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PubMed1998

Neutrophil-dependent goblet cell degranulation: role of membrane-bound elastase and adhesion molecules.

We examined the effect of the neutrophil chemoattractants interleukin (IL)-8 and N-formyl-methionyl-leucyl-phenylalanine on goblet cell (GC) degranulation in guinea pigs. Chemoattractants caused time-dependent neutrophil recruitment and GC degranulation in vivo. NPC 15669 (an inhibitor of leukocyte infiltration) prevented both responses, implicating neutrophils. ICI 200,355 (an inhibitor of neutrophil elastase and proteinase-3) or secretory leukocyte protease inhibitor (an inhibitor of elastase but not of proteinase-3) abolished IL-8-induced GC degranulation, implicating elastase. Incubating tracheal segments with IL-8 plus neutrophils caused GC degranulation in vitro, an effect due to activation of the neutrophils themselves (and not an effect present in the supernatant). Chemoattractant increased surface staining of elastase and the cleavage of elastase-specific fluorogenic substrate by neutrophils. Pretreatment with anti-intercellular adhesion molecule-1, anti-CD18, or anti-CD11b antibody inhibited the chemoattractant-induced GC degranulation in vitro, implicating adhesion molecules. These studies suggest that chemoattractants cause neutrophil-dependent GC degranulation involving adhesive interactions between cells, with elastase activity occurring at the cell interface, causing GC secretion. The findings, reproduced in human airways, suggest novel methods of therapeutic intervention.

Animals↗
PubMed2004

Extensive mast cell degranulation in bovine respiratory syncytial virus-associated paroxystic respiratory distress syndrome.

Bovine respiratory syncytial virus (BRSV) infection is an important cause of outbreaks of respiratory disease among calves. This virus commonly induces mild to severe respiratory signs but, in a substantial proportion of cases, is also reported to be associated with paroxystic respiratory distress syndrome (PRDS). The pathogenesis of this 'malignant' clinical form has not been fully elucidated. The present study aimed at determining whether mast cell (MC) degranulation plays a role in the physiopathologic cascade leading to the PRDS. Paired serum samples were taken in herds during outbreaks of severe respiratory diseases (acute sera) and 3 weeks after (convalescent sera). Based on seroconversion to BRSV and clinical picture, 67 pairs of sera were selected from calves with a BRSV-associated PRDS for circulating MC tryptase determination. A MC metachromatic score was measured in post-mortem lungs from animals died from a BRSV-associated PRDS (principals) and compared with reference scores obtained from healthy lungs (controls). Levels of tryptase were significantly higher in acute sera (26.6 +/- 12.4 microg/l) compared to convalescent sera (8.4 +/- 7.8 microg/l; P<0.001). Metachromatic scores yielded significantly different results between controls and principals (P<0.01), demonstrating a significant disappearance of metachromatic granules from lung MCs in principals. Taken together, these data demonstrate the presence of an extensive MC degranulation in BRSV-associated PRDS.

Animals↗
PubMed1977

The effect of chopped rat lung on the inhibitory actions of prostaglandins, isoprenaline, theophylline and disodium cromoglycate on mast cell degranulation.

Prostaglandins and other drugs that stimulate adenylate cyclase have little inhibitory activity for antigen-induced degranulation of rat peritoneal mast cells. In the presence of chopped rat lung, however, the inhibitory activities of both prostaglandins and isoprenaline were markedly enhanced. A similar effect was also seen with disodium cromoglycate, which is not known to stimulate adenylate cyclase, but which does inhibit cyclic AMP phosphodiesterase. In contrast, however, the chopped lung had no effect on either degranulation in the absence of an inhibitor or on the inhibitory potency of theophylline. Lung tissue suspension pretreated with isoprenaline released a factor into the supernatant which enhanced isoprenaline action on peritoneal mast cells. The activity of this supernatant factor was destroyed by boiling for 5 min. Untreated lung supernatant fluid failed to affect either the level of antigen-induced degranulation or the inhibitory potency of isoprenaline.

Adenylyl Cyclases↗
PubMed1983

Basophil and mast cell degranulation: ultrastructural analysis of mechanisms of mediator release.

