Heparin prevents antigen-induced airway hyperresponsiveness: interference with IP3-mediated mast cell degranulation?
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.
Ahmed
T
T
Division of Pulmonary Disease, Mount Sinai Medical Center, Miami Beach, Florida 33140.
Syriste
T
T
Mendelssohn
R
R
Sorace
D
D
Mansour
E
E
Lansing
M
M
Abraham
W M
WM
Robinson
M J
MJ
D000818:Animals; D000941:Antigens / Q000276:immunology*; D016084:Bronchoconstriction / Q000187:drug effects; D015550:Cell Degranulation / Q000187:drug effects*; D006493:Heparin / Q000494:pharmacology*; D015544:Inositol 1,4,5-Trisphosphate / Q000502:physiology*; D008407:Mast Cells / Q000187:drug effects* / Q000502:physiology; D010972:Platelet Activating Factor; D012130:Respiratory Hypersensitivity / Q000139:chemically induced / Q000276:immunology* / Q000503:physiopathology; D012756:Sheep
D000941:Antigens; D010972:Platelet Activating Factor; D015544:Inositol 1,4,5-Trisphosphate; D006493:Heparin