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PubMed1991

Inhibition of 5-lipoxygenase product formation and polymorphonuclear cell degranulation by tenidap sodium in patients with rheumatoid arthritis.

We studied the effect of tenidap sodium, a new antiinflammatory/antirheumatic drug (120 mg/day for 7 days), on eicosanoid production and neutrophil degranulation in patients with rheumatoid arthritis. Endogenous prostaglandin E2 levels and ex vivo production of leukotriene B4 (LTB4) were measured in synovial fluid samples obtained at baseline and 1 week later. We measured peripheral blood polymorphonuclear cell (PMN) degranulation following surface-bound IgG stimulation, a possible 5-lipoxygenase product-mediated event, by determining lactoferrin and elastase release into the culture fluid. We found decreased levels of endogenous prostaglandin E2 as measured by radioimmunoassay, and decreased ex vivo production of LTB4 by PMN as measured by high performance liquid chromatography, in synovial fluid samples from patients who took tenidap. Release of the granule proteins lactoferrin and elastase was decreased in PMN obtained from patients receiving tenidap, as well as in the PMN incubated in vitro with tenidap. Improvement in clinical measures paralleled the biochemical changes. The unique 5-lipoxygenase inhibitory property of tenidap, as measured by LTB4 production and degranulation, suggests that it may have clinical activity which differentiates it from nonsteroidal antiinflammatory drugs.

Aged↗
PubMed1985

Bombolitins, a new class of mast cell degranulating peptides from the venom of the bumblebee Megabombus pennsylvanicus.

Five structurally related heptadecapeptides rich in hydrophobic amino acids have been discovered in the venom of the bumblebee Megabombus pennsylvanicus. We have named them bombolitin I (Ile-Lys-Ile-Thr-Thr-Met-Leu-Ala-Lys-Leu-Gly-Lys-Val-Leu-Ala-His-Val-NH2 ), bombolitin II (Ser-Lys-Ile-Thr-Asp-Ile-Leu-Ala-Lys-Leu-Gly-Lys-Val-Leu-Ala-His-Val-NH2 ), bombolitin III (Ile-Lys-Ile-Met-Asp-Ile-Leu-Ala-Lys-Leu-Gly-Lys-Val-Leu-Ala-His-Val-NH2 ), bombolitin IV (Ile-Asn-Ile-Lys-Asp-Ile-Leu-Ala-Lys-Leu-Val-Lys-Val-Leu-Gly-His-Val-NH2 ), and bombolitin V (Ile-Asn-Val-Leu-Gly-Ile-Leu-Gly-Leu-Leu-Gly-Lys-Ala-Leu-Ser-His-Leu-NH2 ). Bombolitins are structurally and functionally very similar. They lyse erythrocytes and liposomes, release histamine from rat peritoneal mast cells, and stimulate phospholipase A2 from different sources. The threshold dose is 0.5-2.5 micrograms/ml depending on the peptide and the bioassay. Bombolitin V is as potent as the well-known melittin in lysing guinea pig erythrocytes (ED50 = 0.7 microgram/ml = 4 X 10(-7) M) and is 5 times more potent than mastoparan in causing mast cell degranulation, making it one of the most potent degranulating peptides discovered so far (ED50 = 2 micrograms/ml = 1.2 X 10(-6) M). The bombolitins represent a unique structural class of peptides but they have the same biological properties as melittin (from honeybees), mastoparan (wasps, hornets, and yellow jackets), and crabrolin (European hornets). This unusual circumstance (peptides with different amino acid sequences having the same biological properties) may be a manifestion of their amphiphilic nature, a property these peptides have in common.

Amino Acid Sequence↗
PubMed1999

Potent mast cell degranulation and vascular permeability triggered by urocortin through activation of corticotropin-releasing hormone receptors.

