Heparin prevents antigen-induced airway hyperresponsiveness: interference with IP3-mediated mast cell degranulation?

Abstract

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.

Inhibitory effects of low molecular weight heparin on mediator release by mast cells: preferential inhibition of cytokine production and mast cell-dependent cutaneous inflammation

“…It has been proposed that inhibition of degranulation by UF heparin is probably due to the ability of the drug to uncouple stimulation-secretion by inhibiting binding of 1,4,5-inositoltriphosphate (IP 3 ) (produced during mast cell activation) to the endoplasmic reticulum, thus preventing the subsequent internal release of calcium necessary for degranulation [26,27]. Interestingly, it has recently been reported that unlike exocytosis, IP 3 is not involved in TNF-a production by mast cells [28].…”

L-Arginine deficiency causes airway hyperresponsiveness after the late asthmatic reaction

“…In addition, in asthmatic patients and in allergen-challenged sheep and guinea pigs, (pretreatment with) inhaled heparin was found to inhibit AHR to various contractile agonists [62][63][64][65][66]. Similar to the arginase inhibitor ABH [45], pretreatment with inhaled heparin also reduced allergen-induced bronchial obstructive reactions in allergic sheep and guinea pigs [64,66,67]. Furthermore, both exercise-and allergen-induced asthmatic reactions in asthmatic patients were reduced by inhaled heparin as well [68][69][70].…”

“…Previous studies have indicated that treatment with inhaled heparin before allergen challenge significantly reduced allergen-induced pulmonary eosinophilia in sensitised guinea pigs [61]. In addition, in asthmatic patients and in allergen-challenged sheep and guinea pigs, (pretreatment with) inhaled heparin was found to inhibit AHR to various contractile agonists [62][63][64][65][66]. Similar to the arginase inhibitor ABH [45], pretreatment with inhaled heparin also reduced allergen-induced bronchial obstructive reactions in allergic sheep and guinea pigs [64,66,67].…”

Pharmacology of Heparin and Related Drugs

“…These effects can at least partially be attributed to the binding and neutralization of mediators and enzymes released during the inflammatory response (Tyrrell et al, 1999) that would otherwise lead to inflammatory cell activation, although inhibition of the release of inflammatory mediators from cells may also contribute to the net effect (Rao et al, 1991;Ahmed et al, 1994;Brown et al, 2003;Ji et al, 2004;Zeng et al, 2004) (see below). Furthermore, certain inflammatory cell-derived enzymes and cytotoxic mediators, involved in promotion of the inflammatory response and subsequent tissue damage and remodeling, have also been shown to be inhibited by heparin, including elastase (Redini et al, 1988;Walsh et al, 1991), cathepsin G (Redini et al, 1988), eosinophil peroxidase (Pégorier et al, 2006), ECP (Fredens et al, 1991), and EMBP (Swaminathan et al, 2005).…”