE interaction is highly species specific, and rodent Fc epsilon RI does not bind human IgE. To obtain a "humanized" animal model that responds to human IgE in allergic reactions, transgenic mice expressing the human Fc epsilon RI alpha chain were generated. The human Fc epsilon RI alpha chain gene with a 1.3-kb promoter region as a transgene was found to be sufficient for mast cell-specific transcription. Cell surface expression of the human Fc epsilon RI alpha chain was indicated by the specific binding of human IgE to mast cells from transgenic mice in flow cytometric analyses. Expression of the transgenic Fc epsilon RI on bone marrow-derived mast cells was 4.7 x 10(4)/cell, and the human IgE-binding affinity was Kd = 6.4 nM in receptor-binding studies using 125I-IgE. The transgenic human Fc epsilon RI alpha chain was complexed with the mouse beta and gamma chains in immunoprecipitation studies. Cross-linking of the transgenic Fc epsilon RI with human IgE and antigens led to mast cell activation as indicated by enhanced tyrosine phosphorylation of the Fc epsilon RI beta and gamma chains and other cellular proteins. Mast cell degranulation in transgenic mice could be triggered by human IgE and antigens, as demonstrated by beta-hexosaminidase release in vitro and passive cutaneous anaphylaxis in vivo. The results demonstrate that the human Fc epsilon RI alpha chain alone not only confers the specificity in human IgE binding, but also can reconstitute a functional receptor by coupling with the mouse beta and gamma chains to trigger mast cell activation and degranulation in a whole animal system. These transgenic mice "humanized" in IgE-mediated allergies may be valuable for development of therapeutic agents that target the binding of IgE to its receptor.

Anaphylaxis↗
PubMed1996

Mast cell degranulation following adenosine A3 receptor activation in rats.

The present studies were carried out to provide further evidence for the hypothesis that the hypotensive response to adenosine A3 receptor activation in the anaesthetized rat involves mediator release from mast cells. Male Sprague-Dawley rats were anaesthetized and given just supramaximal hypotensive doses of either the non-selective A3 receptor agonist, N6(-2)-(4-aminophenyl)ethyladenosine (APNEA: 100 micrograms/kg, preceded by the A1/A2 receptor antagonist, 8-p-(sulphophenyl)theophylline, to "isolate' the A3 receptor-mediated component of the response), the mast cell degranulating agent, compound 48/80 (300 micrograms/kg) or the vehicle for APNEA, intravenously. Blood was withdrawn from a carotid artery between 2 and 10 min after the injection and plasma and serum histamine concentrations measured. Samples of connective tissue (surrounding the abdominal musculature), thymus, mesenteric lymph node, kidney, skin and diaphragm were removed for histological analysis. The plasma and serum histamine concentrations were markedly and significantly higher in the APNEA- or compound 48/80-treated animals compared to vehicle-treated controls. Consistent with this, a substantially greater proportion of mast cells was seen to be undergoing degranulation in all tissues removed from animals treated with APNEA or compound 48/80 compared to those from rats treated with vehicle. Thus, adenosine A3 receptor activation results in rapid mast cell degranulation in the anaesthetized rat. The data provide further evidence of a key role for the mast cell in adenosine A3 receptor-mediated hypotension in this species.

Adenosine↗
PubMed1998

Ultrastructural analysis of human skin biopsy specimens from patients receiving recombinant human stem cell factor: subcutaneous injection of rhSCF induces dermal mast cell degranulation and granulocyte recruitment at the injection site.

We performed an ultrastructural analysis of 10 skin biopsy specimens that had been obtained from three women who were undergoing daily subcutaneous dosing with recombinant methionyl-human stem cell factor (rhSCF) as part of a phase I clinical trial. The biopsy specimens were obtained at sites of subcutaneous administration of rhSCF, within approximately 1 to 2 hours of rhSCF injection, and, at the same time, at contralateral control sites that had not been directly injected with rhSCF. We previously reported that subcutaneous dosing with rhSCF in these subjects induced the local development of a wheal and flare response, which was associated with evidence of mast cell degranulation, as well as a systemic increase in numbers of cutaneous mast cells. The present electron microscopic analysis revealed that all biopsies of swollen, erythematous rhSCF-injected sites exhibited anaphylactic degranulation of both mature and immature mast cells, an acute inflammatory response characterized by the migration of neutrophils, basophils (some of which exhibited evidence of piecemeal degranulation), and eosinophils through blood vessel walls into the perivascular and extravascular spaces, and edema and fibrin deposition within the interstitium. By contrast, the control biopsies contained no evidence of mast cell degranulation or acute inflammation. However, both control and rhSCF-injected sites exhibited mast cells that were undergoing granule building and maturation. Thus at the doses tested in these subjects, subcutaneous injection of rhSCF induced anaphylactic-type degranulation of dermal mast cells at the injection site, with an acute inflammatory response that was associated with the recruitment of granulocytes. By contrast, mast cells at sites distant from those directly injected with rhSCF exhibited no evidence of enhanced secretion.