Urocortin (Ucn) is related to corticotropin-releasing hormone (CRH), and both are released in the brain under stress where they stimulate CRH 1 and 2 receptors (CRHR). Outside the brain, they may have proinflammatory actions through activation of mast cells, which are located perivascularly close to nerve endings and degranulate in response to acute psychological stress. Here, we report that a concentration of intradermal Ucn as low as 10 nM induced dose-dependent rat skin mast cell degranulation and increased vascular permeability. This effect appeared to be equipotent to that of calcitonin gene-related peptide and neurotensin. Ucn-induced skin vasodilation was inhibited by pretreatment with the mast cell stabilizer disodium cromoglycate (cromolyn) and was absent in the mast cell-deficient W/Wv mice. The selective nonpeptide CRH receptor 1 antagonist, antalarmin and the nonselective peptide antagonist astressin both reduced vascular permeability triggered by Ucn but not that by Substance P or histamine. In contrast, the peptide antagonist alpha-helical CRH-(9-41) reduced the effect of all three. The vasodilatory effect of Ucn was largely inhibited by pretreatment with H1 receptor antagonists, suggesting that histamine is the major mediator involved in vitro. Neuropeptide depletion of sensory neurons, treatment with the ganglionic blocker hexamethonium, or in situ skin infiltration with the local anesthetic lidocaine did not affect Ucn-induced vascular permeability, indicating that its in situ effect was not mediated through the peripheral nervous system. These results indicate that Ucn is one of the most potent triggers of rat mast cell degranulation and skin vascular permeability. This effect of Ucn may explain stress-induced disorders, such as atopic dermatitis or psoriasis, and may lead to new forms of treatment.

Animals↗
PubMed1986

Mast cell degranulation in nasal polyps.

Light- and electronmicroscopic observations as well as immunohistochemical studies were made on nasal polyps from 15 patients. The patients included 2 cases of aspirin intolerance (AA), 6 cases of allergic rhinitis (NA) and 7 cases of chronic rhinitis (CS) with negative skin tests against major inhalant allergens. Nasal polyps commonly contained many inflammatory cells such as neutrophils (PMN), eosinophils, plasma cells, mast cells, lymphocytes and macrophages. Two morphological features were conspicuous in our study: 1) PMN migration and attachment to the basal lamina, 2) accelerated degranulation of mast cells. Mean values of degranulated granules were 0.532473/micron2 in AA, 0.492615/micron2 in NA and 0.253591/micron2 in CS. These results indicate that mast cell degranulation in CS is much less than that in AA and NA. Immunohistochemical investigations revealed very few IgE-positive cells in both AA and NA, and none in CS. On the other hand IgG and IgA were frequently observed in all cases of nasal polyps. The present study suggests that mast cell degranulation plays an important role in the formation of nasal polyps, but it may not only be an IgE-dependent mechanism. To elucidate other possibilities, more extensive immunological studies will be required.

Cytoplasmic Granules↗
PubMed1978

Cutaneous necrotizing venulitis: a sequential analysis of the morphological alterations occurring after mast cell degranulation in a patient with a unique syndrome.

An unusual patient, with dermal nodules, flexion contractures of the fingers and toes, cold-induced urticaria, dermographism and serum hypocomplementaemia, had necrotizing cutaneous venulitis underlying the spontaneous lesions. Since necrotizing cutaneous venulitis could be experimentally induced by the physical stimuli of cold or trauma, the time-course of histopathological events was documented in the skin of this patient. The histopathological alterations were studied in 1 micron thick, Epon-embedded skin biopsy specimens over an interval of 6 days. The early massive degranulation of the mast cells was followed by the sequential infiltration of neutrophilic, eosinophilic and basophilic polymorphonuclear leucocytes, by the development of venular endothelial cell necrosis and by the deposition of fibrin. The persistent serum hypocomplementaemia involved the classic activating and amplification pathways. It seems possible that the unusual combination of pathobiological processes involving the mast cells and the complement system in this patient has created a unique syndrome, in which venules are damaged and the sheaths of the extensor tendons of the hands and feet become affected in time.

Adult↗
PubMed1999

Quantitative measurement of mast cell degranulation using a novel flow cytometric annexin-V binding assay.