During anaphylactic degranulation, basophilic leukocytes and mast cells stimulated by specific antigen or other appropriate agents rapidly undergo a series of ultrastructural alterations that expose the contents of their cytoplasmic granules to the external milieu. This noncytolytic process results in the release of several potent inflammatory mediators whose combined local and systemic effects largely determine the clinical manifestations of allergic disorders of immediate hypersensitivity. In this report we briefly review our ultrastructural studies of anaphylactic degranulation in basophils purified from the peripheral blood of guinea pigs and humans and in mast cells purified from human lung.

Anaphylaxis↗
PubMed1992

Mesenteric mast cell degranulation in acute T-2 toxin poisoning.

T-2 toxin-induced alterations in rat mesenteric mast cell granulation were measured by cytophotometric analyses of the metachromatic reaction of mast cell granules with azure B. Hypogranulation (diminution of metachromatic material) was observed 8 h following injections of T-2 toxin (0.5-1.5 LD50, i.p.). These data suggest that mast cell activation occurs during acute T-2 intoxication and raise the possibility that mast cell mediators may contribute to toxin-induced cardiovascular collapse.

Animals↗
PubMed2000

Basophil and eosinophil accumulation and mast cell degranulation in the nasal mucosa of patients with hay fever after local allergen provocation.

BACKGROUND: Basophils and mast cells have certain similarities and are believed to be important in upper and lower respiratory allergy. OBJECTIVE: We sought to apply immunohistology to investigate the distribution and numbers of mast cells and basophils in the nasal mucosa after allergen provocation. METHODS: Allergen challenge with grass pollen was performed in 9 patients with seasonal allergic rhinitis out of the hay fever season. Nasal biopsy specimens were taken before and approximately 1 hour, 24 hours, and 1 week after intranasal allergen provocation. We determined relative numbers and their phenotypic characteristics by using mAbs specific for tryptase, chymase, IgE, eosinophils (BMK-13), and a new mAb against basophils (BB1) by using immunohistochemistry in frozen sections. RESULTS: In the nasal mucosa at baseline, practically no basophils were found in the epithelium. A significant increase in numbers was found in the epithelium and lamina propria of the nasal mucosa in the early phase as early as 1 hour after allergen provocation. At 24 hours and 1 week after allergen provocation, a significant increase in basophil numbers was found in the lamina propria only. The proportion of mast cells staining for chymase in the lamina propria decreased from a median of 38% (range, 0%-82%) to 14% (range, 0%-78%) within 1 hour of allergen provocation. The proportion of mast cells staining for chymase increased from 1% (range, 0%-86%) at baseline to 21% (range, 3%-85%) within 1 hour of allergen provocation. One week after provocation, mast cells returned to baseline numbers. A definite tissue eosinophilia was observed after allergen provocation. CONCLUSION: Basophil numbers are increased in the epithelium and lamina propria of the nasal mucosa of subjects with rhinitis after allergen challenge, with influx already apparent at 1 hour. Moreover, changes in mast cell percentages and numbers were observed within 1 hour of allergen provocation.

Adult↗
PubMed2003

The intracellular granzyme B inhibitor, proteinase inhibitor 9, is up-regulated during accessory cell maturation and effector cell degranulation, and its overexpression enhances CTL potency.

Granzyme B (grB) is a serine proteinase released by cytotoxic lymphocytes (CLs) to kill abnormal cells. GrB-mediated apoptotic pathways are conserved in nucleated cells; hence, CLs require mechanisms to protect against ectopic or misdirected grB. The nucleocytoplasmic serpin, proteinase inhibitor 9 (PI-9), is a potent inhibitor of grB that protects cells from grB-mediated apoptosis in model systems. Here we show that PI-9 is present in CD4(+) cells, CD8(+) T cells, NK cells, and at lower levels in B cells and myeloid cells. PI-9 is up-regulated in response to grB production and degranulation, and associates with grB-containing granules in activated CTLs and NK cells. Intracellular complexes of PI-9 and grB are evident in NK cells, and overexpression of PI-9 enhances CTL potency, suggesting that cytoplasmic grB, which may threaten CL viability, is rapidly inactivated by PI-9. Because dendritic cells (DCs) acquire characteristics similar to those of target cells to activate naive CD8(+) T cells and therefore may also require protection against grB, we investigated the expression of PI-9 in DCs. PI-9 is evident in thymic DCs (CD3(-), CD4(+), CD8(-), CD45(+)), tonsillar DCs, and DC subsets purified from peripheral blood (CD16(+) monocytes and CD123(+) plasmacytoid DCs). Furthermore, PI-9 is expressed in monocyte-derived DCs and is up-regulated upon TNF-alpha-induced maturation of monocyte-derived DCs. In conclusion, the presence and subcellular localization of PI-9 in leukocytes and DCs are consistent with a protective role against ectopic or misdirected grB during an immune response.

