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PubMed2004

Interferon-gamma protects against chronic viral myocarditis by reducing mast cell degranulation, fibrosis, and the profibrotic cytokines transforming growth factor-beta 1, interleukin-1 beta, and interleukin-4 in the heart.

Inflammatory fibrosis is a characteristic feature of myocarditis, dilated cardiomyopathy (DCM), and congestive heart failure. Th1-type immune responses, mediated by interleukin (IL)-12-induced interferon (IFN)-gamma, are believed to exacerbate autoimmune diseases including myocarditis. In this study, we examined the effect of IL-12R beta 1 and IFN-gamma deficiency on the development of chronic CB3-induced myocarditis using knockout mice. We found increased chronic CB3-induced myocarditis (14.1 to 43.1%, P < 0.001); pericarditis (1.5 to 7.6%, P < 0.001); fibrosis (9.7 to 27.4%, P < 0.05); and the profibrotic cytokines transforming growth factor-beta(1), IL-1 beta, and IL-4 in the hearts of IFN-gamma-deficient mice. All mice infected with CB3 developed DCM, but IFN-gamma-deficient mice developed a fibrous, adhesive pericarditis associated with increased numbers of degranulating mast cells (MCs) in the pericardium (26.6 to 45.9%, P < 0.01), increased histamine levels (716 to 1930 ng/g of heart, P < 0.01), and reduced survival (100 to 43%). In contrast, IL-12R beta 1 deficiency did not significantly alter the development of chronic myocarditis. Thus, IFN-gamma protects against the development of severe chronic myocarditis, pericarditis, and DCM after CB3 infection by reducing MC degranulation, fibrosis, and the profibrotic cytokines transforming growth factor-beta(1), IL-1 beta, and IL-4 in the heart.

Animals↗
PubMed1999

Evidence that mast cell degranulation, histamine and tumour necrosis factor alpha release occur in LPS-induced plasma leakage in rat skin.

1. In the present study we investigated the role of mast cells during inflammation in rat skin. As the release of several pro-inflammatory mediators, such as histamine and tumour necrosis factor alpha (TNFalpha), occurs following mast cell activation we studied whether mast cell degranulation and the release of both histamine (H) and TNFalpha occurred in a model of lipopolysaccharide (LPS)-induced plasma leakage in rat skin. 2. Plasma leakage in the rat skin was measured over a period of 2 h as the local accumulation of intravenous injection of 125I-human serum albumin (125I-HSA) in response to intradermal injection of LPS. LPS (10 microg site-1) produced an increase of plasma leakage (50.1+/-2.3 microl site-1) as compared to saline (9.0+/-3.2 microl site-1). Histological analysis of rat tissue showed that LPS induced a remarkable mast cell degranulation (59.8+/-2.1%) as compared to saline (13.5+/-2.2%). 3. Ketotifen (10-9 - 10-7 mol site-1), a well-known mast cell-membrane stabilizer, produced a dose-related inhibition of LPS-induced plasma leakage by 36+/-3.5%, 47+/-4.0%, 60+/-3.3% respectively. In addition, ketotifen (10-7 mol site-1) inhibited mast cell degranulation by 59. 2+/-2.7%. 4. Chlorpheniramine maleate (CPM) (10-9 - 10-7 mol site-1), an H1 histamine receptor antagonist only partially inhibited LPS-induced plasma leakage in rat skin (38+/-1.1% at the highest dose). Furthermore, CPM (10-7 mol site-1) did not prevent mast cell degranulation. 5. A polyclonal antibody against TNFalpha (1:500, 1:100, 1:50 v v-1 dilution), locally injected, decreased LPS-induced plasma leakage in the skin by 15+/-2.0%, 24+/-2.1% and 50+/-3.0% respectively. 6. Taken together these results suggest that LPS-induced plasma leakage in rat skin is mediated, at least in part, by mast cell degranulation and by the release of histamine and TNFalpha from these cells.

