Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine the role of mast cells in the recruitment of neutrophils and eosinophils, acute nonspecific pleurisy was induced by injecting isologous serum into normal +/+ and mast cell-deficient Ws/Ws rats. In +/+ rats, neutrophil infiltration peaked 4 h after serum administration, followed by influx of eosinophils after 24-48 h. The levels of neutrophil influx after 4 h as well as the activity of myeloperoxidase (MPO) in pleural lavage-cell extract were significantly lower in Ws/Ws rats than in +/+ rats. In contrast, numbers of eosinophils as well as activity of eosinophil peroxidase (EPO) did not differ significantly between Ws/Ws and +/+ rats. For local reconstitution of mast cells, +/+ rat peritoneal mast cells (PMC) or mesenteric lymph node cells (MLNC) as a control were transferred into the Ws/ Ws pleural cavity. Serum injection into animals with PMC transfer 7 days previously triggered augmented neutrophil influx by approximately 4.7-fold as compared to that in MLNC-transferred animals. Mast cells recovered from the pleural cavity of PMC-transferred rats showed histamine contents equivalent to 20% of that of freshly isolated PMC and retained the reactivity to compound 48/80. These results indicated that dependency of neutrophil recruitment on resident mast cells is greater than that of eosinophils in isologous serum-induced pleurisy.
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PMID:Migration of neutrophils is dependent on mast cells in nonspecific pleurisy in rats. 1054 90

Heparin is a glycosaminoglican used in prophylactic and treatment of thrombosis. Heparin possesses also non-anticoagulant properties, including modulation of various proteases, anticomplement activity, and anti-inflammatory actions. Inhaled heparin has been shown to reduce early phase of asthmatic reaction and suppress allergen induced rise in bronchial hyperreactivity. Heparin inhibits the acute cutaneous reaction due to allergens. Moreover, inhaled heparin prevents exercise-induced asthma. The exact mechanism of heparin action in bronchial asthma remains obscure. It has been observed that heparin acts as a specific blocker of IP3 receptors and inhibits IP3-mediated calcium release in various cell types, including vascular smooth muscle and airway smooth muscle. In this mechanism heparin inhibits allergen induced mast cell degranulation and prevents subsequent development of reaction cascade leading to inflammation, bronchial hyperreactivity and asthma. It also modulates migration of proinflammatory cells, eosinophils and neutrophils, into the site of allergic reaction. Furthermore, heparin inhibits the increased vascular permeability induced by a wide range of agonists acting via specific receptors located on the vascular endothelial cells. The cationic peroxidases, such as major basic protein and eosinophil peroxidase, are neutralized by the highly anionic heparin; thus heparin inhibits the epithelial damage induced by some of these cationic proteins. The mechanism involved in the control of bronchial hyperreactivity by heparin has been studied little and is yet poorly understood. Heparin deserves further investigations in large number of subjects to provide further insight into the pathophysiology of asthma. Heparin may also be of clinical importance and may form the basis of novel therapeutic approaches.
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PMID:[The role of heparin in allergic inflammation]. 1094 59

We have investigated the effect of wortmannin, a potent and selective inhibitor of phosphatidylinositol-3-kinase, on the immediate-type allergic response and the late phase pulmonary inflammation induced by allergen challenge in the ovalbumin-sensitised Brown Norway rat. Intratracheal (i.t.) instillation of ovalbumin induced dose-related bronchoconstrictor responses. Administration of wortmannin (1, 10 or 100 microg kg(-1) i.t., 1 h prior to challenge) induced a marked and dose-dependent inhibition of ovalbumin-induced bronchospasm (ED(50) ca. 5 microg kg(-1) i.t.). At similar doses, wortmannin also suppressed the bronchoconstrictor responses to 5-hydroxytryptamine and methacholine but the degree of blockade of these spasmogens (1.4-1.9-fold) was less than that of ovalbumin (>20-fold). Wortmannin, given intratracheally 1 h prior to allergen challenge, also suppressed the increases in bronchoalveolar lavage fluid leukocyte numbers and eosinophil peroxidase activity measured 24 h post challenge. However, relatively high doses were necessary (ED(50) ca. 100 microg kg(-1) i.t.). The potency of wortmannin was increased when dosed 1 h prior to and 24 h after allergen challenge and the readout was 48 h after challenge (ED(50) 3-5 microg kg(-1) i.t.). Thus, wortmannin is a potent inhibitor of the bronchoconstrictor response induced by allergen in the airways of actively sensitised Brown Norway rats. Inhibition of phosphatidylinositol-3-kinase, an obligatory step in mast cell activation in response to allergen, is the presumed mechanism of action. The fact that similar doses of wortmannin do not suppress the late response to allergen suggests a minimal role for the mast cell in generating the late response to allergen in this model. The striking increase in potency to inhibit the late response when dosed 1 h prior to and 24 h after allergen challenge with the readout taken at 48 h may represent an effect of wortmannin to suppress the migration of leukocytes.
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PMID:Effects of wortmannin on airways inflammation induced by allergen in actively sensitised Brown Norway rats. 1175 55

