Inhibition of antigen-induced airway and cutaneous responses by heparin: a pharmacodynamic study

Abstract

We have previously shown that heparin attenuates the acute bronchoconstrictor response and immediate cutaneous reaction (ICR) to antigen in allergic sheep. In the present investigation, we studied the pharmacodynamics of the antiallergic action of heparin. Specific lung resistance (sRL) was measured in eight sheep, allergic to Ascaris suum antigen, before and 5 min after inhalation challenge with the antigen. On different experiment days, antigen challenge was repeated after pretreatment with 1) aerosol heparin (1,000 U/kg) administered < or = 20 min, 6 h, 12 h, and 24 h and 2) intravenous heparin (1,000 U/kg) administered < or = 20 min, 1 h, 6 h, and 12 h before antigen challenge. sRL increased by 374 +/- 116% (SE) above baseline with antigen alone. Both aerosol and intravenous heparin attenuated the antigen effects on sRL in a time-dependent fashion. Prolonging the lag time between pretreatment and antigen challenge decreased the inhibitory effect of aerosol heparin; delta sRL was 31 +/- 29, 99 +/- 38, 142 +/- 40, and 306 +/- 60% for < or = 20-min, 6-h, 12-h, and 24-h pretreatment protocols, respectively. In contrast, prolonging the lag time increased the inhibitory effect of intravenous heparin: delta sRL was 246 +/- 64, 66 +/- 26, and 76 +/- 32% for < or = 20 min, 1 h, and 6 h, respectively. In seven additional sheep pretreatment with intravenous heparin (1,000 U/kg) attenuated the ICR also in a time-dependent manner; the inhibitory effect of heparin on ICR to antigen was enhanced 60% by increasing the heparin pretreatment interval from 20 to 60 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibitors of Tryptase as Mast Cell-Stabilizing Agents in the Human Airways: Effects of Tryptase and Other Agonists of Proteinase-Activated Receptor 2 on Histamine Release

“…However, heparin was itself able to inhibit the activation of lung mast cells, at least with antiIgE as the stimulus. This is consistent with a previous report by Ahmed et al (1993) who found that addition of heparin to human uterine and rat peritoneal mast cells reduced the degree of IgE-dependent histamine release. Heparin may have mutually antagonistic roles in inhibiting histamine release and in allowing tryptase to act as a stimulus, and this makes it more difficult to assess the contribution of tryptase as an amplification signal.…”

The effect of inhaled heparin on bronchial reactivity to sodium metabisulphite and methacholine in patients with asthma

“…Our failure to show an inhibitory effect of inhaled heparin on sodium metabisulphite-induced bronchoconstriction is unlikely to be due to the timing of the challenge after heparin inhalation, since time course studies have shown that the inhibitory effect of inhaled heparin on allergen-induced bronchoconstriction in Ascaris suum sensitive sheep is maximal less than 20 min after inhalation [4]. Our negative findings may reflect problems with access of inhaled heparin to cholinergic nerve endings.…”

“…Heparin has a number of anti-inflammatory effects including, inhibition of mast cell mediator release [3,4], inhibition of aspects of lymphocyte activation [10], and limitation of the injurious effect of major basic protein [9], and it has been suggested that it serves a defensive role in the airways [11]. Our study suggests that this defensive role does not extend to inhibition of neurallyinduced bronchoconstriction at least if heparin is administered by inhalation.…”

“…Eur Respir J., 1996, 9, 217- Inhaled heparin has been shown to inhibit both the early response to allergen and exercise-induced bronchoconstriction in subjects with asthma [1, 2]. The mechanism of action is unclear, although studies on isolated human mast cells in vitro suggest that heparin inhibits mast cell mediator release [3,4]. The inhibitory effect of heparin in the airway might extend to neural pathways, since animal studies show that heparin reverses allergen-induced inhibitory M 2 receptor dysfunction [5].…”

Heparin Treatment for Allergic Conjunctivitis in the Experimental Balb/c Model

“…The therapeutic effect of heparin is based on many studies and therapeutic trials [38,44,45,46,47,48,49,50,51]. The concept of our thesis has been seen in other allergic responses [38,44,45,46,47,48,49,50,51].…”