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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heparin from degranulating mast cells influences a wide range of cellular and humoral reactions associated with allergic inflammation and asthma. Agents that inhibit mast cell degranulation may therefore compromise the moderating effects of heparin in the tissues and result in worsening inflammation and other associated pathology. This study measures heparin release from allergen-challenged human lung tissue and compares the effect of the mast cell stabilizing beta 2-agonists, salbutamol and fenoterol, and a non-beta 2-agonist, sodium cromoglycate, on the release of heparin. Pieces of lung tissue 2 to 3 mm3 were sensitized with high titer Dermatoaphagoides pteronyssinus-specific IgE serum and challenged with D. pteronyssinus allergen, with and without prior addition of salbutamol, fenoterol, or sodium cromoglycate. Dextran sulfate was added to the mixture to prevent the binding of heparin to tissue proteins. Heparin was released together with histamine after challenge. The mean and 95% confidence interval of prechallenge and postchallenge heparin concentrations in the lung tissue filtrates were 0.10 IU/ml (0.07, 0.12) and 0.24 IU/ml (0.17, 0.30), respectively (P < 0.001). Addition of the beta 2-agonists produced a mean inhibition of released heparin of 71% (50, 92), and 73% (55, 91), respectively. Sodium cromoglycate gave a 35% (20, 51) inhibition that was significantly less than that produced by the beta 2-agonists (P < 0.01). The beta 2-agonists salbutamol and fenoterol strongly inhibited heparin release from mast cells. The therapeutic use of mast cell stabilizing agents may therefore be potentially detrimental to the control of allergic inflammation and other associated pathologies.
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PMID:Effect of salbutamol, fenoterol, and sodium cromoglycate on the release of heparin from sensitized human lung fragments challenged with Dermatophagoides pteronyssinus allergen. 768 96

We hypothesized that heparin, because of its antiallergic and/or anti-inflammatory properties, modifies airway hyperresponsiveness (AHR). We studied the effects of inhaled heparin on AHR induced by specific antigen or by platelet-activating factor (PAF), a proinflammatory mediator. Specific lung resistance (sRL) was measured in 17 allergic sheep before, immediately after, and serially for up to 2 h after airway challenge with either specific antigen or PAF. Airway responsiveness was expressed as the cumulative provocative dose of carbachol that increased sRL to 4 cmH2O/s [PD4, in breath units (BU; 1 BU = 1 breath of 1% carbachol solution)]. PD4 was determined on a baseline day and on various experimental days 2 h after airway challenge with antigen or PAF, without or after pretreatment with inhaled heparin (1,000 U/kg). Pretreatment with inhaled heparin prevented antigen-induced bronchoconstriction and postantigen AHR. PD4 was 26 +/- 2.6 (SE), 12 +/- 1.7, and 22 +/- 2.8 BU on baseline, antigen control, and postheparin days, respectively. Heparin given immediately after the antigen challenge failed to modify the magnitude and/or duration of antigen-induced bronchoconstrictor response or postantigen AHR. Heparin also failed to prevent PAF-induced changes in sRL and AHR. In vitro heparin inhibited anti-immunoglobin E- and 1,4,5-inositol triphosphate-mediated degranulation of rat peritoneal mast cells without attenuating the effects of the Ca2+ ionophore A-23187. These data suggest that in "acute responders" heparin prevents antigen-induced bronchoconstriction and AHR, possibly by inhibiting 1,4,5-inositol triphosphate-dependent mast cell mediator release and not by its anti-inflammatory action.
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PMID:Heparin prevents antigen-induced airway hyperresponsiveness: interference with IP3-mediated mast cell degranulation? 817 4