Anaphylaxis↗
PubMed2003

Inflammatory role of two venom components of yellow jackets (Vespula vulgaris): a mast cell degranulating peptide mastoparan and phospholipase A1.

BACKGROUND: Venom sac extract of yellow jackets Vespula vulgaris was toxic in mice when injected intraperitoneally but not toxic when injected subcutaneously. Necropsy showed the toxicity to be an inflammatory response. METHODS: Venom peptide and protein fractions were tested to identify the inflammatory components. The active components were tested to establish whether they might function as adjuvant for venom protein-specific antibody response. RESULTS: Venom toxicity required the synergistic action of two venom components, a mast cell degranulating peptide mastoparan and phospholipase A1. Both components stimulated prostaglandin E(2) release from murine peritoneal cells and macrophages. Mastoparan showed a weak activity to enhance IgE and IgG1 responses to a yellow jacket venom protein Ves v 5 in BALB/c mice. It was not possible to assess the adjuvant activity of phospholipase A1 because of its suppression of Ves v 5-specific response. Melittin, a mast cell degranulating peptide from bee venom, was inactive as an adjuvant for Ves v 5-specific response. CONCLUSION: Yellow jacket venom contains two inflammatory components, mastoparan and phospholipase A1. Our findings suggest that mastoparan can function as a weak adjuvant for TH2 cell-associated antibody response.

Adjuvants, Immunologic↗
PubMed1978

Effect of mast cell degranulation on gastric mucosal damage produced by sodium taurocholate in the rat.

The source of the histamine released during damage to the gastric mucosa has been investigated in rats using perfused total gastric pouches. Two groups of rats were treated with either intraperitoneal normal saline or compound 48/80, and agent that produces mast cell degranulation, over a 5-day period. On the 5th day, total gastric pouches were prepared and connected to a perfusion circuit that enabled a 20-ml volume to be circulated through the pouches. The experiments consisted of three 30-min periods during which transmucosal potential difference was monitored and ionic (hydrogen and sodium) flux measured; standard acid solution was used in the first two periods and a taurocholate solution in the third. Sodium taurocholate produced a significant increase in ionic flux and fall in the potential difference, the magnitude of the changes being similar in the 48/80- and saline-treated groups. Histamine was released from the mucosa in significantly greater amounts during the taurocholate period, and the increase was similar in both groups of rats. Histological examination of the stomachs confirmed mast cell degranulation in the 48/80-treated groups. We conclude that the histamine released during mucosal damage is probably derived from the "nonmast cell pool" and that this histamine may play a role in mediating the mucosal damage.

Animals↗
PubMed1977

[Basic peptides in bee venom, III. Synthesis of peptide fragments from the sequence of the mast-cell-degranulating peptide (author's transl)].

The synthesis by conventional methods of the following three peptides is described: MCD(8-11) Boc-His(Trt)-Val-Ile-Lys(Z) (III) MCD(5-7) Boc-Cys(SiPr)-Lys(Z)-Arg(Tos) (IV) and MCD(1-4) Boc-Ile-Lys(Z)-Cys(Trt)-Asn(Mbh) (V). These peptides are fragments of the mast cell degranulating peptide from bee venom. The purity of the fragments synthesized was examined by thin-layer chromatography, amino acid and elementary analysis. Including the fragments Boc-Lys(Z)-Ile-Cys(SiPr)-Gly-Lys(Z) (I) and Boc-Pro-His(Trt)-Ile-Cys(Trt)-Arg(Tos) (II), which were described earlier, the synthesis of the mast-cell-degranulating peptide on a polyethylene-asparagine support appears possible.