Animals↗
PubMed1997

Antigen-evoked mast cell degranulation in the isolated rat heart: no effect on subsequent ischemia-reperfusion induced damage.

In the present study, the possible role of mast cells in ischemia/reperfusion-induced myocardial injury was evaluated in the isolated 'mast cell depleted' rat heart. Hearts isolated from sensitized and non-sensitized rats were perfused according to Langendorff. After 30 min of normoxic perfusion, hearts were challenged with antigen, a procedure which is known to result in a massive mast cell degranulation in sensitized hearts. After another 20 min, both 'mast cell depleted' and control hearts were subjected to 30 min of ischemia followed by 30 min of reperfusion. The release of lactate dehydrogenase (LDH) was determined, to quantitate the extent of irreversible injury of cardiomyocytes. Histamine release was measured to establish mast cell degranulation. Coronary flow (CF) and left ventricular developed pressure (LVDP) were monitored to study the consequences of the procedures on hemodynamic recovery. It was found that both CF and LVDP significantly increased during the first min after antigen challenge. These changes were accompanied by an almost complete degranulation of cardiac mast cells. The increase in CF and LVDP values were rapidly followed by a decrease, reaching minimal values of 159 +/- 4% and 85 +/- 4% of those before administration of antigen, respectively, at 2-3 min after antigen challenge. No effect of antigen challenge on LDH release were found indicating that mast cell degranulation did not compromise myocyte integrity. During reperfusion following 30 min of ischemia both the increase in CF and LVDP in 'mast cell-depleted' hearts were not significantly different from those in control (non-sensitized) hearts. Similarly, at the end of the reperfusion-phase, CF and LVDP values in sensitized hearts were comparable to those in control hearts. Reperfusion results in increased LDH release, which at no point in time was significantly different between sensitized and non-sensitized hearts. In non-sensitized hearts histamine release during the reperfusion phase was not detectable. Therefore, the results indicate that in the isolated rat heart, mast cells are most likely not involved in acute ischemia/reperfusion-induced myocardial injury.

Animals↗
PubMed1997

Inosine binds to A3 adenosine receptors and stimulates mast cell degranulation.

We investigated the mechanism by which inosine, a metabolite of adenosine that accumulates to > 1 mM levels in ischemic tissues, triggers mast cell degranulation. Inosine was found to do the following: (a) compete for [125I]N6-aminobenzyladenosine binding to recombinant rat A3 adenosine receptors (A3AR) with an IC50 of 25+/-6 microM; (b) not bind to A1 or A2A ARs; (c) bind to newly identified A3ARs in guinea pig lung (IC50 = 15+/-4 microM); (d) lower cyclic AMP in HEK-293 cells expressing rat A3ARs (ED50 = 12+/-5 microM); (e) stimulate RBL-2H3 rat mast-like cell degranulation (ED50 = 2.3+/-0.9 microM); and (f) cause mast cell-dependent constriction of hamster cheek pouch arterioles that is attenuated by A3AR blockade. Inosine differs from adenosine in not activating A2AARs that dilate vascular smooth muscle and inhibit mast cell degranulation. The A3 selectivity of inosine may explain why it elicits a monophasic arteriolar constrictor response distinct from the multiphasic dilator/constrictor response to adenosine. Nucleoside accumulation and an increase in the ratio of inosine to adenosine may provide a physiologic stimulus for mast cell degranulation in ischemic or inflamed tissues.

Adenine↗
PubMed1979

The effect of disodium cromoglycate on in vitro mast cell degranulation in human jejunal mucosa.

The in vitro effect of disodium cromoglycate (DSCG) on IgE antigen-induced mast cell degranulation is described. Serum from an egg white allergic patient was used to sensitize jejunal mucosa from nine individuals. Egg white was used to challenge the IgE sensitized mast cells. DSCG in concentrations 3 x 10(-7) M to 3 x 10(-4) M was added to the mucosal specimens before antigen challenge. Mast cell degranulation in the sensitized specimens challenged with egg white was 38%. Mast cell degranulation in sensitized specimens treated with DSCG before and during antigen challenge was reduced to 2% at a concentration of 3 x 10(-5) M of DSCG (P=0.006) and to 28% at a concentration of 3 x 10(-6) M (P=0.027). No significant reduction of mast cell degranulation was seen at concentrations of 3 x 10(-7) M and 3 x 10(-4) M. The results support a role for DSCG in the treatment of gastrointestinal allergy.

