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

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.

• Authors: David C L Lam, Stanley C H Chan, Judith C W Mak, Craig Freeman, Mary S M Ip, Daisy K Y Shum
• Journal: Scientific reports (Sci Rep) Vol. 5 Pg. 12945 (Aug 10 2015) ISSN: 2045-2322 [Electronic] England
• PMID: 26256047 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chemokine CXCL1
• Cxcl1 protein, rat
• Glucans
• Inflammation Mediators
• Syndecan-1
• alpha 1-Antitrypsin
• maltoheptaose
• Chitosan
• Heparitin Sulfate
• Peroxidase
• Leukocyte Elastase

Topics

• Aged
• Animals
• Bronchi (metabolism)
• Bronchoalveolar Lavage Fluid (chemistry, cytology)
• Case-Control Studies
• Chemokine CXCL1 (metabolism)
• Chitosan (chemistry)
• Disease Models, Animal
• Enzyme-Linked Immunosorbent Assay
• Female
• Glucans (chemistry, toxicity)
• Heparitin Sulfate (chemistry, metabolism)
• Humans
• Inflammation (metabolism)
• Inflammation Mediators (metabolism)
• Leukocyte Elastase (metabolism)
• Male
• Middle Aged
• Neutrophils (drug effects, enzymology, metabolism)
• Peroxidase (metabolism)
• Pulmonary Disease, Chronic Obstructive (metabolism, pathology)
• Rats
• Rats, Sprague-Dawley
• Smoking
• Syndecan-1 (chemistry, metabolism)
• alpha 1-Antitrypsin (analysis)