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PubMed2003

Mast cell degranulation requires N-ethylmaleimide-sensitive factor-mediated SNARE disassembly.

Mast cells possess specialized granules that, upon stimulation of surface FcR with IgE, fuse with the plasma membrane, thereby releasing inflammatory mediators. A family of membrane fusion proteins called SNAREs, which are present on both the granule and the plasma membrane, plays a role in the fusion of these granules with the plasma membrane of mast cells. In addition to the SNAREs themselves, it is likely that the SNARE accessory protein, N-ethylmaleimide-sensitive factor (NSF), affects the composition and structure of the SNARE complex. NSF is a cytoplasmic ATPase that disassembles the SNARE complexes. To investigate the role of NSF in mast cell degranulation, we developed an assay to measure secretion from transiently transfected RBL (rat basophilic leukemia)-2H3 mast cells (a tumor analog of mucosal mast cells). RBL-2H3 cells were cotransfected with a plasmid encoding a human growth hormone secretion reporter along with either wild-type NSF or an NSF mutant that lacks ATPase activity. Human growth hormone was targeted to and released from secretory granules in RBL-2H3 cells, and coexpression with mutant NSF dramatically inhibited regulated exocytosis from the transfected cells. Biochemical analysis of SNARE complexes in these cells revealed that overexpression of the NSF mutant decreased disassembly and resulted in an accumulation of SNARE complexes. These data reveal a role for NSF in mast cell exocytosis and highlight the importance of SNARE disassembly, or priming, in regulated exocytosis from mast cells.

Adenosine Triphosphatases↗
PubMed1999

Possible role of adrenergic component and cardiac mast cell degranulation in preconditioning-induced cardioprotection.

The present study was designed to investigate the role of adrenergic component and cardiac mast cell degranulation in the cardioprotective effect of ischaemic preconditioning. Isolated rat hearts were subjected to 30 min of global ischaemia followed by 30 min of reperfusion. Ischaemic/norepinephrine (100 microm) preconditioning markedly reduced ischaemia-reperfusion-induced release of lactate dehydrogenase (LDH) and creatine kinase (CK) in coronary effluent and the incidence of ventricular premature beats (VPBs) and ventricular tachycardia/fibrillation (VT/VF) during the reperfusion phase. Moreover, ischaemic/norepinephrine preconditioning significantly reduced ischaemia-reperfusion-induced release of mast cell peroxidase (MPO), a marker of mast cell degranulation. Prazosin (0.1 microm), a alpha(1)adrenoceptor blocker, administered during ischaemic/norepinephrine preconditioning attenuated the cardioprotective and antiarrhythmic effect of ischaemic/norepinephrine preconditioning. MPO release increased immediately after ischaemic/norepinephrine preconditioning and the release was found to be inhibited in hearts subjected to ischaemic/norepinephrine preconditioning in the presence of prazosin. However, prazosin (0.1 microm) treatment per se produced cardioprotective and antiarrhythmic effects and reduced ischaemia-reperfusion-induced MPO release. These findings tentatively suggest that ischaemic preconditioning produced cardioprotective and antiarrhythmic effect by activating alpha(1)adrenoceptors and consequent degranulation of cardiac mast cells. Prazosin administered during ischaemic preconditioning abolished its ameliorative effect.

Adrenergic alpha-Agonists↗
PubMed1986

Ultraviolet-B radiation suppresses mast cell degranulation induced by compound 48/80.

This study was designed to investigate the effect of middle-wave ultraviolet (UVB) radiation on mast cell functions using mouse ear skin as an in vivo model. Groups of UVB-irradiated BALB/c mice were given an intradermal injection of the mast cell degranulator compound 48/80 into ears at various time intervals (30 min-7 days) after a single exposure to a bank of fluorescent sunlamp tubes (10-100 mJ/cm2). Both the compound-evoked ear swelling response (ESR) and mast cell degranulation were significantly suppressed by preexposure to UVB (25-100 mJ/cm2) after 0 (30 min) to 3 days postirradiation, with a subsequent recovery by day 7. No such effects were observed in mice irradiated with 10 mJ/cm2. The ESR induced by 5-hydroxytryptamine was not significantly affected by UVB radiation during the experimental period. While within this dose range UV radiation itself caused neither loss of mast cell counts nor a measurable degree of degranulation in ear skin, exposure to larger amounts of UV energy (200-500 mJ/cm2) produced tremendous ear swelling with histologic features of mast cell degranulation in an early phase of inflammation. The results suggest that UVB radiation exerts a dual effect on mast cells and that administration of smaller amounts of UVB may alter the mast cell/vasoactive amine system, suppressing ear swelling in response to the degranulator. Vascular reactivities to vasoactive amines were not affected by UVB irradiation.