Antigens↗
PubMedDate not supplied

Differential effects on sympathetic neurotransmission of mast cell degranulation by compound 48/80 or antigen in the rat isolated perfused heart.

The aim of the present study was to investigate whether or not release of endogenous mast cell mediators modulates exocytotic noradrenaline overflow. Therefore, we perfused rat isolated hearts with the right sympathetic innervation intact and investigated the effect of mast cell degranulation on the efflux of noradrenaline. Compound 48/80 (48/80), a mast cell degranulating agent, caused a large release of histamine and serotonin and a facilitation of evoked noradrenaline overflow. When 48/80 was introduced into the perfusion medium 4 min before sympathetic nerve stimulation (SNS), evoked noradrenaline overflow was increased by about 60%. In the presence of the uptake 1-blocker cocaine, facilitation was attenuated (increase by only 30%). This effect was abolished by the histamine H2 receptor antagonist cimetidine or the inhibitor of nitric oxide synthesis NG-nitro-(L)-(-)-arginine. When the preexposure time to 48/80 was reduced to 30 s, the facilitation was less pronounced (15%) and inverted to an inhibition in the presence of cocaine (plus idazoxan) by 17% and/or cimetidine (by about 30%). The resulting inhibition of noradrenaline efflux was attenuated by the serotonin 5-HT1/2 receptor antagonist methiothepin or the 5-HT2 antagonist ketanserin. Infusion of ovalbumin into hearts of not specifically sensitized, but sham treated rats (in vivo injection of a saline-alumina mixture 10-12 days before the in vitro experiment) did not affect histamine, serotonin or (basal and evoked) noradrenaline efflux. In hearts from rats that were previously sensitized by an injection of an ovalbumin-alumina adsorbate, ovalbumin induced a marked increase of histamine and serotonin efflux. When the infusion of the antigen started 30 s before SNS, evoked noradrenaline overflow was inhibited by about 60%. The inhibition was unaffected by histamine receptor antagonists, but attenuated by purinoceptor (suramin plus 1,3-dipropyl-8-cyclopentylxanthine), or serotonin receptor (methiothepin, rauwolscine or ketanserin) antagonists. When the preexposure time to ovalbumin was prolonged to 4 min before SNS, no significant change of stimulation-induced noradrenaline overflow was observed. Basal, immunologically and non-immunologically induced histamine and serotonin efflux were not significantly affected by SNS or any of the drugs tested. The results indicate a complex influence of various mediators released upon mast cell degranulation induced by two different stimuli on exocytotic noradrenaline release from rat heart. Depending on the stimulus and on the time interval between the start of the application of the mast cell degranulating agent and SNS, a histamine- and nitric oxide-mediated facilitation, or a serotonin- and purine-mediated inhibition prevails.

Animals↗
PubMed2003

Somatostatin inhibits intestinal mucosal mast cell degranulation in normal conditions and during mast cell hyperplasia.

