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

Lam DC, Chan SC, Mak JC, Freeman C, Ip MS, Shum DK - Sci Rep (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, HKSAR, China.

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.

No MeSH data available.


Related in: MedlinePlus

Decrease in airway accumulation of neutrophils and CINC-1 following treatment with S-maltoheptaose.(A) Lung tissue sections were stained for NE (a, c, e) or CINC-1 (b, d, f) and then counter-stained with haematoxylin. NE-positive cells lining the basal side of the bronchial epithelium were rarely observed in cases treated with S-maltoheptaose (a vs c, arrows). CINC-1 immuno-positivity enriched along the luminal and basal sides of the bronchial epithelium were barely observable in cases treated with S-maltoheptaose (b vs d, arrowheads). Neither immuno-positivity for NE nor CINC-1 was observable in the sham air controls (e & f). (B) Double immunofluorescence for syndecan-1 (SDC-1) and CINC-1. (a) and (b): Bright field images of the lung tissue sections. Tissues treated with mere carrier revealed localisation of SDC-1 (c) and CINC-1 (e) to the bronchial epithelium, more prominent on the luminal side than on the basal side. The merged image (g) further revealed co-localisation of SDC-1 and CINC-1. Tissue sections treated with S-maltoheptaose indicated weaker immunofluorescence for SDC-1 (d) and hardly any detectable CINC-1 (f) at the bronchial epithelium. This was reinforced by the sole immunofluorescence of SDC-1 at the bronchial epithelium in the merged image (h). Arrows in (g) indicate sites where SDC-1 and CINC-1 are co-localised at the luminal side of the bronchial epithelium. *bronchial lumen. Scale bar = 100 μm.
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f5: Decrease in airway accumulation of neutrophils and CINC-1 following treatment with S-maltoheptaose.(A) Lung tissue sections were stained for NE (a, c, e) or CINC-1 (b, d, f) and then counter-stained with haematoxylin. NE-positive cells lining the basal side of the bronchial epithelium were rarely observed in cases treated with S-maltoheptaose (a vs c, arrows). CINC-1 immuno-positivity enriched along the luminal and basal sides of the bronchial epithelium were barely observable in cases treated with S-maltoheptaose (b vs d, arrowheads). Neither immuno-positivity for NE nor CINC-1 was observable in the sham air controls (e & f). (B) Double immunofluorescence for syndecan-1 (SDC-1) and CINC-1. (a) and (b): Bright field images of the lung tissue sections. Tissues treated with mere carrier revealed localisation of SDC-1 (c) and CINC-1 (e) to the bronchial epithelium, more prominent on the luminal side than on the basal side. The merged image (g) further revealed co-localisation of SDC-1 and CINC-1. Tissue sections treated with S-maltoheptaose indicated weaker immunofluorescence for SDC-1 (d) and hardly any detectable CINC-1 (f) at the bronchial epithelium. This was reinforced by the sole immunofluorescence of SDC-1 at the bronchial epithelium in the merged image (h). Arrows in (g) indicate sites where SDC-1 and CINC-1 are co-localised at the luminal side of the bronchial epithelium. *bronchial lumen. Scale bar = 100 μm.

Mentions: In contrast to the dense accumulation of neutrophils along the vascular endothelium adjacent to the basal side of the bronchial epithelium as shown by smoke-exposed rats treated with blank carrier (Fig. 5A, panel a), airway treatment with S-maltoheptaose resulted in marked reduction of neutrophils (Fig. 5A, panel c). The minimal neutrophils in airways of the sham air controls were unaffected by treatment with carrier, loaded with S-maltoheptaose or without (Fig. 5A, panel e).


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

Lam DC, Chan SC, Mak JC, Freeman C, Ip MS, Shum DK - Sci Rep (2015)

Decrease in airway accumulation of neutrophils and CINC-1 following treatment with S-maltoheptaose.(A) Lung tissue sections were stained for NE (a, c, e) or CINC-1 (b, d, f) and then counter-stained with haematoxylin. NE-positive cells lining the basal side of the bronchial epithelium were rarely observed in cases treated with S-maltoheptaose (a vs c, arrows). CINC-1 immuno-positivity enriched along the luminal and basal sides of the bronchial epithelium were barely observable in cases treated with S-maltoheptaose (b vs d, arrowheads). Neither immuno-positivity for NE nor CINC-1 was observable in the sham air controls (e & f). (B) Double immunofluorescence for syndecan-1 (SDC-1) and CINC-1. (a) and (b): Bright field images of the lung tissue sections. Tissues treated with mere carrier revealed localisation of SDC-1 (c) and CINC-1 (e) to the bronchial epithelium, more prominent on the luminal side than on the basal side. The merged image (g) further revealed co-localisation of SDC-1 and CINC-1. Tissue sections treated with S-maltoheptaose indicated weaker immunofluorescence for SDC-1 (d) and hardly any detectable CINC-1 (f) at the bronchial epithelium. This was reinforced by the sole immunofluorescence of SDC-1 at the bronchial epithelium in the merged image (h). Arrows in (g) indicate sites where SDC-1 and CINC-1 are co-localised at the luminal side of the bronchial epithelium. *bronchial lumen. Scale bar = 100 μm.
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Related In: Results  -  Collection

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f5: Decrease in airway accumulation of neutrophils and CINC-1 following treatment with S-maltoheptaose.(A) Lung tissue sections were stained for NE (a, c, e) or CINC-1 (b, d, f) and then counter-stained with haematoxylin. NE-positive cells lining the basal side of the bronchial epithelium were rarely observed in cases treated with S-maltoheptaose (a vs c, arrows). CINC-1 immuno-positivity enriched along the luminal and basal sides of the bronchial epithelium were barely observable in cases treated with S-maltoheptaose (b vs d, arrowheads). Neither immuno-positivity for NE nor CINC-1 was observable in the sham air controls (e & f). (B) Double immunofluorescence for syndecan-1 (SDC-1) and CINC-1. (a) and (b): Bright field images of the lung tissue sections. Tissues treated with mere carrier revealed localisation of SDC-1 (c) and CINC-1 (e) to the bronchial epithelium, more prominent on the luminal side than on the basal side. The merged image (g) further revealed co-localisation of SDC-1 and CINC-1. Tissue sections treated with S-maltoheptaose indicated weaker immunofluorescence for SDC-1 (d) and hardly any detectable CINC-1 (f) at the bronchial epithelium. This was reinforced by the sole immunofluorescence of SDC-1 at the bronchial epithelium in the merged image (h). Arrows in (g) indicate sites where SDC-1 and CINC-1 are co-localised at the luminal side of the bronchial epithelium. *bronchial lumen. Scale bar = 100 μm.
Mentions: In contrast to the dense accumulation of neutrophils along the vascular endothelium adjacent to the basal side of the bronchial epithelium as shown by smoke-exposed rats treated with blank carrier (Fig. 5A, panel a), airway treatment with S-maltoheptaose resulted in marked reduction of neutrophils (Fig. 5A, panel c). The minimal neutrophils in airways of the sham air controls were unaffected by treatment with carrier, loaded with S-maltoheptaose or without (Fig. 5A, panel e).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, HKSAR, China.

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.

No MeSH data available.


Related in: MedlinePlus