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Am. J. Respir. Cell Mol. Biol., Volume 26, Number 3, March, 2002 290-297

Protection Against Acute Lung Injury by Intravenous or Intratracheal Pretreatment with EPI-HNE-4, a New Potent Neutrophil Elastase Inhibitor

Christophe Delacourt, Sabine Hérigault, Christophe Delclaux, Alain Poncin, Micheline Levame, Alain Harf, François Saudubray, and Chantal Lafuma

Institut National de la Santé et de la Recherche Scientifique, Faculté de Médecine, Créteil, France; Service de Pédiatrie, Hôpital Intercommunal, Créteil, France; Service de Physiologie, Hôpital Henri-Mondor, Créteil, France; Eurogentec, Serain, Belgium; and Debiopharm SA, Lausanne, Switzerland

Excessive accumulation of active neutrophil elastase (NE) in pulmonary fluids and tissues of patients with cystic fibrosis (CF) is thought to act on the lungs, compromising their structure and function. The aim of this study was to investigate the in vitro and in vivo protective effect of a new, rapidly acting, potent (Ki = 5.45 × 10-12 M and Kon = 8 × 106 M-1 s-1) and specific human NE inhibitor, EPI-HNE-4, engineered from the Kunitz domain. The results demonstrated that this inhibitor was able to (i) effectively inhibit in vitro the high levels of active NE present in a medium as complex as sputum from children with CF, with a measured IC50 equal or close to the calculated IC50 in 60% of cases, and (ii) almost completely block (91%) the N-formyl-methionine-leucine-phenylalanine-induced migration of purified human neutrophils across a Matrigel basement membrane. Intratracheal administration (250, 175, or 100 µg per rat) of the inhibitor 5 min before instillation of pure human NE (HNE) (150 µg per rat) to rats induced effective, dose-dependent protection of the lungs, 4 h later, from hemorrhage, serum albumin leakage, residual active NE, and discrete neutrophil influx in air spaces induced by instillation of pure HNE. Intravenous administration (3 mg per rat) of EPI-HNE-4, 15 min before instillation of the soluble fraction of pooled sputum (delivering 120 µg of active NE per rat) from children with CF, effectively reduced (64%), 4 h later, the massive neutrophil influx induced by sputum instillation. Overall, these data strongly suggest that associated aerosol and systemic administration of EPI-HNE-4 would be beneficial in the treatment of CF.


Abbreviations: bronchoalveolar lavage, BAL; cystic fibrosis, CF; N-formyl-methionine-leucine-phenylalanine, FMLP; human neutrophil elastase, HNE; neutrophil elastase, NE; secretory leucoprotease inhibitor, SLPI.




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