Adjuvants, Immunologic↗
PubMed1997

Increased growth promoting but not mast cell degranulation potential of a covalent dimer of c-Kit ligand.

The native form of soluble c-kit ligand (KL) is a noncovalent dimer. We have isolated a soluble, disulfide-linked dimer of murine KL (KL-CD) by expressing KL in Escherichia coli and refolding the denatured protein under conditions that promote the formation of both noncovalent dimers (KL-NC) and KL-CD. KL-CD exhibits a 10- to 15-fold increase in the ability to stimulate the growth of both the human megakaryocytic cell line MO7e and murine bone marrow-derived mast cells relative to KL-NC. Colony-forming assays of murine bone marrow progenitor cells also reflected this increased potency. However, KL-CD and KL-NC are equally able to prime mast cells for enhanced IgE-dependent degranulation in vitro and activate mast cells in vivo. Improving the growth-promoting activity of KL without changing its mast cell activation potential suggests that KL-CD or a related molecule could be administered in the clinic at doses that stimulate hematopoietic recovery while avoiding significant mast cell activation.

Animals↗
PubMed1986

Nerve growth factor induces mast cell degranulation without changing intracellular calcium levels.

Nerve growth factor (NGF) induces degranulation of rat peritoneal mast cells (RPMC) in a dose-dependent manner, providing direct evidence for its action on non-neuronal tissues. Activation of RPMC by NGF depends on lysophosphatidylserine and extracellular calcium. NGF-mediated RPMC degranulation is not coupled to a transient increase in intracellular free calcium ([Ca2+]i). It is suggested that NGF has a unique mode of action independent of [Ca2+]i and presumably also without involving protein kinase C activation as indicated by the effects of phorbol esters and NGF on antigen-evoked [Ca2+]i rise.

Animals↗
PubMed1995

Stress-induced intracranial mast cell degranulation: a corticotropin-releasing hormone-mediated effect.

Stress is known to precipitate or worsen a number of disorders, such as migraines, in which mast cells are suspected of being involved by releasing vasoactive, nociceptive, and proinflammatory mediators. However, no functional association has been demonstrated yet between a migraine trigger and brain mast cell activation. Nontraumatic immobilization (restrain) stress has been shown to stimulate the hypothalamic-pituitary-adrenal axis and to cause redistribution of immune cells. Here, restrain stress caused degranulation in 70% of rat dura mast cells within 30 min, as shown both by light and electron microscopy. These morphologic findings were accompanied by cerebrospinal fluid elevation of rat mast cell protease I, but not II, indicating secretion from connective tissue type mast cells. Mast cell activation due to stress was abolished in animals that had been treated neonatally with capsaicin, indicating that neuropeptides in sensory nerve endings are involved in this response. Complete inhibition was also achieved by pretreating the animals ip with polyclonal antiserum to CRH. Mast cells in the dura were localized close to nerve processes containing substance P, but no CRH-positive fibers were identified even though these were found close to mast cells in the median eminence. This is the first time that stress is shown to activate intracranial mast cells; apparently through the sequential action of CRH and sensory neuropeptides. These findings may have implications for the pathophysiology and possible therapy of neuroinflammatory disorders such as migraines, which are induced or exacerbated by stress.

Animals↗
PubMed1981

Liquid-phase synthesis of naturally occurring peptides, II. Syntheses of three mast cell degranulating tetradecapeptide amides from wasp venoms.

