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Shed Syndecan-1 Restricts Neutrophil Elastase from ₁-Antitrypsin in Neutrophilic Airway Inflammation

Departments of Biochemistry¹ and Medicine² , Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Special Administrative Region, China

Correspondence and requests for reprints should be addressed to Daisy K. Y. Shum, Ph.D., Department of Biochemistry, LKS Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Hong Kong, SAR, China. E-mail: shumdkhk{at}hkucc.hku.hk

Persistent proteolytic imbalance in chronic inflammatory diseases has been ascribed to neutrophil elastase (NE)/antielastase imbalance in wound fluids. In sputum sols of patients with bronchiectasis, we found unopposed NE activity, despite overwhelming excess of the physiological antielastase, ₁-antitrypsin (₁-AT). Western blot analysis found NE in a supramolecular complex with shed ectodomains of syndecan (Syn)-1 in sputum sol samples and, as such, inhibition of NE activity was incomplete, even with addition of exogenous ₁-AT. To confirm that NE binding to heparan sulfate (HS) components of Syn-1 limits the antielastase effect, recombinant human Syn-1 was recovered from stable Syn-1 transfectants of a human B-lymphoid cell line (ARH-77). Western ligand blot confirmed that NE bound to HS moieties and ₁-AT to the core protein of the recombinant product. Inhibition of NE activity by standard additions of ₁-AT was incomplete unless Syn-1 had been deglycanated by heparitinase treatment. Surface plasmon resonance analysis revealed that NE binding to HS (equilibrium dissociation constant, 14 nM) could be outcompeted by heparin variants. We conclude that the HS moiety of shed Syn-1 binds and restricts NE from inhibition by ₁-AT.

Key Words: neutrophil elastase • ₁-antitrypsin • heparin • bronchiectasis • sputum

CLINICAL RELEVANCE Our findings bring a new focus to the heparan sulfate moiety as a target for availing neutrophil elastase to inhibition by 1-antitrypsin in attempts to restore elastase/antielastase balance in chronic bronchial inflammation.

 

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