We have explored the effects of bacterial endotoxin (lipopolysaccharide; LPS) on the response of the airways of Brown Norway (BN) rats to adenosine. Comparisons have been drawn with the effects on responses to methacholine and 5-hydroxytryptamine. In vehicle-challenged animals, adenosine, given i.v. was only a weak bronchoconstrictor. In contrast, 1 h following intratracheal administration of LPS, 0.3 mg kg-1, bronchoconstrictor responses to adenosine were markedly and selectively enhanced. At this time point, there were no significant changes in leukocyte numbers, eosinophil peroxidase and myeloperoxidase activities or protein concentrations in bronchoalveolar lavage (BAL) fluid. Twenty-four hours after challenge, the sensitivity of the airways to both adenosine and methacholine was reduced relative to the earlier time point and there were substantial increases in each marker of inflammation in BAL fluid. The bronchoconstrictor response to adenosine was blocked selectively by methysergide, disodium cromoglycate and the broad-spectrum adenosine receptor antagonist, 8-SPT, but not by DPCPX or ZM 243185, selective antagonists for the A1 and A2A receptors, respectively. Thus, the response to adenosine augmented following LPS is mast cell mediated and involves a receptor which can be blocked by 8-SPT but not by selective A1 or A2A receptor antagonists. It thus bears similarity to the augmented response to adenosine induced by allergen challenge in actively sensitized BN rats. Exposure to LPS could be a factor along with allergen in determining the increased sensitivity of the airways of asthmatics to adenosine.
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PMID:Airway hyperresponsiveness to adenosine induced by lipopolysaccharide in Brown Norway rats. 1197 75

We assessed mast cell influence on eosinophils, the prominent cells in late and chronic allergic reactions, by comparing the proteomic pattern of eosinophils incubated with mast cells, tumor necrosis factor alpha (TNF-alpha) or granulocyte macrophage colony stimulating factor (GM-CSF). Eosinophils were incubated with the human mast cell line HMC-1 cellular sonicate and their survival and GM-CSF production were evaluated. For proteomic studies, eosinophils were cultured with HMC-1 sonicate, TNF-alpha or GM-CSF in the presence of [(35)S]methionine, solubilized and submitted to isolelectric focusing separation and sodium dodecyl sulfate polyacrylamide gel electrophoresis in the ISODALT system, followed by radiofluorography and computer image analysis. HMC-1-incubated eosinophils displayed increased survival partly mediated by mast cell-associated TNF-alpha, and produced GM-CSF. Metabolically labeled eosinophils incubated with either HMC-1, TNF-alpha or GM-CSF released eosinophil peroxidase. Comparison of two-dimensional gel spots from the eosinophils revealed that each of the three activating signals yielded a distinctly different proteomic pattern of labeled polypeptides. GM-CSF provided the strongest signal and the highest rate of protein synthesis (1,018 spots) followed by TNF-alpha (747 spots) and HMC-1 sonicate (611 spots). A portion of spots differed both in terms of quality and quantity. Although each stimulus induced similar functional effects, the resulting biosynthetic programs of the eosinophils greatly differed. The presented proteomic analysis is the first step in the exploration of molecular mechanisms involved in eosinophil activation.
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PMID:Proteomic analysis of human eosinophil activation mediated by mast cells, granulocyte macrophage colony stimulating factor and tumor necrosis factor alpha. 1244 59