Heparin is a sulfated glycosaminoglycan, synthesized by connective tissue-type mast cells. Rat mast cell protease 1 (RMCP-1), a chymotrypsin-like serine protease expressed specifically by connective tissue-type mast cells, is recovered in a macromolecular complex with heparin proteoglycan. The heparin.RMCP-1 complexes are stored in the secretory granules of the cells and are released following mast cell activation. We showed previously that dissociation of RMCP-1 from heparin resulted in loss of protease activity, as measured by its ability to inactivate thrombin. In the present report the binding of heparin to RMCP-1 was characterized. Affinity chromatography on heparin-Sepharose showed that RMCP-1 displayed high affinity for heparin, with approximately 1.2 M NaCl being required for elution of RMCP-1 from the affinity matrix. The structural requirements for the binding of heparin to RMCP-1 were investigated. Heparan sulfate, chondroitin sulfate, and dermatan sulfate, three glycosaminoglycans structurally related to heparin, were > or = 80-fold less effective in binding to RMCP-1 than heparin. The 2-O-sulfate, 6-O-sulfate, and N-sulfate groups in heparin were all shown to contribute in the binding. The minimal heparin sequence required for binding to RMCP-1 was found in a 14-saccharide fraction. 14-Saccharide species, obtained after separation by anion exchange chromatography, showed continuously increased binding with increasing anionic charge densities. The 16-18-saccharides were the smallest heparin oligosaccharides capable of accelerating the inactivation of thrombin by RMCP-1.
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PMID:Interaction of heparin with rat mast cell protease 1. 818 50

Heparin is a sulphated glycosaminoglycan derived from mast cells and has a number of functions including the inhibition of proliferation in several cell types and interactions with a range of heparin-binding growth factors. We report that heparin is a trophic factor in primary cultures of rat small intestinal epithelium. Heparin elicits a dose-dependent increase in epithelial proliferation and inhibits the growth of associated mesenchyme. The trophic effect of this molecule is not reproduced by other glycosaminoglycans including heparan sulphate but is dependent upon extensive molecular sulphation. Highly sulphated polysaccharides that are structurally unrelated to heparin (e.g. dextran sulphate and pentosan polysulphate) also stimulate epithelial proliferation in primary cultures. Heparin may act by the potentiation of mesenchyme-derived heparin-binding growth factors and these data suggest an in vivo role for mast cell-derived heparin in mucosal wound regeneration.
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PMID:Heparin stimulates the proliferation of intestinal epithelial cells in primary culture. 820 71

The staining property of skin mast cells changed from Alcian blue+/berberine sulfate- to Alcian blue+/berberine sulfate+ in the skin of normal (+/+) and Wv/Wv mice. In contrast, this change did not occur in the skin of mi/mi mice. Heparin content and histamine content per a mi/mi skin mast cell were estimated to be 34% and 18% those of a +/+ skin mast cell, respectively. The low heparin content of mi/mi skin mast cells seemed to be consistent with the Alcian blue+/berberine sulfate- staining property. Expression of genes encoding mast cell-specific proteolytic enzymes was examined by Northern blotting and in situ hybridization. Messenger RNA of mast cell carboxypeptidase A was expressed most of all by +/+, Wv/Wv, and mi/mi skin mast cells, but mRNA of mouse mast cell protease (MMCP)-6 was expressed by approximately a half of +/+ and Wv/Wv skin mast cells and by only 3% of mi/mi skin mast cells. A significant amount of MMCP-2 mRNA was not expressed in the skin of all +/+, Wv/Wv and mi/mi mice. This shows the presence of at least three phenotypes in skin mast cells of mice: berberine sulfate+/MMCP-6+, berberine sulfate+/MMCP-6-, and berberine sulfate-/MMCP-6-. The in situ hybridization of mRNA of mast cell-specific proteolytic enzymes seemed to be useful to describe abnormalities of mast cell differentiation in the skin of mi/mi mice.
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PMID:Deficient differentiation of mast cells in the skin of mi/mi mice. Usefulness of in situ hybridization for evaluation of mast cell phenotype. 823 51

We have previously shown that heparin attenuates allergic bronchoconstriction in sheep, inhibits anti-IgE mediated histamine release in isolated mast cells, and prevents the bronchoconstrictor response in subjects with exercise-induced asthma (EIA). The purpose of the present study was to determine the pharmacokinetics of anti-asthmatic activity of inhaled heparin in EIA and compare it with cromolyn sodium, a mast cell stabilizing agent with established efficacy in EIA. Nine subjects with a history of EIA were studied on 10 different experiment days. After obtaining baseline pulmonary functions on day 1, subjects performed a standardized exercise challenge to document the presence of EIA. While monitoring minute ventilation and heart rate, exercise challenge was performed on a treadmill with increasing workload, until 85% of predicted maximum heart rate was achieved. The subjects then continued the exercise at that workload for 10 min. EIA was assessed by measurements of specific airway conductance (SGaw) before and after exercise. On experiment days 2-10, the exercise challenge was performed after the subjects inhaled 4 ml of either heparin (20,000 u/ml), cromolyn (20 mg), or placebo solutions with increasing pretreatment intervals of 15 min, 1 h, 3 h, or 6 h in a single-blind, randomized fashion. Maximum decreases in SGaw (mean +/- SE) at 3 to 5 min after exercise on control (39 +/- 2.1%) and placebo (37 +/- 2.6%) days were reproducible. Heparin and cromolyn had no effect on baseline SGaw but attenuated the EIA in a time-dependent fashion. Heparin inhibited the bronchoconstrictor responses to exercise by 58%, 78%, and 67% (p < 0.05) when nebulized 15 min, 1 h and 3 h, respectively, before exercise; cromolyn attenuated the responses by 37%, 46%, and 41%, respectively, (p < 0.05). Although heparin offered greater protection than cromolyn (at 1 to 3 h), both agents were ineffective when administered 6 h before exercise. These data demonstrate that inhaled heparin prevents EIA for up to 3 h and is more effective than cromolyn.
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PMID:Time course of the protective effect of inhaled heparin on exercise-induced asthma. 863 Jun 24