BACKGROUND: Mast cells are primary mediators of allergic inflammation. Antigen-mediated crosslinking of their cell surface immunoglobulin E (IgE) receptors results in degranulation and the release of proinflammatory mediators including histamine, tumor necrosis factor-alpha, and leukotrienes. METHODS: Mast cells were stimulated to degranulate by using either IgE crosslinking or ionophore treatment. Exogenously added annexin-V was used to stain exocytosing granules, and the extent of binding was measured flow cytometrically. Release of the enzyme beta-hexosaminidase was used for population-based measurements of degranulation. Two known inhibitors of degranulation, the phosphatidylinositol 3 kinase inhibitor wortmannin and overexpression of a mutant rab3d protein, were used as controls to validate the annexin-V binding assay. RESULTS: Annexin-V specifically bound to mast cell granules exposed after stimulation in proportion to the extent of degranulation. Annexin-V binding was calcium dependent and was blocked by phosphatidylserine containing liposomes, consistent with specific binding to this membrane lipid. Visualization of annexin-V staining showed granular cell surface patches that colocalized with the exocytic granule marker VAMP-green fluorescent protein (GFP). Wortmannin inhibited both annexin-V binding and beta-hexosaminidase release in RBL-2H3 cells, as did the expression of a dominant negative rab3d mutant protein. CONCLUSIONS: The annexin-V binding assay represents a powerful new flow cytometric method to monitor mast cell degranulation for functional analysis.

Androstadienes↗
PubMed2004

Phospholipase D1 regulates high-affinity IgE receptor-induced mast cell degranulation.

To investigate the role of phospholipase D (PLD) in FcepsilonRI signaling, the wild-type or the catalytically inactive forms of PLD1 or PLD2 were stably overexpressed in RBL-2H3 mast cells. FcepsilonRI stimulation resulted in the activation of both PLD1 and PLD2. However, PLD1 was the source of most of the receptor-induced PLD activity. There was enhanced FcepsilonRI-induced degranulation only in cells that overexpressed the catalytically inactive PLD1. This dominant-negative PLD1 enhanced FcepsilonRI-induced tyrosine phosphorylations of early signaling molecules such as the receptor subunits, Syk and phospholipase C-gamma which resulted in faster release of Ca(2+) from intracellular sources. Therefore, PLD1 negatively regulates signals upstream of the Ca(2+) response. However, FcepsilonRI-induced PLD activation required Syk and was downstream of the Ca(2+)response, suggesting that basal PLD1 activity rather than that activated by cell stimulation controlled these early signaling events. Dominant-negative PLD1 reduced the basal phosphatidic acid formation in unstimulated cells, which was accompanied by an increase in FcepsilonRI within the lipid rafts. These results indicate that constitutive basal PLD1 activity by regulating phosphatidic acid formation controls the early signals initiated by FcepsilonRI aggregation that lead to mast cell degranulation.

Animals↗
PubMed2002

Passive sensitization of human airways induces mast cell degranulation and release of tryptase.

BACKGROUND: This study was designed to examine the effect of passive sensitization (PS) on human bronchial mast cells. PS with asthmatic serum induces a hyper-responsiveness to nonspecific agonists, and immunoglobulin (Ig)E binding mainly on mast cells. METHODS: Bronchi dissected out from 19 lung specimens were incubated in normal or asthmatic serum. Immunohistochemistry was performed using monoclonal antibodies (MoAbs) directed against tryptase, chymase, or c-kit. Mast cells were classified as fully granulated (type I), partly (type II) or largely degranulated (type III). Tryptase was measured in supernatant using ELISA. Contractile response was recorded in a separated set of experiments using an organ bath system. RESULTS: PS decreased both tryptase positive cells (47.9 +/- 10.0 vs. 26.7 +/- 4.8 cell/mm2, P = 0.003) and chymase positive cells (26.1 +/- 3.3 vs. 14.9 +/- 1.8 cell/mm2, P = 0.01), but did not alter the number of c-kit positive cell. PS decreased the proportion of type I (55.4 vs. 28.9%, P < 0.0001) and, concomitantly increased that of types II (23.2 vs. 41.0%, P < 0.0001) and III (21.4 vs. 30.1%, P = 0.04). Following PS, tryptase concentration significantly increased and the magnitude of histamine response, was correlated with the amount of type II mast cells. CONCLUSION: PS of human isolated bronchi induces a mast cell degranulation related to in vitro hyper-responsiveness, along with a tryptase release.

