S-maltoheptaose targets syndecan-bound effectors to reduce smoking-related neutrophilic inflammation.

David CL Lam,Daisy KY Shum,Stanley CH Chan,Mary SM Ip,Craig Freeman,Judith CW Mak

doi:10.1038/srep12945

David CL Lam, Daisy KY Shum + Show 4 more

Open Access

https://doi.org/10.1038/srep12945

Copy DOI

Abstract

Cigarette smoke induces injury and neutrophilic inflammation in the airways of smokers. The stability and activity of inflammatory effectors, IL8 and neutrophil elastase (NE), can be prolonged by binding to airway heparan sulfate (HS)/syndecan-1, posing risk for developing chronic obstructive pulmonary disease(COPD). We hypothesize that antagonizing HS/syndecan-1 binding of the inflammatory effectors could reduce smoking-related neutrophil-mediated airway inflammation. Analysis of bronchoalveolar lavage fluid(BALF) of COPD patients found both total and unopposed NE levels to be significantly higher among smokers with COPD than non-COPD subjects. Similar NE burden was observed in smoke-exposed rats compared to sham air controls. We chose sulfated-maltoheptaose(SM), a heparin-mimetic, to antagonize HS/sydecan-1 binding of the inflammatory mediators in airway fluids and lung tissues of the smoke-exposed rat model. Airway treatment with SM resulted in displacement of CINC-1 and NE from complexation with bronchio-epithelial HS/syndecan-1, dissipating the chemokine gradient for neutrophil flux across to the bronchial lumen. Following SM displacement of NE from shed HS/syndecan-1 in bronchial fluids, NE became accessible to inhibition by α1-antitrypsin endogenous in test samples. The antagonistic actions of SM against syndecan-1 binding of NE and CINC-1 in smoke-exposed airways suggest new therapeutic opportunities for modulating airway inflammation in smokers with SM delivery.

Highlights

Number of subjects Male Gender Age Smoking status Current smokers Ex-smokers Non-smokers FEV1% predicted FEV1/forced vital capacity (FVC)
In the Bronchoalveolar lavage fluid (BALF) of Chronic obstructive pulmonary disease (COPD) subjects and of smoke-exposed rats, we demonstrated unopposed neutrophil elastase (NE) activity in the presence of an excess of α 1-AT
The unopposed NE was high in BALF from smokers with COPD compared to non-smokers or smokers without COPD

Summary

Introduction

Number of subjects Male Gender Age (years) Smoking status Current smokers Ex-smokers Non-smokers FEV1% predicted FEV1/FVC. That 2-O, 3-O-desulfated heparin showed minimal anti-coagulant activity but anti-protease and anti-inflammatory activities in a murine model of NE-induced airway inflammation[20] added impetus to the pursuit of oligosaccharide alternatives. We assessed BALF samples from smokers/ex-smokers with and without COPD for unopposed versus total NE burden and IL-8 and confirmed that findings were observable in a rat model of smoking-induced lung inflammation. Sulfated-maltoheptaose (S-maltoheptaose) was tested as a heparin mimetic to target associations of airway NE and CINC-1 (the closest functional counterpart of human IL-8 in rats)[21] with HS/syndecan-1. In smoke-exposed rats, airway delivery of S-maltoheptaose antagonized HS/syndecan-1 binding of NE and CINC-1 providing for dampened activities of the effectors in neutrophilic inflammation of the airways

Methods

Results

Conclusion