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 inhib its anti-IgE-mediated mast-cell degranulation. We hypothesized that th e antiallergic action of heparin may be dependent on molecular weight and related to its nonanticoagulant properties. Therefore, in the pres ent investigation we studied the effects of a nonanticoagulant fractio n of heparin (LA-heparin) on antigen-induced bronchoconstriction, airw ay hyperresponsiveness (AHR), and mast-cell degranulation, and compare d its antiallergic activity with that of a low molecular weight hepari n (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 p retreatment with inhaled fractionated heparins at doses of 2.5 and 5 m g/kg. Airway responsiveness was estimated before, and 2 h after antige n as the cumulative provocating dose (PD400) of carbachol in breath un its, which increased SRL by 400% (one breath unit was defined as one b reath of 1% carbachol solution). LA-heparin caused a dose-dependent in hibition of antigen-induced bronchoconstriction, and a 5-mg/kg nebuliz ed dose caused a 67% inhibition of allergic bronchoconstriction, where as 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 ineffecti ve. 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 fragm in, with IC50 of 80 and 320 mu g/ml, respectively. These data suggest that: (1) fractionated heparins attenuate antigen-induced acute bronch oconstriction, (2) nonanticoagulant fractions mediate the antiallergic activity of inhaled heparin, and (3) antiallergic activity of nonanti coagulant heparin and LMW-heparin may be related to prevention of mast -cell degranulation.