title: 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.affiliation: Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, HKSAR, China.
authors.forename: David C L
authors.initials: DC
authors.lastname: Lam
authors.affiliation: 1] Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, HKSAR, China. [2] Department of Biochemistry, LKS Faculty of Medicine, The University of Hong Kong, HKSAR, China.
authors.forename: Stanley C H
authors.initials: SC
authors.lastname: Chan
authors.affiliation: 1] Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, HKSAR, China. [2] Department of Pharmacology &Pharmacy, LKS Faculty of Medicine, The University of Hong Kong, HKSAR, China.
authors.forename: Judith C W
authors.initials: JC
authors.lastname: Mak
authors.affiliation: Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
authors.forename: Craig
authors.initials: C
authors.lastname: Freeman
authors.affiliation: Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, HKSAR, China.
authors.forename: Mary S M
authors.initials: MS
authors.lastname: Ip
authors.affiliation: Department of Biochemistry, LKS Faculty of Medicine, The University of Hong Kong, HKSAR, China.
authors.forename: Daisy K Y
authors.initials: DK
authors.lastname: Shum
mesh_terms: D000368:Aged; D000818:Animals; D001980:Bronchi / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D016022:Case-Control Studies; D054360:Chemokine CXCL1 / Q000378:metabolism; D048271:Chitosan / Q000737:chemistry; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005936:Glucans / Q000737:chemistry* / Q000633:toxicity; D006497:Heparan Sulfate / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D019272:Leukocyte Elastase / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012907:Smoking; D053668:Syndecan-1 / Q000737:chemistry / Q000378:metabolism*; D000515:alpha 1-Antitrypsin / Q000032:analysis
chemical_list: D054360:Chemokine CXCL1; D048271:Chitosan; D005936:Glucans; D006497:Heparan Sulfate; D018836:Inflammation Mediators; D019272:Leukocyte Elastase; D009195:Peroxidase; D053668:Syndecan-1; D000515:alpha 1-Antitrypsin; C513297:Cxcl1 protein, rat; C031146:maltoheptaose