Animals↗
PubMed1992

Mast cell degranulation inhibits IL-2-induced microvascular protein leakage.

The therapeutic efficacy of interleukin-2 (IL-2) in the treatment of cancer has been limited by a "vascular leak syndrome" and related toxicities. To better understand the pathophysiology of the "vascular leak syndrome," we tested a hypothesis that mast cell degranulation mediated the acute increase in microvascular protein leakage seen immediately following IL-2 administration. After the cremaster muscle was prepared for intravital microscopy, anesthetized Sprague-Dawley rats were injected with fluorescein isothiocyanate-labeled albumin for fluorescent microscopy. Animals were treated by the intravenous injection of IL-2 (1 x 10(6) U/kg) (n = 6), the control IL-2-vehicle (n = 5), or IL-2 (1 x 10(6) U/kg) after mast cell degranulation with compound 48/80 (n = 6). Relative interstitial fluorescent intensity was quantitated by a computerized image analysis system as an index of microvascular protein leakage. IL-2 acutely induced protein leakage from the microcirculation. Mast cell degranulation with 48/80 prior to IL-2 treatment prevented protein leakage, but did not alter IL-2-induced leukocyte-endothelial adherence. These data suggest that mast cell-mediated events may be responsible for the acute increase in microvascular permeability seen with IL-2 administration and that leukocyte-endothelial adherence alone is not solely responsible.

Animals↗
PubMed1985

A comparison between in vitro jejunal mast cell degranulation and intragastric challenge in patients with suspected food intolerance.

Fifteen patients with suspected food intolerance were investigated. Ten patients showed a positive reaction to double-blind intragastric food challenge. Mast cell degranulation induced by in vitro challenge with foods or food antigens on mucosal specimens corresponded well with the results of intragastric food challenge. There was agreement in 13 positive and 18 negative tests; there was disagreement in 5 tests. Thus only one in vitro challenge failed to produce mast cell degranulation when the intragastric challenge gave a clinical reaction, and four mucosal specimens showed mast cell degranulations despite no clinical reaction. The results of radioallergosorbent and skin tests afforded little information as to whether the patient would react to the intragastric food challenge.

Adolescent↗
PubMed2006

Streptococcus pneumoniae induces mast cell degranulation.

Streptococcus pneumoniae colonizes the nasopharynx of healthy human carriers, but occasionally can spread in the body causing severe diseases. The mucosa of the respiratory tract is enriched in mast cells, key players of the innate immune response. Here, we report on the interaction of various strains of S. pneumoniae with the mast cell line RBL-2H3. Live, but not heat-killed, bacteria were found to induce mast cell degranulation in a dose- and time-dependent manner, only partially controlled by cytosolic calcium, with no production of TNF-alpha and IL-6. Non-encapsulated pneumococcal strains exhibited different potencies in triggering mast cells. We propose here that the induction of mast cell degranulation by pneumococcal factors not accompanied by the production of pro-inflammatory cytokines may be a specific strategy elaborated by this bacterium to promote its own spreading from the respiratory mucosa into the environment.

Animals↗
PubMed1995

Mast cell degranulation and blood-nerve barrier permeability in rat sciatic nerve after 7 days of hyperglycemia.

The association between hyperglycemia and altered blood-nerve barrier permeability was examined after 7 days of experimental diabetes. In nerves of rats fed a diet of 40% galactose, permeability to [14C]mannitol [13.43 +/- 2.47 x 10(-5) (SD) ml.s-1.g dry wt-1] and water content [3.43 +/- 0.24 (SD) mg/mg dry wt] were significantly increased compared with control (9.24 +/- 2.09 x 10(-5) ml.s-1.g dry wt-1 and 2.15 +/- 0.28 mg/mg dry wt) and streptozotocin-diabetic animals (8.43 +/- 2.94 x 10(-5) ml.s.-1.g dry wt-1 and 2.35 +/- 0.56 mg/mg dry wt). Electron microscopy revealed significant increases in the number of degranulating perivascular mast cells and in an index of vasoconstriction in galactose-treated rats (3.8 +/- 1.6 and 0.160 +/- 0.062, respectively) compared with control (0.5 +/- 0.8 and 0.072 +/- 0.017, respectively) and diabetic animals (1.4 +/- 1.7 and 0.083 +/- 0.033, respectively). The data are consistent with a role for mast cells in permeability changes occurring after only 7 days of galactose intoxication.

Animals↗
PubMed2004

Mast cells degranulation affects angiogenesis in the rat uterine cervix during pregnancy.