Amino Acid Sequence↗
PubMed1991

Involvement of 5-hydroxytryptamine in the intestinal motor disturbances induced by mast cell degranulation in rats.

Fasted rats with chronically implanted electrodes were used for investigation of the effects of mast cell degranulation induced by compound 48/80 and BrX-537A and their antagonism by previous administration of 5-hydroxytryptamine (5-HT) antagonists on duodenal and jejunal myoelectric activity. Administered i.p., both 48/80 (1 mg/kg i.p.) and BrX-537A (2 mg/kg i.p.) abolished the intestinal spiking activity of duodeno-jejunum with a progressive recovery, BrX-537A being less active. These effects were dose-related. Injected prior to 48/80, methysergide (1 mg/kg) reduced by about 80% both duodenal and jejunal inhibition of spiking activity with early recovery of a normal pattern. In contrast, ketanserin (1 mg/kg) had selective reducing effects on the duration of the spiking inhibition induced by 48/80 and BrX-537A on the duodenum only. Zacopride (1 mg/kg) and ICS 205-930 (50 micrograms/kg) shortened and suppressed, respectively, the inhibition of intestinal spiking activity with early restoration of intestinal motility in both duodenum and jejunum. We conclude that, in fasted rats (i) the degranulation of peritoneal mast cells induces alterations in intestinal myoelectric activity through the release of 5-HT (ii) these effects are mainly mediated through both 5-HT1 and 5-HT3 receptors.

Animals↗
PubMed2006

Cromolyn administration (to block mast cell degranulation) reduces necrosis of dystrophic muscle in mdx mice.

Duchenne muscular dystrophy is a lethal muscle wasting disorder, resulting from mutations in the gene encoding for the skeletal muscle protein dystrophin. The absence of functional dystrophin leaves the muscle membrane vulnerable to damage during contraction. Damage initially occurs as 'tears' in the membrane, this damage can be exacerbated by the inflammatory response leading to myofibre necrosis rather than repair. Mast cells resident within skeletal muscle represent an immediate source of pro-inflammatory cytokines. We hypothesise that blockade of mast cell degranulation would reduce the extent of myofibre necrosis in the mdx mouse. Daily cromolyn injections were performed on young and exercised adult mdx mice and histological analysis confirmed that mast cell degranulation contributes to myofibre necrosis. This research identified high biological variation between individual mdx mice in the severity of the dystrophic pathology, and supported a relationship between extent of muscle damage in adult mdx mice and their individual enthusiasm for voluntary wheel running.

Animals↗
PubMed1989

Interactions between discrete neuronal membrane binding sites for the putative K+-channel ligands beta-bungarotoxin, dendrotoxin and mast-cell-degranulating peptide.

1. beta-Bungarotoxin, a presynaptically active neurotoxin from the venom of Bungarus multicinctus, was radiolabelled with 125I and its binding to synaptic membranes from rat brain was analyzed. The interaction of these binding sites with those for dendrotoxin (a convulsant polypeptide from mamba venom) and mast-cell-degranulating peptide (from bee venom) was examined in the light of the known effects of all three toxins on voltage-dependent K+ currents. 2. When measured in Krebs/phosphate buffer, the binding appeared monotonic at low concentrations of radioiodinated beta-bungarotoxin (Kd 0.4 nM; Bmax 0.42 pmol/mg protein); higher concentrations of labelled toxin revealed an additional binding component of lower affinity, but computer analysis of the data failed to provide well-defined estimates of its Kd and Bmax values. 3. Equilibrium binding experiments conducted in imidazole-based buffers yielded distinctly biphasic Scatchard plots; computer analysis of the data revealed two populations of sites [Kd 0.26 (+/- 0.30) nM and 6.14 (+/- 5.68) nM; Bmax 0.16 (+/- 0.20) and 2.65 (+/- 1.21) pmol/mg protein]. 4. In Krebs medium, beta-bungarotoxin was a very weak antagonist of the binding of 125I-labelled dendrotoxin. In imidazole medium, however, the efficacy of the inhibition was markedly increased; analysis of this inhibition showed it to be non-competitive. 5. Dendrotoxin inhibited the binding of radioiodinated beta-bungarotoxin in Krebs medium with high potency, although the interaction was by a complex, non-competitive mechanism. 6. Mast-cell-degranulating peptide inhibited non-competitively the binding of both radiolabelled dendrotoxin and beta-bungarotoxin but with relatively low potency. 7. A speculative schematic model of the dendrotoxin/beta-bungarotoxin/mast-cell-degranulating peptide binding component(s) is proposed. Findings are discussed in terms of the likely involvement of these sites with voltage-dependent K+-channel proteins.

