Effects of heparin and related molecules upon neutrophil aggregation and elastase releasein vitro

Brown, R.A., Lever, R., Jones, N.A. and Page, C.P. (2003) Effects of heparin and related molecules upon neutrophil aggregation and elastase releasein vitro. British Journal of Pharmacology, 139 (4). pp. 845-853. 10.1038/sj.bjp.0705291.

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DOI: 10.1038/sj.bjp.0705291

Abstract

1. Neutrophil-derived elastase is an enzyme implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Heparin inhibits the enzymatic activity of elastase and here we provide evidence for the first time that heparin can inhibit the release of elastase from human neutrophils. 2. Unfractionated and low molecular weight heparins (UH and LMWH, 0.01-1000 U ml -1) and corresponding concentrations (0.06-6000 μg ml -1) of nonanticoagulant O-desulphated heparin (ODH), dextran sulphate (DS) and nonsulphated poly-L-glutamic acid (PGA) were compared for their effects on both elastase release from and aggregation of neutrophils. 3. UH, ODH and LMWH inhibited (P < 0.05) the homotypic aggregation of neutrophils, in response to both N-formyl-methionyl-leucyl-phenylalanine (fMLP, 10 -6 M) and platelet-activating factor (PAF, 10 -6 M), as well as elastase release in response to these stimuli, in the absence and presence of the priming agent tumour necrosis factor-alpha (TNF-α, 100 U ml -1). 4. DS inhibited elastase release under all the conditions of cellular activation tested (P < 0.05) but had no effect on aggregation. PGA lacked efficacy in either assay, suggesting general sulphation to be important in both effects of heparin on neutrophil function and specific patterns of sulphation to be required for inhibition of aggregation. 5. Further investigation of the structural requirements for inhibition of elastase release confirmed the nonsulphated GAG hyaluronic acid and neutral dextran, respectively, to be without effect, whereas the IP 3 receptor antagonist 2-aminoethoxydiphenylborate (2-APB) mimicked the effects of heparin, itself an established IP 3 receptor antagonist, suggesting this to be a possible mechanism of action.

Item Type:Article
Uncontrolled Keywords:Neutrophils;aggregation;elastase;heparin;fMLP;PAF;sulphation;polyanionic charge;nonanticoagulant
Departments, units and centres:Department of Pharmacology > Department of Pharmacology
ID Code:3191
Journal or Publication Title:British Journal of Pharmacology
Deposited By:Library Staff
Deposited On:10 May 2012 15:32
Last Modified:10 May 2012 15:32

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