Asthma↗
PubMed1987

Morphologically distinctive forms of cutaneous mast cell degranulation induced by cold and mechanical stimuli: an ultrastructural study.

To determine whether morphological differences in the response of cutaneous mast cells characterize clinically distinct forms of urticaria, we used ultrastructural techniques to examine skin biopsy specimens from three patients with cold-induced urticaria and four patients with dermographism. Biopsy specimens were obtained before application of the stimulus and at the time of lesion formation. Patients with cold-induced urticaria exhibited morphological alterations only after stimulus application consisting of enlargement and uniform disorganization of some, but not all, granules, fusion of the membranes of adjacent granules, fusion of granule membranes with mast cell membranes, and discharge of electron-lucent and disorganized granule contents into the extracellular space. Mast cells from patients with immediate as well as delayed dermographism exhibited alterations before and after stimulus application consisting of enlargement of most granules, nonuniform (zonal) disorganization or solubilization of granule contents, fusion of granule membranes with mast cell membranes, and extracellular discharge of granule contents. Small cytoplasmic vesicles containing disorganized granular material were associated with the degranulation process. Endothelial cells lining nearby postcapillary venules exhibited prominent perinuclear condensation of contractile microfilaments during degranulation in both groups. Both before and after application of the stimulus, the walls of the superficial dermal vessels of the patients with dermographism were thinner and contained less extracellular matrix material than vessel walls of the patients with cold-induced urticaria. The morphologically distinctive types of mast cell degranulation that characterize these two clinically separable urticarial disorders may indicate different pathogenic mechanisms of lesion formation.

Adolescent↗
PubMed1988

Intraarticular injection of arthritogenic factor causes mast cell degranulation, inflammation, fat necrosis, and synovial hyperplasia.

Arthritis resembling human rheumatoid arthritis is produced in rats either by immunization with type II collagen or injection of complete Freund's adjuvant. The development of arthritis in both models may be mediated by a T cell-derived, type II collagen-specific protein that has been termed arthritogenic factor. Here, the morphologic changes produced after intraarticular injection of this factor were determined. T cell lines were derived from type II collagen-immunized rats. Arthritogenic factor was isolated from culture supernatants by affinity chromatography on type II collagen-conjugated Sepharose and injected into rat knees. The synovium covering the infrapatellar fat pad was examined by light and electron microscopy at 6 hours to 7 days after injection. By 6 hours, the synovium and fat pad were edematous and heavily infiltrated with neutrophils and a few mononuclear cells. Fibrin was present in the synovium and joint space. Most mast cells had partially degranulated. By 24 hours, the infiltrate became primarily mononuclear and fewer neutrophils were seen. Fat necrosis and edema occurred in the subsynovium. By 48 hours and 7 days, the synovium was hyperplastic, some fibrin persisted, and macrophages were present. Control knees, injected with material obtained from T cell lines established with the antigen, ovalbumin, and subjected to type II collagen affinity chromatography, had less fibrin deposition, milder cellular infiltrates, and less mast cell degranulation than knees injected with arthritogenic factor. These studies suggest that arthritogenic factor stimulates acute cellular infiltration and mast cell secretion which is followed by fat necrosis, synovial hyperplasia, and mononuclear cell infiltration.

Adipose Tissue↗
PubMed2006

Histamine modulates mast cell degranulation through an indirect mechanism in a model IgE-mediated reaction.