Animals↗
PubMed1990

Hypotension induced by vasopressin antagonists in rats: role of mast cell degranulation.

SK&F 101926, a synthetic peptide, is a potent antagonist of vasopressin at both the V2 and the V1 receptors. Following intravenous administration of SK&F 101926 (5 mg/kg), mean arterial pressure (MAP) immediately fell 75 mm Hg. Heart rate increased approximately 50 beats/min. Cutaneous flushing and cyanosis appeared approximately 2 to 5 min after the SK&F 101926 administration. Three of the five rats died within 40 min with no improvement in either color or MAP. The two surviving animals slowly recovered from these symptoms. The hypotension and flushing recorded in these studies resembled the effects during hypotensive shock. SK&F 101926 degranulated rat peritoneal mast cells in vitro as measured by the liberation of histamine. Analogs of SK&F 101926 were identified having reduced activity to release histamine from mast cells in vitro. The activity of these analogs to release histamine in vivo was also tested, as reflected by rat paw edema. A positive correlation was found between the potency to produce edema in vivo and the potency to release mast cell histamine in vitro (r = 0.94, p less than 0.05). In addition, compounds that released mast cell histamine and induced rat paw edema also produced hypotension and death when administered intravenously, while analogs which produced minimal histamine release in vitro produced minimal or no cardiovascular changes or lethality in vivo at the same dosages (5 mg/kg). Finally, cyproheptadine (10 mg/kg), an antagonist at both the serotonin and the histamine receptors, blunted the effects of SK&F 101926 on MAP and blocked the lethality. Pretreatment with a combination of histamine (H1 and H2) antagonists provided little protection against the SK&F 101926-induced toxicity. These data indicate that the cardiovascular toxicity of SK&F 101926 (and related peptides) is mediated via the release of autocoids from mast cells. Serotonin appears to play a major role in mediating the cardiovascular toxicity of SK&F 101926.

Animals↗
PubMed2004

Mast cell degranulation during abdominal surgery initiates postoperative ileus in mice.

BACKGROUND & AIMS: Inflammation of the intestinal muscularis following manipulation during surgery plays a crucial role in the pathogenesis of postoperative ileus. Here, we evaluate the role of mast cell activation in the recruitment of infiltrates in a murine model. METHODS: Twenty-four hours after control laparotomy or intestinal manipulation, gastric emptying was determined. Mast cell degranulation was determined by measurement of mast cell protease-I in peritoneal fluid. Intestinal inflammation was assessed by determination of tissue myeloperoxidase activity and histochemical staining. RESULTS: Intestinal manipulation elicited a significant increase in mast cell protease-I levels in peritoneal fluid and resulted in recruitment of inflammatory infiltrates to the intestinal muscularis. This infiltrate was associated with a delay in gastric emptying 24 hours after surgery. Pretreatment with mast cell stabilizers ketotifen (1 mg/kg, p.o.) or doxantrazole (5 mg/kg, i.p.) prevented both manipulation-induced inflammation and gastroparesis. Reciprocally, in vivo exposure of an ileal loop to the mast cell secretagogue compound 48/80 (0.2 mg/mL for 1 minute) induced muscular inflammation and delayed gastric emptying. The manipulation-induced inflammation was dependent on the presence of mast cells because intestinal manipulation in mast cell-deficient Kit/Kitv mice did not elicit significant leukocyte recruitment. Reconstitution of Kit/Kitv mice with cultured bone marrow-derived mast cells from congenic wild types restored the manipulation-induced inflammation. CONCLUSIONS: Our results show that degranulation of connective tissue mast cells is a key event for the establishment of the intestinal infiltrate that mediates postoperative ileus following abdominal surgery.

Abdomen↗
PubMed2002

Receptors and signaling mechanisms required for prostaglandin E2-mediated regulation of mast cell degranulation and IL-6 production.

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.

Alprostadil↗