Effect of heparin and a low‐molecular weight heparinoid on PAF‐induced airway responses in neonatally immunized rabbits

Abstract

We have investigated the effect of an unfractionated heparin preparation, a low‐molecular weight heparinoid (Org 10172) and the polyanionic molecule polyglutamic acid against PAF‐induced airway hyperresponsiveness and pulmonary cell infiltration in neonatally immunized rabbits in vivo. Exposure of neonatally immunized rabbits to aerosolized platelet activating factor (PAF) (80 μg ml−1 for 60 min) elicited an increase in airway responsiveness to inhaled histamine 24 h and 72 h following challenge which was associated with an infiltration of inflammatory cells into the airways, as assessed by bronchoalveolar lavage (BAL). A significant increase in the total numbers of cells recovered from BAL fluid was associated with significantly increased cell numbers of neutrophils, eosinophils and mononuclear cells 24 h following PAF exposure. The numbers of eosinophils and neutrophils in the airways remained elevated 72 h after challenge. The intravenous administation of an unfractionated preparation of heparin (100 units kg−1) or Org 10172 (100 μg kg−1) 30 min prior to PAF exposure significantly inhibited the airway hyperresponsiveness induced by PAF, 24 h and 72 h following challenge. PAF‐induced hyperresponsiveness was not significantly affected by prior intravenous administration of polyglutamic acid (100 μg kg−1). The intravenous administration of unfractionated heparin (100 units kg−1), Org 10172 (100 μg kg−1) or polyglutamic acid (100 μg kg−1) 30 min prior to PAF exposure significantly inhibited the expected increase in total cell infiltration. This study shows that unfractionated heparin and a low‐molecular weight heparinoid, Org 10172, are capable of inhibiting both the airway hyperresponsiveness and pulmonary cell infiltration induced by PAF in the rabbit.

The effects of heparin on the adhesion of human peripheral blood mononuclear cells to human stimulated umbilical vein endothelial cells

“…Again, this observation is in accordance with previous reports, which have found PGA to lack the e ects of heparin on neutrophil adhesion (Lever et al, 2000) and accumulation of in¯ammatory cells in vivo (Sasaki et al, 1993;Seeds et al, 1993). As sulphation is deemed to be essential for many of the biological properties of this drug, we examined the e ects of two dextran sulphate preparations, of di erent molecular weights and found, on the whole, these molecules to lack e ect in our experiments.…”

“…In addition, heparin is known to bind a number of adhesion molecules involved in leucocyte tra cking into tissues, including mac-1 (CD11b/CD18; Diamond et al, 1995) and L-selectin (Koenig et al, 1998) on in¯ammatory cells and the endothelial adhesion molecules P-selectin (Revelle et al, 1996;Skinner et al, 1991) and platelet endothelial adhesion molecule-1 (PECAM-1; Watt et al, 1993). Accordingly, heparin and related molecules have been found to inhibit leucocyte-endothelial interactions both in vitro (Bazzoni et al, 1992;Lever et al, 2000;Silvestro et al, 1994) and in vivo (Ley et al, 1991;Salas et al, 2000;Xie et al, 1997), as well as in¯ammatory cell accumulation in tissue sites such as the lung (Sasaki et al, 1993;Seeds et al, 1993), skin (Teixeira & Hellewell, 1993) and peritoneal cavity (Nelson et al, 1993). …”

In vivo neutralization of eosinophil-derived major basic protein inhibits antigen-induced bronchial hyperreactivity in sensitized guinea pigs.

“…However, the formal recognition that in vivo inhibition or neutralization of locally released eosinophil-derived cationic proteins, particularly MBP, would prevent allergic bronchopulmonary hyperreactivity was still missing. Circumstantially, heparin, which binds to cationic proteins (21), has been shown to inhibit experimental bronchial hyperreactivity (22). Here, we bring evidence that the intranasal treatment of sensitized guinea pigs with purified rabbit Igs raised against guinea pig MBP, given 1 h before and 5 h after antigen challenge, suppresses the increased airway response to inhaled acetylcholine that develops at 72 h. This suggests that secretion of MBP by activated eosinophils is a key event for the subsequent acquisition of bronchial hyperreactivity in this model.…”

Pharmacology of Heparin and Related Drugs

“…Heparin has been shown to inhibit the adhesion of leukocytes to endothelium both in vitro (Bazzoni et al, 1993;Silvestro et al, 1994;Lever et al, 2000;Smailbegovic et al, 2001) and in vivo (Ley et al, 1991;Tangelder and Arfors, 1991;Nelson et al, 1993;Xie et al, 1997;Salas et al, 2000;Johnson et al, 2004;Lever et al, 2010). Furthermore, the ultimate accumulation of cells in inflamed tissue sites, in response to both allergic (Sasaki et al, 1993;Seeds et al, 1995;Seeds and Page, 2001;Vancheri et al, 2001) and nonallergic (Nelson et al, 1993;Teixeira and Hellewell, 1993;Yanaka and Nose, 1996;Johnson et al, 2004;Lever et al, 2010) stimuli, is inhibited by heparin.…”

“…Pretreatment with heparin in animal models of inflammation has been shown to inhibit eosinophil infiltration into the lung (Sasaki et al, 1993;Seeds et al, 1993Seeds et al, , 1995 and skin in response to a range of inflammatory insults (Teixeira and Hellewell, 1993), neutrophil accumulation in the inflamed peritoneal cavity (Nelson et al, 1993;Lever et al, 2010), independently of anticoagulant activity (Lever et al, 2010), and vascular permeability in the skin (Carr, 1979;Jones et al, 2002). Furthermore, heparin has been shown to inhibit bronchial hyper-responsiveness in rabbits in response to platelet-activating factor (Sasaki et al, 1993); in sheep in response to inhaled allergen (Ahmed et al, 1992), an effect that was shared by very low molecular weight and non-anticoagulant heparins (Ahmed et al, 1997); and in guinea-pigs, in which the protective effect of heparin against airway hyper-responsiveness to methacholine was found to be attributable to preservation of nitric oxide signaling (Maarsingh et al, 2004).…”