During pregnancy, it is essential that sufficient nutrients are supplied by the vascular system to support the dramatic modifications of the rat uterine cervix. Angiogenesis refers to the growth of new blood vessels from pre-existing microcirculation and mast cells have been associated with this process. This study examined the modifications of the vascular compartment and the distribution of mast cells on cervical tissue during pregnancy. Using disodium cromoglycate as a mast cell stabilizer, we determined the effects of the mast cell degranulation on cervical angiogenesis. Mast cell distribution and their degranulation status were evaluated by immunohistochemistry. Endothelial cell proliferation was measured by bromodeoxyuridine incorporation. Vascular areas (absolute and relative) and maturation indices were assessed by quantitative immunohistochemistry of von Willebrand factor and alpha-smooth muscle actin respectively. Mast cells were predominantly observed during the first half of pregnancy in the perivascular zones. The values of bromodeoxyuridine incorporation, absolute vascular area and vascular maturation index exhibited a significant increase throughout pregnancy. All animals that received mast cell stabilizer showed more than 40% of non-degranulated mast cells. Treated rats exhibited a decrease in endothelial proliferation and in relative vascular area; in addition, a large proportion of mature blood vessels was observed, suggesting a diminished level of new vessel formation. The effects of the mast cell stabilizer were sustained beyond the end of treatment. This is the first report that brings evidence that mast cell degranulation could be a necessary process to contribute to the normal angiogenesis of the rat cervix during pregnancy. Further investigations are needed to elucidate the possible implications of abnormal vascular development of the uterine cervix on the physiological process of ripening and parturition.

Animals↗
PubMed1991

Neuropeptide Y, a putative cotransmitter in noradrenergic neurons, induces mast cell degranulation but not prostaglandin D2 release.

Recent evidence suggests that neural transmitters, including neuropeptides, may modulate the release of mast cell mediators. Because neuropeptide Y (NPY) has recently been recognized as a putative cotransmitter in noradrenergic neurons, we studied the effect of NPY on purified rat peritoneal mast cells. NPY induced mast cell degranulation, as assessed by a dose-dependent increase in net release of beta-hexosaminidase. The concentration that produced 50% of the maximal effect, approximately 10 mumol/L, evoked a 40% +/- 3% release. As previously reported for other neuropeptides, release was fast with maximal release already achieved at 60 seconds. Release was at 4 degrees C. In contrast to its effects on mast cell degranulation, NPY had no effect on the generation of prostaglandin D2, the major mast cell cyclooxygenase product. By comparison, the calcium ionophore A23187, at doses (4 mumol/L) that evoked comparable release of beta-hexosaminidase, stimulated a net release of 37 +/- 9 ng of PGD2 per 10(6) mast cells. These results raise the possibility that NPY may act as a modulator between the autonomic nervous system and mast cells. The results also imply that with neuropeptide stimulation, the release of preformed and newly formed mast cell mediators are mediated through independent pathways.

Animals↗
PubMed1999

Environmental stress causes mast cell degranulation, endothelial and epithelial changes, and edema in the rat intestinal mucosa.

OBJECTIVE: Mental stress has been shown to produce intestinal disease, but the effects of a mild environmental stress on intestinal physiology have not been elucidated. This study was performed to determine the effects of environmental stress on the ultrastructure of the intestinal mucosa, using the rat as an experimental model. METHODS: One group of rats (group A, n = 3) was examined immediately upon arrival at the animal care facility. Groups B (n = 6) and C (n = 6) were housed in rooms with high and low personnel activity, respectively, for up to 4 wk. Group D (n = 8) was housed in the high activity room for 3 to 4 wk followed by 1, 2, or 3 in the low activity room. RESULTS: Rats in group B had the greatest number of degranulated intestinal mucosal mast cells, and activated goblet cells. Intestinal villi were edematous and epithelial cells were detaching from the basement membrane at villus tips. Changes were observed in capillary endothelial ultrastructure. In group B there were greater numbers of vesicles and multilamellar fenestral diaphragms compared to group C. Rats in groups A and C had the lowest numbers of degranulated mast cells and activated goblet cells. Intestinal villi showed normal ultrastructure. Group D was in a recovery phase and the condition of the intestinal mucosa was improved relative to group B, but the number of degranulated mast cells was not significantly reduced. CONCLUSIONS: This study demonstrates that environmentally induced stress causes pathological changes in the rat intestinal mucosa that compromise the epithelial-endothelial exchange barrier. These results emphasize the importance of closely monitoring the environment of experimental animals and provide evidence to stimulate further research into the mechanisms linking mental stress to gastrointestinal dysfunction in humans.