The liquid-phase synthesis of three tetradecapeptideamides corresponding to the amino acid sequences of the wasp venoms mastoparan, mastoparan X, and Polistes mastoparan is described. The 4-(aminomethyl)-3-nitrobenzoyl-amino-poly(ethylene glycol) monomethyl ether was employed as the soluble support, and the completed peptideamides were cleaved from it by photolysis at 350 nm. After removal of protecting groups, the free peptide amides were purified by column chromatography on Sephadex G-25, and found to have expected elemental and amino acid composition; a satisfactory recovery of tryptophan from synthetic Mastoparan X and Polistes Mastoparan suggests that no extensive destruction of its indole ring occurred during the photolysis. The peptideamides so obtained are active in degranulating the rat peritoneal mast cells.

Amino Acid Sequence↗
PubMed2001

Hapten-specific tolerance induced by acute, low-dose ultraviolet B radiation of skin requires mast cell degranulation.

The deleterious effects of ultraviolet B radiation (UVR) on cutaneous immunity are mediated in part by cytokines released from cutaneous cells following radiation exposure. On the one hand, TNF-alpha has been advocated as the primary mediator of failed contact hypersensitivity induction, and, on the other hand, IL-10 has been held responsible for tolerance. While keratinocytes exposed to UVR have been found to produce both TNF-alpha and IL-10, there is reason to question whether these major cellular constituents of the epidermis are the relevant source of immunomodulatory cytokines after UVR. Dermal mast cells also produce TNF-alpha and IL-10, and we have recently reported that mast cell-derived TNF-alpha is required for UVR-induced impairment of CH induction. In this study, we have examined whether mast cells are also a relevant source of IL-10 in UVR-dependent tolerance. We found that (a) UVR fails to induce tolerance in mast cell-deficient mice, and (b) that tolerance occurs if mast cells are triggered to degranulate after ligation of the IgE receptor. Both types of tolerance were neutralized with anti-IL-10 antibodies, are hapten specific, and are associated with regulatory lymphoid cells. We conclude that mast cells are required in UVR-induced tolerance and may be one of the major sources of IL-10 that mediates the tolerance induced by acute, low-dose UVR.

Adjuvants, Immunologic↗
PubMed1988

[Lipoxygenase inhibitors and mast cell degranulation].

Lipoxygenase inhibitors block the release of histamine from protaminesulfate-stimulated peritoneal mast cells of the rat in vitro. The order of this inhibitory activity of the agents does not correlate with the order of this inhibitory activity of the agents does not correlate with the order of their inhibitory activity against lipoxygenases from reticulocytes and peas. Antioxidants/radical scavengers, which do not inhibit lipoxygenase activity (mannitol, hydrochinone) block the protaminesulfate-activated degranulation of peritoneal rat mast cells, too. Therefore we assume that activated oxygen radicals are generated by stimulation of pRMZ with protaminesulfate. These oxygen radicals could be promotors for the histamine secretion of the peritoneal mast cells. Consequently, lipoxygenase inhibitors with radical scavenging properties may influence degranulation of peritoneal mast cells of the rat by two mechanisms, namely by reduction of the synthesis of 5-LOX-products (promotors of the histamine release) and by reduction of the toxic effects of activated oxygen radicals.

Animals↗
PubMed1999

The ultrastructural patterns of mast cell degranulation in Kimura's disease.

BACKGROUND: Although Kimura's disease has been considered an atopic disease because of the association of peripheral blood eosinophilia and elevated serum IgE, the mechanisms of these phenomena are still unknown. OBJECTIVE: It is now established that mast cells are a source of cytokines that are involved in eosinophil recruitment or IgE production. In order to understand the role of mast cells in Kimura's disease, we conducted ultrastructural studies. METHOD: The 45 mast cells obtained from 2 patients with Kimura's disease were classified into two subgroups: S type, with a predominance of scroll or crystal subelements in their granules, and P type, predominantly possessing a particulate or filamentous substructure. RESULTS: We observed numerous P type mast cells with focal losses of granule contents in the absence of granule extrusion in Kimura's disease. CONCLUSION: These results indicate the possibility that slow release of mediators or cytokines from mast cells by piecemeal degranulation may contribute to the pathomechanism of Kimura's disease.

Adult↗