Histamine is released in inflammatory reactions and exerts an immunoregulatory function on cells present in the microenvironment. In this study, we compared the effect of histamine on degranulation of mast cells derived from animals bearing a parasitic infection with those from uninfected animals. Peritoneal mast cells (PMC) were obtained 24 days after infection of Wistar rats with Toxocara canis. The degree of degranulation was assessed either morphologically or by measuring the release of beta-hexosaminidase and TNF-alpha. Non-purified PMC or mast cells immunomagnetically purified with mAb AA4 were used. An increase in degranulation of non-purified mast cells from infected animals was observed after incubation with histamine in vitro or when histamine was injected into the peritoneal cavity. When a purified mast cell population was used, this effect was no longer observed. Supernatants from spleen cells stimulated with histamine induced degranulation of purified mast cells, and again, this was potentiated with PMC from infected animals. However, when supernatants from peritoneal macrophages similarly stimulated were used, a reduction in the degranulation of PMC from infected animals was observed. Our results suggest that histamine may act as a regulator of mast cell degranulation, thus modulating inflammatory responses due to infection with certain parasites.

Animals↗
PubMed2001

Role of complement activation and mast cell degranulation in the pathogenesis of rapid intestinal ischemia/reperfusion injury in rats.

The aim of this study is to define the putative role of complement activation and mucosal mast cell (MMC) degranulation in the pathogenesis of rapid ischemia-reperfusion (I/R) injury. We prepared complement activity-depleted rats by the administration of the anti-complementary agent K-76COONa. To assess the role of MMC degranulation, we used the MMC stabilizer MAR-99 and genetically mast cell-deficient Ws/Ws rats. Autoperfused segments of the jejunum were exposed to 60 min of ischemia, followed by 60 min reperfusion. The epithelial permeability was assessed by (51)Cr-EDTA clearance rate, and the number of MMC was immunohistochemically assessed. I/R treatment induced a marked increase in mucosal permeability and MMC degranulation. The treatment with K-76COONa and MAR-99 significantly attenuated these changes. Furthermore, in Ws/Ws rats the increase in mucosal permeability and MMC degranulation was significantly attenuated. These findings indicate the role of complement activation and MMC activation in the pathogenesis of rapid intestinal I/R injury. A regulation of the complement activation and MMC degranulation may be one of the clinical strategies for prevention of I/R-induced mucosal injury.

Animals↗
PubMed1976

Bovine reaginic antibody. I. Rat mast cell degranulation by bovine allergic serum.

A method of utilizing morphological changes in rat mast cells to determine reaginic antibody activity in bovine serum is described. This technique, which has been shown to be useful for the diagnosis of allergies in man, relies on the ability of antigen to degranulate mast cells sensitized with allergic serum. Experiments with radioactively-labelled allergic bovine globulin indicated the specificity of the binding of such proteins to rat mast cells. Cross-reaction between reaginic bovine antibody and human IgE was shown by a binding assay involving the uptake of 125I-labelled anti-human IgE globulin by mast cells incubated with bovine passive cutaneous anaphylaxis positive globulin.

Animals↗
PubMed2005

Signal 3 tolerant CD8 T cells degranulate in response to antigen but lack granzyme B to mediate cytolysis.

Naive CD8 T cells that respond in vivo to Ag and costimulation in the absence of a third signal, such as IL-12, fail to develop cytolytic function and become tolerized. We show in this study that CD8 T cells purified from TCR transgenic mice and stimulated in vitro in the presence or absence of IL-12 form conjugates with specific target cells, increase intracellular Ca2+, and undergo degranulation to comparable extents. Perforin is also expressed at comparable levels in the absence or presence of a third signal, but expression of granzyme B depends upon IL-12. Levels of granzyme B also correlate strongly with the cytolytic activity of cells responding in vivo. In contrast, an increase in CD107a (lysosomal-associated membrane protein 1) expression resulting from degranulation cannot distinguish in vivo generated lytic effector cells from tolerized, noncytolytic cells. Thus, it appears that cells rendered tolerant as a result of stimulation in the absence of a third signal fail to lyse target cells because they are "shooting blanks."

Animals↗