Animals↗
PubMed1978

In vitro sensitization and mast cell degranulation in human jejunal mucosa.

Sera from 3 allergic patients with specific IgE antibodies as shown by RAST were used to sensitize jejunal mucosa obtained from surgical patients. The sensitized specimens were challenged with the appropriate antigens to the specific IgE shown in the sera, Non-challenged sensitized specimens were used as controls to determine mast cell degranulation. The mast cells were counted in a defined area in the mucosa immediately adjacent to the muscularis mucosa. Mast cell degranulation was 47 percent in a timothy pollen system, 40 percent in an eggwhite system, and 33 percent in a codfish system. The results of the investigation indicates that mast cells in the human jejunal mucosa are able to react in the same manner as mast cells in the human lung. The experimental model described appears suitable for studying the allergic reaction in the gastrointestinal tract and the effect of pharmacotherapy in this respect.

Antibodies↗
PubMed1979

The indirect rat mast cell degranulation test reconsidered.

The indirect rat mast cell degranulation test for the detection of human reaginic antibodies was reinvestigated. When the mast cells were incubated with human reaginic serum at concentrations exceeding approximately 3%, a massive, non-specific histamine release occurred, irrespective of the presence or absence of allergen. At tolerated serum concentrations (below 3%), the allergen concentration did not influence the release process. We conclude that the indirect rat mast cell test is not applicable as an alternative test system for the study of immediate hypersensitivity in humans.

Allergens↗
PubMed2000

Localization of protease-activated receptors-1 and -2 in human mast cells: indications for an amplified mast cell degranulation cascade.

Protease-activated receptors (PARs) belong to a family of G-coupled seven transmembrane receptors that are activated by a proteolytic cleavage of their N-termini. Recent studies suggest the involvement of protease-activated receptors-1 and -2 (PAR-1, PAR-2) activators in mast cell degranulation in various physiological and pathophysiological processes in inflammatory responses. Although PAR-1 and PAR-2 activating proteases, thrombin and tryptase, have been associated with mast cell activation, PAR-1 and PAR-2 have not been localized within these cells. We describe here the localization of PAR-1 and PAR-2 in mast cells from various normal human tissues using immunohistochemical and double immunofluorescence techniques. The presence of these receptors on the membrane may explain the actions of accessible extracellular thrombin and tryptase for mast cell activation. In addition to the membrane labeling, these receptors are also localized on the membrane of the intracellular tryptase-positive granules, which may function to sustain further mast cell degranulation upon exocytosis. The localization of these two receptors in mast cells suggests a novel mechanism for controlling mast cell activation through regulation of PAR-1 and PAR-2.

Cell Degranulation↗
PubMed2001

delta-opioid receptors inhibit neurogenic intestinal secretion evoked by mast cell degranulation and type I hypersensitivity.

Histamine and the mast cell degranulator, compound 48/80 produced elevations in short-circuit current, an electrical measure of active anion secretion, across porcine ileal mucosa sheets mounted in Ussing chambers. Luminally-applied beta-lactoglobulin produced similar effects in mucosal sheets from cow's milk-sensitized pigs. Their secretory effects were attenuated by blockers of H(1)-histamine receptors, neuronal conduction or epithelial Na(+)/K(+)/Cl(-) cotransport. The delta-opioid agonist [D-Pen(2), D-Pen(5)]enkephalin suppressed mucosal responses to these substances in a naltrindole-reversible manner. Furthermore, submucosal mast cells and delta-opioid receptor-immunoreactive nerve fibers were observed in close juxtaposition. Intestinal neural pathways linking immediate hypersensitivity to secretory host defense appear to express inhibitory delta-opioid receptors.

Animals↗
PubMed1988

The role of mast cells in demyelination. 1. Myelin proteins are degraded by mast cell proteases and myelin basic protein and P2 can stimulate mast cell degranulation.

Incubation of bovine peripheral myelin with supernatants from degranulated rat serosal mast cells led to extensive loss of P0. Similarly, when myelinated axons prepared from guinea pig CNS were incubated with degranulation supernatants, a significant loss of basic protein (MBP) was observed. As cationic peptides can stimulate mast cell degranulation, rat serosal mast cells were incubated with MBP, and with P2. Degranulation was assayed by measurement of release of the granule enzyme beta-hexosaminidase and it was found that both MBP and P2 stimulated 40-50% degranulation at a concentration of 50 micrograms/ml. The results of this study suggest that release of mast cell proteases could contribute to myelin damage in both the PNS and CNS, and that subsequent release of P2 or MBP or their breakdown products could potentiate further mast cell degranulation.