Eosinophils are effector cells that play an important role in the damage induced by the allergic process by releasing inflammatory mediators and proteolytic factors after activation. Stem cell factor (SCF) is a primary cytokine involved in hematopoiesis and mast cell differentiation, proliferation, and activation. Studies have also indicated that SCF is directly involved in pathogenesis of allergic airway inflammation. In the present study, we examined the ability of SCF to activate murine eosinophils for increased mediator release and up-regulation of chemokines. Initial data demonstrated that eosinophils have significant levels of surface c-kit protein, SCF receptor. SCF-activated eosinophils degranulate and release eosinophil peroxidase and leukotriene C(4) in a dose-dependent manner. In addition, SCF was further shown to induce the release of CC chemokines, RANTES, macrophage-derived chemokine (MDC), macrophage inflammatory protein-1beta (MIP-1beta), and C10 from eosinophils. To identify the extent of SCF-induced activation of eosinophils, we also performed gene array analysis using an array containing 1153 genes related to inflammation, including cytokines and their receptors, growth factors, structural and cytoskeletal genes, signal transduction genes as well as several other classes related to immune/inflammatory responses. The gene analysis indicated that more than 150 genes were significantly up-regulated in eosinophils after SCF stimulation. The gene array results were verified using a quantitative real-time polymerase chain reaction analysis to identify the expression of several chemokine and chemokine receptor genes. Altogether, these studies indicate that SCF is a potent eosinophil degranulator and activator that may play a number of roles during an inflammatory/immune response.
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PMID:Stem cell factor induces eosinophil activation and degranulation: mediator release and gene array analysis. 1245 75

Hypereosinophilic syndromes are often associated with thrombosis through unclear mechanisms, and mastocytosis has been associated with a variety of bleeding disorders. The present studies were aimed at defining the roles and interactions of eosinophil and mast cell constituents on the kinetics of blood clotting as measured by thromboelastograms. Eosinophil granule proteins and purified eosinophil peroxidase markedly reduced the anticoagulant properties of the mast cell tryptase/heparin complex. Moreover, eosinophil peroxidase by itself functioned as a powerful procoagulant and also inhibited the anticoagulant actions of heparin in a chromogenic assay for antithrombin III/factor Xa activity. The anticoagulant activity of the tryptase/heparin complex was attributable exclusively to the associated heparin and not to the intrinsic enzymatic activity of tryptase. Eosinophil granule proteins also strongly inhibited the enzymatic activity of tryptase in the presence of hydrogen peroxide, thus implicating a critical role for eosinophil peroxidase. We conclude that eosinophil granule proteins and eosinophil peroxidase both function as powerful procoagulants and also inhibit the anticoagulant and enzymatic activities of mast cell tryptase. The present results thus provide a mechanistic rationale for the well-established link between certain eosinophilic inflammatory disorders and hypercoagulant states. They also suggest that eosinophils may play an important role in neutralizing the anticoagulant activity of mast cell tryptase/heparin in various diseases.
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PMID:Effects of human mast cell tryptase and eosinophil granule proteins on the kinetics of blood clotting. 1270 Nov 15