Several studies demonstrate that intestinal mucosal mast cells (IMMC) are modulated by nervous reflexes as well as by intraluminal content. We recently demonstrated that peptones, such as ovalbumin hydrolysate (OVH), induce the release of rat mast cell protease II (RMCP II), indicating IMMC degranulation. The response is due to complex neuroendocrine reflexes. Somatostatin (SS) and its analogues have been used as potential treatments for inflammation in other body systems with contradictory results. The aim of this study was to evaluate if somatostatin could contribute to the reduction of intestinal mucosal mast cell degranulation. Anesthetized rats were prepared for duodenal perfusion and mast cell activation was measured by analysis of RMCP II concentration in the duodenal perfusate. Somatostatin significantly decreased RMCP II concentration in both nonstimulated conditions and after ovalbumin hydrolysate perfusion. However, when somatostatin was given previously to OVH, the peptone still induced a slight increase of RMCP II. Similar effects were observed in animals previously treated with capsaicin. These protocols were repeated in animals infected with Trichinella spiralis, which induces mucosal mast cell hyperplasia. In these cases, somatostatin blocked the effect of OVH, thus, preventing an increase in RMCP II concentration. Fresh frozen tissue sections from the duodenum were processed in an attempt to demonstrate the presence of SS receptors in mast cells using immunofluorescence and Fluo-peptide labeling techniques. Confocal images from duodenum specimens demonstrate the existence of SS receptors in positive cells for RMCP II. Taken together, these results indicate that somatostatin diminishes mast cell activity and in consequence could prevent the intestinal responses to mast cell hyperplasia.

Animals↗
PubMed1986

Elevated blood glucose after compound 48/80 treatment is not related to hepatic mast cell degranulation in rats.

Blood glucose, hepatic glycogen, and the histological integrity of hepatic mast cells, were evaluated in anesthetized rats receiving iv injections of 0.125 mg/kg body weight compound 48/80 (a mast cell degranulator) and/or of 0.001 to 10.0 mg/kg body weight lodoxamide tromethamine (an inhibitor of mast cell degranulation). A nonglucogenic dose of lodoxamide, 0.001 mg/kg body weight, prevented dissipation of histochemically demonstrable fluorescence in mast cells (degranulation) without inhibiting compound 48/80-induced hyperglycemia and hepatic glycogenolysis. These results suggest that this glucotropic response is independent of compound 48/80-evoked release of mediators such as serotonin from mast cells.

Animals↗
PubMed1989

Time course of human conjunctival mast cell degranulation in response to compound 48/80.

Compound 48/80, a non-immunogenic mast cell degranulatory agent, is known to produce the signs and symptoms of ocular allergy. Maximal mast cell degranulation of human conjunctiva occurred within the first hour after stimulation by a single topical dose of compound 48/80 (20 microliters, 7.5 mg/ml). The average percentage of fully degranulated mast cells in treated specimens (n = 9) was 31% (range 5-60%) versus 6% (range 0-20%) in control specimens (n = 5). Exact correlates of representative granulated, partially degranulated, and fully degranulated mast cells were determined by light and transmission electron microscopy.

Conjunctiva↗
PubMed1978

Mesenteric mast cell degranulation is not essential for conditioned taste aversion.

The possible role of mesenteric mast cell degranulation as the mediator of the initial UCS effects in the complex sequences leading to conditioned taste aversion (CTA) was studied. Both LiCl and Compound 48/80, a potent mast cell degranulator, produced CTA to 10% sucrose. Whereas the Compound 48/80 groups displayed massive mast cell degranulation, neither the LiCl treated nor saline control groups demonstrated any histologically determinable alterations. Administration of the antihistamine chlorpheniramine at dosages known to block radiation-induced CTA before the sucrose CS-UCS pairings did not block either LiCl- or Compound 48/80-induced CTA; the antihistamine actually facilitated the aversion. However, pretreatment with the antihistamine did not alter mesenteric mast cell morphology.

Animals↗
PubMed2004

Endothelin-1 mediates cardiac mast cell degranulation, matrix metalloproteinase activation, and myocardial remodeling in rats.