Tryptase (EC 3.4.21.59), the major secretory product of human mast cells, has become widely used as a biochemical marker for mast cells and mast cell activation, and is attracting attention as a mediator of allergic disease. However, there is little information available on the properties, or even the presence, of this protease in commonly used species of laboratory animals. We, here, report the demonstration and characterisation of this enzyme in the guinea pig lung. Tryptic activity resistant to alpha 1-proteinase inhibitor and soybean trypsin inhibitor was detected in sections of guinea pig lung tissue with the histochemical substrate Z-Gly-Pro-Arg-MNA. It was localised to mast cells and appeared to be present in all mast cells staining with Alcian Blue. A tryptic protease was purified 2400-fold from whole lung tissue by high salt extraction, cetylpyridinium chloride precipitation, heparin agarose chromatography, and gel filtration. This enzyme was found to be multimeric with a subunit of 38 kDa and a native molecular mass of 860 +/- 100 kDa. Inhibitor studies identified it as a serine protease. Like human tryptase, it was inhibited by leupeptin, benzamidine, and APC 366 (N-(1-hydroxy-2- naphthoyl)-L-arginyl(-L-prolinamide hydrochloride), but not by alpha 1-proteinase inhibitor, soybean trypsin inhibitor, or antithrombin III. Its response to changes in pH and ionic strength was similar to that of human tryptase. Differences between the guinea pig and human enzymes were seen in activity toward a panel fo 10 tryptic p_nitroanilide peptide substrates. Kinetic constants were determined for two of these: with L-Pyr-Pro-Arg-pNA the guinea pig tryptase had a similar Km but a 5-fold lower kcat than human tryptase, and with L-Pyr-Gly-Arg-pNA the guinea pig enzyme had a 10-fold lower Km and a 30% greater kcat than human counterpart. Heparin stabilised guinea pig tryptase, but did not alter its kinetic parameters as it did with human tryptase, decreasing the Km towards both substrates. The presence of a protease with similarities to human tryptase in the mast cells of guinea pigs suggests that this species may be an appropriate model to investigate the actions to tryptase in vivo, provided cognizance is taken of the differences that do exist.
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PMID:Guinea pig lung tryptase. Localisation to mast cells and characterisation of the partially purified enzyme. 869 58

Glycosaminoglycan heparin possesses multiple noncoagulant properties including antiinflammatory actions. We have previously shown that heparin attenuates the methacholine-induced bronchoconstriction in humans. In contrast to methacholine, a stimulus that induces airway constriction mainly by "direct" stimulation of airway smooth muscle cells, adenosine airway responsiveness reflects "indirectly" induced airway narrowing via inflammatory mediators or neural reflex mechanisms. Whether heparin modulates bronchial hyperreactivity induced by adenosine, is not well known. We investigated the effect of inhaled heparin on adenosine-induced bronchoconstriction and compared the inhibitory role of heparin on the adenosine challenge test with that on the methacholine challenge test. Fifteen subjects (7 males, 8 females) with mild asthma were included in the study. Bronchial provocation tests were performed in a single-blind, crossover, randomized order, and repeated 45 minutes after placebo or aerosolized heparin inhalation (1,000 U/kg). The heparin increased the geometric mean log methacholine PD20 value from 0.47 +/- 0.16 (2.95 mg/ml) to 0.96 +/- 0.10 (8.91 mg/ml), (P < 0.0009) in 15 patients and the geometric mean log adenosine PD20 values from 1.59 +/- 0.23 (38.9 mg/ml) to 1.98 +/- 0.14 (97.7 mg/ml) (NS) in 7 patients whose baseline adenosine PD20 levels were less than 200 mg/ml. The degree of protection by heparin against adenosine-induced bronchoconstriction was not correlated with that against methacholine-induced bronchoconstriction (r = 0.60, NS). The data suggest that inhaled heparin may have an inhibitory effect on the methacholine bronchial challenge, and thus, most likely directs its effect against smooth muscle. Heparin caused less attenuation of a challenge with adenosine and probably does not affect mast cell degranulation.
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PMID:Effect of inhaled heparin on adenosine-induced bronchial hyperreactivity. 917 76

