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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

EPI-hNE4, a Proteolysis-Resistant Inhibitor of Human Neutrophil Elastase and Potential Anti-Inflammatory Drug for Treating Cystic Fibrosis

Institut National de la Santé et de la Recherche Médicale U618 (Protéases et Vectorisation Pulmonaires) (S.A., A.G., B.K., M.F., P.Di., F.G.) and l'Institut Fédératif de Recherches 135 (S.A., P.Di., F.G.), Université François Rabelais, Tours, France; Institut National de la Santé et de la Recherche Médicale U613, Université de Bretagne Occidentale, Brest, France (P.De.); and Debiopharm S.A., Lausanne, Switzerland (F.S.)

EPI-hNE4 (depelstat) is a potent inhibitor of human neutrophil elastase derived from human inter--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 (MMPs) 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. Therefore, EPI-hNE4 seems to be an elastase inhibitor suitable for use in aerosols to treat patients with cystic fibrosis.

Address correspondence to: Dr. Francis Gauthier, INSERM U618 (Protéases et Vectorisation Pulmonaires), Université François Rabelais, 10 Bd Tonnellé, 37032 Tours Cedex, France. E-mail: gauthier{at}univ-tours.fr

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