Non-Anticoagulant Fractions of Enoxaparin Suppress Inflammatory Cytokine Release from Peripheral Blood Mononuclear Cells of Allergic Asthmatic Individuals

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Abstract

Background

Enoxaparin, a low-molecular-weight heparin, is known to possess anti-inflammatory properties. However, its clinical exploitation as an anti-inflammatory agent is hampered by its anticoagulant effect and the associated risk of bleeding.

Objective

The aim of the current study was to examine the ability of non-anticoagulant fractions of enoxaparin to inhibit the release of key inflammatory cytokines in primed peripheral blood mononuclear cells derived from allergic mild asthmatics.

Methods

Peripheral blood mononuclear cells from allergic asthmatics were activated with phytohaemag glutinin (PHA), concanavalin-A (ConA) or phorbol 12-myristate 13-acetate (PMA) in the presence or absence of enoxaparin fractions before cytokine levels were quantified using specific cytokine bead arrays. Together with nuclear magnetic resonance analysis,time-dependent and target-specific effects of enoxaparin fractions were used to elucidate structural determinants for their anti-inflammatory effect and gain mechanistic insights into their anti-inflammatory activity.

Results

Two non-anticoagulant fractions of enoxaparin were identified that significantly inhibited T-cell activation. A disaccharide fraction of enoxaparin inhibited the release of IL-4, IL-5, IL-13 and TNF-α by more than 57% while a tetrasaccharide fraction was found to inhibit the release of tested cytokines by more than 68%. Our data suggest that the observed response is likely to be due to an interaction of 6- O-sulfated tetrasaccharide with cellular receptor(s).

Conclusion and Clinical Relevance

The two identified anti-inflammatory fractions lacked anticoagulant activity and are therefore not associated with risk of bleeding. The findings highlight the potential therapeutic use of enoxaparin-derived fractions, in particular tetrasaccharide, in patients with chronic inflammatory disorders.

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Most cited references 51

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Uncontrolled asthma: a review of the prevalence, disease burden and options for treatment.

Gary Ferguson, Colin Reisner, Yamo Deniz … (2006)

An estimated 300 million people are affected by asthma worldwide and the burden is likely to rise substantially in the next few decades. Estimates of the prevalence of asthma range from 7% in France and Germany to 11% in the USA and 15-18% in the United Kingdom. Approximately 20% of these patients have severe asthma, of which 20% is inadequately controlled. Patients with inadequately controlled severe persistent asthma are at a particularly high risk of exacerbations, hospitalization and death, and often have severely impaired quality of life. Current management of asthma focuses on a stepwise approach tailored to disease severity. In addition to needing high-dose inhaled corticosteroids (ICS) and long-acting beta(2)-agonists (LABAs), patients with severe persistent asthma often require additional controller medications, such as anti-leukotrienes, oral LABAs, oral corticosteroids and/or anti-IgE therapy. There is currently little evidence on which to base treatment decisions in patients with inadequately controlled severe persistent asthma already treated with ICS and LABAs. The anti-IgE monoclonal antibody omalizumab is the most recent addition to the list of treatment options for these patients and has been shown to reduce exacerbations and emergency visits and improve lung function, symptom scores and quality of life in patients with difficult-to-treat asthma whose symptoms remain inadequately controlled despite receiving ICS and LABAs. Comparative trials are needed to determine the merits of different treatments and strategies for patients with inadequately controlled severe persistent asthma and to identify patients likely to benefit from new treatment options.

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The degradation of human endothelial cell-derived perlecan and release of bound basic fibroblast growth factor by stromelysin, collagenase, plasmin, and heparanases.

