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Published ahead of print on April 17, 2003, doi:10.1164/rccm.200208-829OC

Am. J. Respir. Crit. Care Med., Volume 168, Number 2, July 2003, 192-198

A more recent version of this article appeared on July 15, 2003
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Submitted on August 14, 2002
Accepted on April 13, 2003

Sputum sol neutrophil elastase activity in bronchiectasis. Differential modulation by syndecan-1

Stanley C. H. Chan1, Daisy K. Y. Shum1*, and Mary S. M. Ip2

1 Biochemistry, The University of Hong Kong, Hong Kong, China, 2 Medicine, The University of Hong Kong, Hong kong, China

* To whom correspondence should be addressed. E-mail: shumdkhk{at}hkucc.hku.hk.

The persistently dominant activity of neutrophil elastase in bronchial secretions replete with anti-elastases is crucial to the pathogenesis of bronchiectasis. We hypothesize that components in the bronchial secretions bind neutrophil elastase and compromise the inhibitory efficiency of prevailing anti-elastases. Zymographic analysis of sputum sols from patients with bronchiectasis found elastase activity in a polydisperse, Alcian Blue-stained zone of high molecular mass. This suggested that neutrophil elastase was complexed with polyanionic partners. Western blot analysis found not only the polyanionic partner, heparan sulfate/syndecan-1, but also the physiological anti-elastases, secretory leukoproteinase inhibitor and alpha-1-antitrypsin, in the complex. Both dissociative density gradient ultracentrifugation and heparin displacement revealed that elastase dissociated from heparan sulfate/syndecan-1 was fully inhibited by the endogenous anti-elastases. This contrasts with the effects of exogenous anti-elastases on sputum neutrophil elastase activity- that of alpha-1-antitrypsin was limited, but that of secretory leukoproteinase inhibitor was facilitated. Similarly, complexed elastase on blots of sputum sol zymographs was bound and inhibited by exogenous secretory leukoproteinase inhibitor but not by exogenous alpha-1-antitrypsin. Taken together, the results bring a new focus to heparan sulfate/syndecan-1 complexed with neutrophil elastase in inflamed bronchial secretions as a target for modulating elastase susceptibility to physiological anti-elastases.
Key words: heparan sulfate proteoglycan, Secretory leukoproteinase inhibitor, alpha-1-antitrypsin, proteinase




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