Inhibition of allergic airway responses by inhaled low-molecular-weight heparins: molecular-weight dependence

Abstract

Inhaled heparin prevents antigen-induced bronchoconstriction and inhibits anti-immunoglobulin E-mediated mast cell degranulation. We hypothesized that the antiallergic action of heparin may be molecular weight dependent. Therefore, we studied the effects of three different low-molecular-weight fractions of heparin [medium-, low-, and ultralow-molecular-weight heparin (MMWH, LMWH, ULMWH, respectively)] on the antigen-induced acute bronchoconstrictor response (ABR) and airway hyperresponsiveness (AHR) in allergic sheep. Specific lung resistance was measured in 22 sheep before and after airway challenge with Ascaris suum antigen, without and after pretreatment with inhaled fractionated heparins at doses of 0.31-5.0 mg/kg. Airway responsiveness was estimated before and 2 h postantigen as the cumulative provocating dose of carbachol in breath units that increased specific lung resistance by 400%. All fractionated heparins caused a dose-dependent inhibition of ABR and AHR. ULMWH was the most effective fraction, with the inhibitory dose causing 50% protection (ID50) against ABR of 0.5 mg/kg, whereas ID50 values of LMWH and MMWH were 1.25 and 1.8 mg/kg, respectively. ULMWH was also the most effective fraction in attenuating AHR; the ID50 values for ULMWH, LMWH, and MMWH were 0.5, 2.5, and 4.7 mg/kg, respectively. These data suggest that 1) fractionated low-molecular-weight heparins attenuate antigen-induced ABR and AHR; 2) there is an inverse relationship between the antiallergic activity of heparin fractions and molecular weight; and 3) ULMWH is the most effective fraction preventing allergic bronchoconstriction and airway hyperresponsiveness.

Heparin attenuates symptoms and mast cell degranulation induced by AMP nasal provocation

“…22 On the other hand, inhaled unfractionated heparin and low-molecular-weight heparins inhibited antigen-induced histamine release in bronchoalveolar lavage fluid by 81% and 75%; thus, the inhibitory effects of unfractionated heparin and fractionated heparins on histamine release are not strictly molecular weight-dependent. 23 In our current study, the unfractionated heparin was used mainly because we have shown previously that inhaled unfractionated heparin attenuated the airway response to AMP bronchial provocation.…”

Heparin, Derived from the Mast Cells of Human Lungs Is Responsible for the Generation of Kinins in Allergic Reactions due to the Activation of the Contact System

“…It was found that mainly heparin of low MW modifies the antigen–induced airway response and that heparin of ultra low MW is the most effective fraction in the prevention of allergic bronchoconstriction and airway hyperresponsiveness [33, 34, 35]. An influence on immunologically active cells, such as mast cells, basophils, eosinophils, endothelial cells, cell migration, as well as IL–4, IL–5 and TNF–α has also been described.…”

Low-Molecular-Weight Heparin and Unfractionated Heparin Decrease Th-1, 2, and 17 Expressions

“…In addition, several studies showed biologic actions of heparin are molecular weight-dependent [6], [7]. The anti-allergic activity of heparin fractions shows an inverse relationship to the molecular weight [8]. Enoxaparin, a low-molecular-weight (lmw) heparin, is an anticoagulant used to prevent and treat deep vein thrombosis or pulmonary embolism.…”