Protection of rat lung from elastase-induced elastic fiber degradation in vitro and from emphysema in vivo by a trifluoroacetylpeptide anilide inhibitor.
Trifluoroacetylpeptide anilides are powerful reversible inhibitors of human neutrophil elastase (HNE), a serine protease implicated in the pathogenesis of pulmonary emphysema. The in vitro effectiveness of three inhibitors, CF3CO-Phe-Ala-NH-p-C6H4-CF3 (1), CF3CO-Val-Ala-NH-p-C6H4-CF3 (2) and CF3CO-Lys-Ala-NH-p-C6H4-CH(CH3)2 (3) was analyzed. The protection of lung tissue sections of rats from the degradation induced by HNE has been evaluated quantitatively by automated image analysis. Inhibitor 1 (22 microM), 2 (50 microM) or 3 (35 and 70 microM) significantly reduced the HNE-induced degradation of the elastin network by 75, 42, 54 and 44%, respectively. Inhibitor 3 was tested intratracheally on an experimental model of pulmonary emphysema. Rats that received the elastase inhibitor 1 h before instillation of HNE were significantly protected by 40% from experimental emphysema. Reduced protections were observed with the treatment by the inhibitor 1 or 4 h after challenge with the enzyme.
Amour
A
A
Laboratoire d'Enzymologie Moléculaire et Fonctionnelle, Institut Jacques Monod, Paris, France.
Smaoui
H
H
Heudes
D
D
Reboud-Ravaux
M
M
D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D004547:Elastic Tissue / Q000187:drug effects*; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D008297:Male; D010455:Peptides / Q000494:pharmacology*; D011656:Pulmonary Emphysema / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*
D000813:Anilides; D010455:Peptides; D015842:Serine Proteinase Inhibitors