The objective of this study was to determine whether elevated circulating levels of endothelin (ET)-1 are capable of mediating left ventricular (LV) mast cell degranulation and thereby induce matrix metalloproteinase (MMP) activation. After the administration of 20 pg/ml ET-1 to blood-perfused isolated rat hearts, LV tissue was analyzed for signs of mast cell degranulation and MMP activation. Relative to control, ET-1 produced extensive mast cell degranulation as well as a significant increase in myocardial water content (78.8 +/- 1.5% vs. 74.2 +/- 2.2%, P <0.01), a marked 107% increase in MMP-2 activity (P <0.05), and a substantial decrease in collagen volume fraction (0.69 +/- 0.09% vs. 0.99 +/- 0.04%, P <0.001). Although the myocardial edema would be expected to increase ventricular stiffness, compliance was not altered, and moderate ventricular dilatation was observed (end-diastolic volume at end-diastolic pressure of 0 mmHg of 330.2 +/- 22.1 vs. 298.9 +/- 17.4 microl in ET-1 treated vs. control, respectively, P=0.07). Additionally, pretreatment with the mast cell stabilizer nedocromil prevented ET-1-induced changes in MMP-2 activity, myocardial water content, collagen volume fraction, and end-diastolic volume. These findings demonstrate that ET-1 is a potent cardiac mast cell secretogogue and further indicate that ET-1-mediated mast cell degranulation is a potential mechanism responsible for myocardial remodeling.

Animals↗
PubMed1978

[3H]serotonin release: an improved method to measure mast cell degranulation.

A method based on the release of tritium-labelled serotonin by activated mast cells in rodents is described. Mast cells incorporate labelled serotonin selectively and release the label after activation by non-specific stimulators (compound 48/80, polymyxin B sulphate, ATP, bovine chymotrypsin and L-alpha-lysophosphatidylcholine) or anaphylactic antibody and the corresponding antigen. These two types of activation were investigated in comparison with the toluidine blue microscopic rat mast cell degranulation test, and a methodological study of the release of [3H]serotonin is described. The measurement of labelled serotonin release provides a simple and quick assay of mast cell degranulation compared to the time required for the classical rat mast cell degranulation technique and achieves a greater sensitivity.

Animals↗
PubMed2002

Endogenous mast cell degranulation modulates cervical contractility in the guinea pig.

OBJECTIVE: The purpose of this study was to investigate the effect of endogenous mast cell degranulation on the contractility of isolated cervical strips from nonpregnant and pregnant guinea pigs. STUDY DESIGN: Longitudinal cervical strips from nonpregnant and pregnant (mid and term) guinea pigs were used for isometric tension recording. Responses to the mast cell degranulating agent, compound 48/80, were compared in the absence or presence of different inhibitors and receptor antagonists. Concentration-response curves were obtained to histamine and 5-hydroxytryptamine in strips that were incubated with antagonists or solvent. RESULTS: Compound 48/80 and histamine significantly increased contractility of cervical strips in all 3 groups of animals. The inhibitor of mast cell degranulation significantly reduced responses to compound 48/80 and histamine-1 receptor antagonist reduced responses to histamine in all 3 groups. Histamine-1 receptor antagonist significantly inhibited responses to compound 48/80 in nonpregnant and mid pregnant guinea pigs. Histamine-2 receptor antagonist did not alter responses to compound 48/80 nor to histamine. The receptor antagonist 5-hydroxytryptamine-2 significantly inhibited cervical contractility that was induced by compound 48/80 in tissues from mid pregnant and term pregnant guinea pigs. Lipoxygenase inhibitor was effective in mid pregnant guinea pigs. Cyclooxygenase inhibitor, 5-hydroxytryptamine, and a combination of lipoxygenase and cyclooxygenase inhibitors had no effect on cervical contractility. CONCLUSION: The degranulation of mast cells releases histamine and other mediators that stimulate cervical contractility through histamine-1 receptors. Cervical infiltration and modulation of contractility by mast cells may play an important physiologic and/or pathologic role in the control of cervical function during pregnancy.

Animals↗
PubMed1998

Goblet cell degranulation after antigen challenge in sensitized guinea pigs. Role of neutrophils.