Heparin, well known anticoagulant, can also modulate inflammatory and immunologic processes. Some investigators suggest that heparin inhibits mast cell degranulation. Mast cells play very important role in early phase of asthmatic reaction, releasing many proinflammatory mediators including histamine. The purpose of study was to determine the effect of heparin on early asthmatic response and on histamine level in plasma after allergen challenge. Eleven patients with mild and moderate asthma were studied in a double blind placebo controlled manner. Sodium heparin or placebo were taken via nebulizer, and 15 minutes later allergen challenge (Dpt./grass pollen) was performed. FEV1 was measured at 5, 15, 30 and 60 minutes after challenge and PC20 for allergen was calculated. Peripheral blood was collected before and 30 minutes after challenge to assess histamine concentration in plasma by an immunoenzymatic assay. We observed that heparin significantly decreased early asthmatic response in all patients. After challenge with the same concentration of allergen FEV1 fell 36% for placebo and 8% for heparin. Heparin also prevented rise in histamine level in plasma after allergen challenge. The concentration of histamine before and after challenge were respectively 9.55 +/- 4.08 and 13.06 +/- 3.86 nM for placebo (p < 0.05) and 8.88 +/- 1.50 and 11.18 +/- 1.84 nM for heparin (p > 0.05). There was no correlation between FEV1 and histamine level before and after challenge. Our results suggest that heparin diminishes allergen induced early phase of asthmatic recreation by inhibition of mast cells degranulation.
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PMID:[The influence of heparin on histamine level in plasma during the early reaction phase of asthma]. 923 56

Protease activated receptors (PARs) compose a family of G protein signal transduction receptors activated by proteolysis. In this study, the susceptibility of PARs expressed on human keratinocytes and dermal fibroblasts to the human mast cell proteases tryptase and chymase was evaluated. PAR activation was measured by monitoring cytosolic [Ca2+] in cells loaded with the fluorescent Ca2+ probe Fura-2. Tryptase produced transient cytosolic Ca2+ mobilization in keratinocytes, but not in fibroblasts. Ca2+ mobilization in keratinocytes required enzymatically active tryptase, demonstrated desensitization, and was blocked by pretreatment of cells with the PAR-2 peptide agonist SLIGKV, trypsin, or the phospholipase inhibitor U73122. Heparin, a GAG that binds to tryptase, stabilizing its functional form, also inhibited tryptase-induced Ca2+ mobilization. The maximal response elicited by tryptase was smaller than that observed upon treatment of keratinocytes with trypsin, a known activator of PAR-2, and keratinocytes made refractory to tryptase by pretreatment with the protease remained responsive to trypsin. Pretreatment of keratinocytes with thrombin, an activator of PAR-1 and -3 (thrombin receptors), had no detectable effect on the tryptase or trypsin responses. These data suggest that in keratinocytes tryptase may be activating a subpopulation of PAR-2 receptors. Treatment of keratinocytes or fibroblasts with human chymase did not produce Ca2+ mobilization, nor did it affect Ca2+ mobilization produced by trypsin. However, chymase pretreatment of fibroblasts rapidly inhibited the ability of these cells to respond to thrombin. Inhibition was dependent on chymase enzymatic activity and was not significantly affected by the presence of heparin. This finding is consistent with studies indicating that PAR-1 may be susceptible to proteases with chymotrypsin-like specificity. These results suggest that the proteases tryptase and chymase secreted from mast cells in skin may affect the behavior of surrounding cells by the hydrolysis of PARs expressed by these cells.
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PMID:Reaction of mast cell proteases tryptase and chymase with protease activated receptors (PARs) on keratinocytes and fibroblasts. 964 24


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