R Iozzo, J Whitelock, A Murdoch … (1996)

Perlecan is a modular heparan sulfate proteoglycan that is localized to cell surfaces and within basement membranes. Its ability to interact with basic fibroblast growth factor (bFGF) suggests a central role in angiogenesis during development, wound healing, and tumor invasion. In the present study we investigated, using domain specific anti-perlecan monoclonal antibodies, the binding site of bFGF on human endothelial perlecan and its cleavage by proteolytic and glycolytic enzymes. The heparan sulfate was removed from perlecan by heparitinase treatment, and the approximately 450-kDa protein core was digested with various proteases. Plasmin digestion resulted in a large fragment of approximately 300 kDa, whereas stromelysin and rat collagenase cleaved the protein core into smaller fragments. All three proteases removed immunoreactivity toward the anti-domain I antibody. We showed also that perlecan bound bFGF specifically by the heparan sulfate chains located on the amino-terminal domain I. Once bound, the growth factor was released very efficiently by stromelysin, rat collagenase, plasmin, heparitinase I, platelet extract, and heparin. Interestingly, heparinase I, an enzyme with a substrate specificity for regions of heparan sulfate similar to those that bind bFGF, released only small amounts of bFGF. Our findings provide direct evidence that bFGF binds to heparan sulfate sequences attached to domain I and support the hypothesis that perlecan represents a major storage site for this growth factor in the blood vessel wall. Moreover, the concerted action of proteases that degrade the protein core and heparanases that remove the heparan sulfate may modulate the bioavailability of the growth factor.

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Author and article information

Contributors

Muriel Moser: Role: Academic Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 5 June 2015

Publication date Collection: 2015

Volume: 10

Issue: 6

Electronic Location Identifier: e0128803

Affiliations

[1 ]Pharmacy, School of Medicine, Faculty of Health, University of Tasmania, Hobart, Tasmania, Australia

[2 ]Central Science Laboratory, University of Tasmania, Hobart, Tasmania, Australia

[3 ]Menzies Institute for Medical Research, Faculty of Health, University of Tasmania, Hobart, Tasmania, Australia

[4 ]Breathe Well Centre of Research Excellence for Chronic Respiratory Disease and Lung Ageing, School of Medicine, Faculty of Health, University of Tasmania, Hobart, Tasmania, Australia

Université Libre de Bruxelles, BELGIUM

Author notes

Competing Interests: NG acts as an academic editor of PLOS ONE. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Conceived and designed the experiments: MS RP NG GP. Performed the experiments: MS NS JH SS HK. Analyzed the data: MS STZ. Wrote the paper: MS RP NG GP.

‡ These authors also contributed equally to this work.

* E-mail: Rahul.Patel@ 123456utas.edu.au

Article

Publisher ID: PONE-D-15-02916

DOI: 10.1371/journal.pone.0128803

PMC ID: 4457428

PubMed ID: 26046354

SO-VID: 6a3fa545-8864-4e35-9366-e0b56aafced2

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

History

Date received : 20 January 2015

Date accepted : 30 April 2015

Page count

Figures: 7, Tables: 0, Pages: 21

Funding

This work was supported by the Starter Grant from Royal Hobart Hospital Research Foundation, Australia (Grant Number- H22074) awarded to NS, RP and MS ( http://www.rhhresearchfoundation.org/index.php/site/research/), Research Enhancement Grant Schemes from University of Tasmania, Australia (Grant Number- 105557) awarded to RP and NG ( http://www.utas.edu.au/research-admin/funding/funding-options/internal-funding). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Data Availability All relevant data are within the paper and its Supporting Information files.

Non-Anticoagulant Fractions of Enoxaparin Suppress Inflammatory Cytokine Release from Peripheral Blood Mononuclear Cells of Allergic Asthmatic Individuals

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Abstract

Background

Objective

Methods

Results

Conclusion and Clinical Relevance

Related collections

PLOS Climate

Most cited references 51

Allergy and allergic diseases. First of two parts.

Uncontrolled asthma: a review of the prevalence, disease burden and options for treatment.

The degradation of human endothelial cell-derived perlecan and release of bound basic fibroblast growth factor by stromelysin, collagenase, plasmin, and heparanases.

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