Mucus hypersecretion is a common characteristic of asthma. Acute severe asthma is often associated with neutrophilic infiltration into airways. Neutrophils contain elastase, a potent secretagogue in airways. Therefore, we hypothesized that instillation of ovalbumin in sensitized guinea pigs causes goblet cell secretion by releasing elastase from recruited neutrophils. When we instilled ovalbumin into the trachea of ovalbumin-sensitized guinea pigs, early recruitment of neutrophils identified by 3,3'- diaminobenzidine staining, and goblet cell degranulation measured with a semiautomatic computer-based imaging system occurred. The Leumedin NPC 15669 (a drug that inhibits leukocyte recruitment) and an antibody to intercellular adhesion molecule-1 (ICAM-1) both prevented neutrophil recruitment and goblet cell degranulation, implicating leukocytes in the response. Using immunofluorescence we showed that the leukocytes recruited early after antigen challenge were CD-16-positive, implicating neutrophils. Pretreatment with the selective neutrophil elastase inhibitor ICI 200,355 also prevented ovalbumin-induced goblet cell degranulation, implicating elastase. We conclude that ovalbumin-induced goblet cell degranulation is due to neutrophil recruitment and elastase release.

3,3'-Diaminobenzidine↗
PubMed1984

The characterization of high-affinity binding sites in rat brain for the mast cell-degranulating peptide from bee venom using the purified monoiodinated peptide.

The preparation of a pure, monoiodinated derivative of mast cell-degranulating peptide (MCD peptide), the mast cell-degranulating peptide from bee venom, has enabled us to identify binding sites in rat brain membranes that have a high affinity and specificity for this peptide. These binding sites are evenly distributed throughout the brain and copurify with synaptic membranes. Saturation-binding curves, determined by rapid centrifugation or filtration assays, indicate a single population of sites with a concentration of 200 fmol/mg membrane protein in partially fractionated, lysed brain membranes. Dissociation constants of 150 and 140 pM were calculated for the iodinated and native peptides, respectively. These binding sites are probably associated with the neurotoxic action of MCD peptide in the central nervous system. No similar binding sites have been identified in peripheral tissue preparations, and other polycationic mast cell-degranulating agents including compound 48/80 show no such specificity. Specific modification of the primary amines, arginine residues, or disulfide bridges of MCD peptide results in a complete loss of binding activity. Other components of bee venom show specificity for the MCD peptide-binding site, suggesting that a class of neurotoxins in bee venom (possibly including secapin and tertiapin, but not apamin) share the specific action of MCD peptide on the central nervous system.

Amino Acid Sequence↗
PubMedDate not supplied

Mast cell degranulation alters lymphatic contractile activity through action of histamine.

OBJECTIVE: Mast cells reside in most tissues and in close association with blood vessels and nerves, areas where lymphatic vessels are also present. Mast cells and lymphatic vessels are two important players in the development of the inflammatory process. This study was designed to examine the effects of mast cell degranulation on the contractile activity of mesenteric lymphatic vessels. METHODS: Lymphatic vessel contractile activity was assessed in vitro by video microscopy of the mesentery of cow's milk-sensitized guinea pigs upon application of beta-lactoglobulin and compared to the response measured in sham animals. RESULTS: Application of 5-10 microM beta-lactoglobulin increased lymphatic vessel constriction frequency and decreased constriction amplitude (n = 12). This effect was not seen in sham-treated animals (n = 16) and was not due to an increased number of mast cells in the mesentery of the milk-sensitized animals, as revealed by histological examination. Two known mast cell-derived mediators, histamine and thromboxane A2, via stable mimetic U46619 also altered lymphatic pumping in a similar manner, but only pretreatment with the histamine H1 receptor antagonist pyrilamine (1 microM) could reduce the beta-lactoglobulin-induced response. The thromboxane A2 receptor antagonist, SQ 29548, and the 5-lipoxygenase inhibitor, caffeic acid, were without significant effect. CONCLUSION: In the in vitro mesenteric preparation, mast cell degranulation altered lymphatic contractile activity via the release of a mediator suggested to be histamine and the subsequent activation of H1 receptors. This action could potentially interfere with the expected ability of lymphatic vessels to reduce edema during inflammation.

