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.
Ahmed
T
T
Division of Pulmonary Disease, University of Miami School of Medicine, Mount Sinai Medical Center, Miami Beach, Florida 33140, USA.
Campo
C
C
Abraham
M K
MK
Molinari
J F
JF
Abraham
W M
WM
Ashkin
D
D
Syriste
T
T
Andersson
L O
LO
Svahn
C M
CM
D000208:Acute Disease; D000818:Animals; D000925:Anticoagulants / Q000737:chemistry / Q000627:therapeutic use*; D000941:Antigens / Q000276:immunology*; D001980:Bronchi / Q000187:drug effects; D016535:Bronchial Hyperreactivity / Q000188:drug therapy / Q000276:immunology*; D016084:Bronchoconstriction / Q000187:drug effects / Q000276:immunology*; D015550:Cell Degranulation / Q000187:drug effects*; D017985:Dalteparin / Q000494:pharmacology; D006493:Heparin / Q000737:chemistry / Q000627:therapeutic use*; D008407:Mast Cells / Q000187:drug effects*; D008970:Molecular Weight; D012756:Sheep
D000925:Anticoagulants; D000941:Antigens; D006493:Heparin; D017985:Dalteparin