We have recently demonstrated a marked and selective augmentation of the bronchoconstrictor response to adenosine in actively sensitised Brown Norway (BN) rats challenged with ovalbumin (OA). The augmented response is mediated by 5-hydroxytryptamine (5-HT) released as a consequence of mast cell activation. We describe here the effects of budesonide, a clinically used glucocorticosteroid, IMM125, a hydroxyethyl derivative of D-serine-cyclosporine, MLD987, a close analogue of ascomycin and SAR943, a rapamycin derivative, on the hyperresponsiveness to adenosine induced in actively sensitised BN rats by exposure to allergen. Bronchoconstrictor responses to adenosine elicited 3 h following intratracheal (i.t.) instillation of OA, 0.3 mg kg(-1) were reduced dose-dependently by budesonide, IMM125, and MLD987, given i.t. 25 and 1 h prior to allergen challenge. In contrast, SAR943 had no effect on responses to adenosine. Responses to methacholine and 5-HT were minimally affected by these agents. Bronchoconstrictor responses to bradykinin were dose-dependently reduced by budesonide, but unaffected following IMM125, MLD987 or SAR943 pre-treatment. Challenge with OA at a dose of 0.3 mg kg(-1), induced increases in bronchoalveolar lavage (BAL) fluid, leukocyte numbers, eosinophil peroxidase (EPO) and myeloperoxidase (MPO) activities and protein concentration measured 24 h post challenge. Budesonide (1 mg kg(-1) given i.t. 25 and 1 h prior to OA challenge) induced reductions in the BAL fluid parameters of inflammation; IMM125 and MLD987, at a dose of 1 mg kg(-1) had no significant effect whereas SAR943 reduced lymphocyte numbers. Thus, budesonide, IMM125 and MLD987 block the hyperresponsiveness to adenosine induced by allergen challenge in sensitised rats. In the case of budesonide the effect is associated with a powerful, generalised anti-inflammatory effect although an effect directly on the mast cells is also likely. With IMM125 and MLD987, the effect is seen at doses that are not anti-inflammatory and may reflect direct suppression of mast cell activation by these agents.
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PMID:Effects of immunomodulators on airways hyperresponsiveness to adenosine induced in actively sensitised Brown Norway rats by exposure to allergen. 1282 16

In allergic disorders, the role of tumor necrosis factors (TNF) is not well established. We investigated the role of TNF in allergic peritonitis induced by ovalbumin (OVA) challenge in double TNF (TNF-alpha(-/-)/lymphotoxin-alpha(-/-)) knock out (TNF-KO) mice. In the peritoneal lavage of TNF-KO mice, mast cell number and histamine level (radioenzymatic assay) were similar to that in wild type (WT) mice. TNF-alpha (ELISA) and histamine were increased 1 h after challenge in WT mice. However, three days later eosinophil number and eosinophil peroxidase (EPO) levels (colorimetric-enzymatic assay) were found to be lower in TNF-KO mice. A second challenge three days after the first, increased EPO, histamine and IL-6 (ELISA) but did not alter eosinophil and mast cell numbers in both types of mice. On the other hand histamine and IL-6 were higher, while EPO was lower in TNF-KO mice. In conclusion, our findings show that TNF is involved in eosinophil accumulation and inflammatory mediators' release in a murine model of allergy.
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PMID:Tumor necrosis factors in a murine model of allergic peritonitis: effects on eosinophil accumulation and inflammatory mediators' release. 1458 Oct 1

Eosinophil lineage-committed progenitors (EoPs) are phenotypically isolatable in the steady-state murine bone marrow. Purified granulocyte/monocyte progenitors (GMPs) gave rise to eosinophils as well as neutrophils and monocytes at the single cell level. Within the short-term culture of GMPs, the eosinophil potential was found exclusively in cells activating the transgenic reporter for GATA-1, a transcription factor capable of instructing eosinophil lineage commitment. These GATA-1-activating cells possessed an IL-5Ralpha(+)CD34(+)c-Kit(lo) phenotype. Normal bone marrow cells also contained IL-5Ralpha(+)CD34(+)c-Kit(lo) EoPs that gave rise exclusively to eosinophils. EoPs significantly increased in number in response to helminth infection, suggesting that the EoP stage is physiologically involved in eosinophil production in vivo. EoPs expressed eosinophil-related genes, such as the eosinophil peroxidase and the major basic protein, but did not express basophil/mast cell-related mast cell proteases. The enforced retroviral expression of IL-5Ralpha in GMPs did not enhance the frequency of eosinophil lineage read-outs, whereas IL-5Ralpha(+) GMPs displayed normal neutrophil/monocyte differentiation in the presence of IL-5 alone. Thus, IL-5Ralpha might be expressed specifically at the EoP stage as a result of commitment into the eosinophil lineage. The newly identified EoPs could be the cellular target in the treatment of a variety of disorders mediated by eosinophils.
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PMID:Identification of eosinophil lineage-committed progenitors in the murine bone marrow. 1595 40


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