Animals↗
PubMed2006

Platelet-derived growth factor BB-mediated normalization of dermal interstitial fluid pressure after mast cell degranulation depends on beta3 but not beta1 integrins.

Interstitial fluid pressure (PIF) is one of the determinants of transcapillary fluid flux and thereby interstitial fluid volume. Cell-mediated control of PIF regulates fluid content in the loose interstitial connective tissues that surround the capillary bed. To maintain a normal PIF in dermis, beta1 integrins mediate the tensile strength applied by connective tissue cells on the extracellular matrix. Platelet-derived growth factor (PDGF)-BB normalizes anaphylaxis-induced reduction of PIF. Anti-beta3 integrin IgG and a cyclic RGD peptide that inhibits the alphaVbeta3 integrin blocked the ability of PDGF-BB to normalize the lowered PIF resulting from mast cell degranulation. PDGF-BB was unable to normalize PIF lowered as a result of mast cell degranulation in beta3-negative mice. Monoclonal anti-beta3 integrin IgG had no effect on PIF in normal mouse dermis. In contrast, administration of anti-beta1 integrin IgM lowered PIF in normal dermis but had no effect on PDGF-BB-induced normalization of PIF after anaphylaxis. Furthermore, collagen gel contraction mediated by wild-type mouse embryonal fibroblasts were only marginally affected by function-blocking anti-beta1 integrin antibodies, especially in the presence of PDGF-BB. In contrast, contraction mediated by alphaV-negative mouse embryonic fibroblasts was completely blocked by anti-beta1 integrin antibodies, even after stimulation with PDGF-BB. These results show a previously unrecognized in vivo function for the alphaVbeta3 integrin, as a participant in the control of PIF during inflammatory reactions. Furthermore, our data demonstrate that PDGF-BB induces connective tissue cells to generate tensile forces via alphaVbeta3 during such reactions.

Animals↗
PubMed2004

Transactivation of sphingosine-1-phosphate receptors by FcepsilonRI triggering is required for normal mast cell degranulation and chemotaxis.

Mast cells secrete various substances that initiate and perpetuate allergic responses. Cross-linking of the high-affinity receptor for IgE (FcepsilonRI) in RBL-2H3 and bone marrow-derived mast cells activates sphingosine kinase (SphK), which leads to generation and secretion of the potent sphingolipid mediator, sphingosine-1-phosphate (S1P). In turn, S1P activates its receptors S1P1 and S1P2 that are present in mast cells. Moreover, inhibition of SphK blocks FcepsilonRI-mediated internalization of these receptors and markedly reduces degranulation and chemotaxis. Although transactivation of S1P1 and Gi signaling are important for cytoskeletal rearrangements and migration of mast cells toward antigen, they are dispensable for FcepsilonRI-triggered degranulation. However, S1P2, whose expression is up-regulated by FcepsilonRI cross-linking, was required for degranulation and inhibited migration toward antigen. Together, our results suggest that activation of SphKs and consequently S1PRs by FcepsilonRI triggering plays a crucial role in mast cell functions and might be involved in the movement of mast cells to sites of inflammation.

Animals↗
PubMed2005

The protective effects of melatonin against water avoidance stress-induced mast cell degranulation in dermis.

Nontraumatic psychological water avoidance stress has been shown to induce mucosal degeneration, inflammatory cell infiltration and mast cell degranulation in stomach, ileum, colon and urinary bladder. Many skin disorders, such as atopic dermatitis and psoriasis, worsen during stress and seem to be related with infiltration and activation of mast cells releasing vasoactive and proinflammatory mediators. Melatonin is a free radical scavenger and has cytoprotective effects in inflammatory conditions. The aim of the present study was to investigate the effects of melatonin on water avoidance stress (WAS)-induced degranulation of mast cells in the dermis. Wistar rats were exposed to acute WAS (aWAS group) or chronic WAS (cWAS group). Before exposing to acute WAS, one group of animals was treated with 10mg/kg melatonin (aWAS+mel group). In the cWAS+mel group, treatment with melatonin lasted for 5 days. Dermal mast cells were stained with toluidine blue and investigated using light microscopy. Numbers of mast cells were increased in both aWAS and cWAS groups, but numbers of degranulated mast cells were increased significantly only in the cWAS group when compared to the control group. Numbers of mature granulated and degranulated mast cells were decreased in the cWAS+mel group when compared to the cWAS group. In conclusion, chronic melatonin treatment reduced WAS-induced infiltration and activation of mast cells in dermis and may provide a useful therapeutic option in stress-induced skin disorders.

Animals↗