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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on April 20, 2006; DOI: 10.1124/jpet.106.103440

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Received for publication February 24, 2006.
Revised April 19, 2006.
Accepted for publication April 19, 2006.

EPI-hNE4, a proteolysis-resistant inhibitor of human neutrophil elastase and potential anti-inflammatory drug for treating cystic fibrosis

Sylvie Attucci 1, Alexandre Gauthier 1, Brice Korkmaz 1, Pascal Delepine 2, Michele Ferrer-DiMartino 1, Francois Saudubray 3, Patrice Diot 1, Francis Gauthier 1*

1 Inserm U618, Tours 2 Inserm U613, Brest 3 Debiopharm SA, Lausanne

* Address correspondence to: E-mail: gauthier{at}univ-tours.fr

Abstract

EPI-hNE4 is a potent inhibitor of human neutrophil elastase derived from human inter-{alpha}-trypsin inhibitor and designed to control the excess proteolytic activity in the sputum of cystic fibrosis patients. We analyzed its resistance to the proteolysis it is likely to encounter at inflammatory sites in vivo. EPI-hNE4 resisted hydrolysis by neutrophil matrix metalloproteases and serine proteases that are released from activated neutrophils in inflammatory lung secretions, including MMP-8 and MMP-9, and the elastase-related protease 3 and cathepsin G. It also resisted degradation by epithelial lung cell MMP-7, but was broken down by the Pseudomonas aeruginosa metalloelastase pseudolysin, when used in a purified system, but not when this protease competed with equimolar amounts of neutrophil elastase. We also investigated the inhibitory properties of EPI-hNE4 at the surface of purified blood neutrophils and in the sputum of cystic fibrosis patients where neutrophil elastase is in both a soluble and a gel phase. The elastase at the neutrophil surface was fully inhibited by EPI-hNE4 and formed soluble complexes. The elastase in cystic fibrosis sputum supernatants was inhibited by stoichiometric amounts of EPI-hNE4, allowing titration of the protease. But the percentage of inhibition in whole sputum homogenates varied from 50 to 100% depending on the sample tested. EPI-hNE4 was rapidly cleaved by the digestive protease pepsin in vitro. EPI-hNE4 therefore appears to be an elastase inhibitor suitable for use in aerosols to treat patients with cystic fibrosis.


Key words: cystic fibrosis, inflammation, lung, neutrophil, protease inhibitor, serine protease


This article has been cited by other articles:


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M. Griese, M. Kappler, A. Gaggar, and D. Hartl
Inhibition of airway proteases in cystic fibrosis lung disease
Eur. Respir. J., September 1, 2008; 32(3): 783 - 795.
[Abstract] [Full Text] [PDF]


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