Animals↗
PubMed1999

Mast cell degranulation prior to ischemia decreases ischemia-reperfusion injury in the canine small intestine.

OBJECTIVE: To determine the impact of previous mast cell degranulation on intestinal ischemia-reperfusion-induced mucosal damaged. MATERIALS: The hemodynamic and morphological consequences of complete arterial occlusion were evaluated in anesthetized dogs. The mast cell degranulator Cremophor-E1 (n = 5) and Compound 48/80 (n = 5) were used to investigate the involvement of gastrointestinal mast cells in ischemia-reperfusion-induced tissue reactions. Seven dogs subjected to complete segmental arterial occlusion served as controls. Intestinal biopsies taken at the end of 120-min ischemia and after 120 min of reperfusion were evaluated histologically. METHODS: The number of mast cells was determined and the degree of mucosal damage was evaluated according to the 5 grade Chiu scale. Mucosal histidine decarboxylase activity was measured in tissue samples and the rate of release of histamine was determined from the venous effluent of the ileal segment. RESULTS: In the control group, 120-min reperfusion significantly increased the plasma histamine level, and induced a severe tissue injury. In the compound 48/80 and Cremophor-E1-pretreated groups, the reduction in the baseline number of mast cells in the villi was 37% and 53%, respectively, and the ischemia-reperfusion-induced release of histamine was significantly decreased. In these groups, the basal mucosal histidine decarboxylase activity was significantly increased and the degree of damage of the intestinal mucosa was significantly reduced. CONCLUSION: It is proposed that mast cell degranulation prior to ischemia may induce a potentially protective mechanism in the small bowel mucosa and decreases ischemia-reperfusion injury in the dog.

Animals↗
PubMed1997

Inhibition of antigen-induced acute bronchoconstriction, airway hyperresponsiveness, and mast cell degranulation by a nonanticoagulant heparin: comparison with a low molecular weight heparin.

Inhaled heparin prevents antigen-induced bronchoconstriction and inhibits anti-IgE-mediated mast-cell degranulation. We hypothesized that the antiallergic action of heparin may be dependent on molecular weight and related to its nonanticoagulant properties. Therefore, in the present investigation we studied the effects of a nonanticoagulant fraction of heparin (LA-heparin) on antigen-induced bronchoconstriction, airway hyperresponsiveness (AHR), and mast-cell degranulation, and compared its antiallergic activity with that of a low molecular weight heparin (LMW-heparin, fragmin). Specific lung resistance (SRL) was measured in 15 sheep before, immediately after, and serially for as long as 2 h after airway challenge with Ascaris suum antigen, without and after pretreatment with inhaled fractionated heparins at doses of 2.5 and 5 mg/kg. Airway responsiveness was estimated before, and 2 h after antigen as the cumulative provocating dose (PD400) of carbachol in breath units, which increased SRL by 400% (one breath unit was defined as one breath of 1% carbachol solution). LA-heparin caused a dose-dependent inhibition of antigen-induced bronchoconstriction, and a 5-mg/kg nebulized dose caused a 67% inhibition of allergic bronchoconstriction, whereas a 2.5-mg/kg dose was ineffective (20% inhibition). Inhaled fragmin was more potent than LA-heparin, as shown by 84% (2.5 mg/kg) and 82% (5 mg/kg) inhibition of allergic bronchoconstriction. Fragmin (5 mg/kg) also attenuated the postantigen AHR, whereas LA-heparin was ineffective. In vitro, preincubation with both LA-heparin and fragmin inhibited the anti-IgE-induced degranulation of rat peritoneal mast-cells in a dose-dependent fashion. LA-heparin was fourfold more potent than fragmin, with IC50 of 80 and 320 microg/ml, respectively. These data suggest that: (1) fractionated heparins attenuate antigen-induced acute bronchoconstriction, (2) nonanticoagulant fractions mediate the antiallergic activity of inhaled heparin, and (3) antiallergic activity of nonanticoagulant heparin and LMW-heparin may be related to prevention of mast-cell degranulation.

Acute Disease↗