Inhibition of human neutrophil elastase-induced acute lung injury in hamsters by recombinant human pre-elafin (trappin-2).
OBJECTIVE
Pre-elafin, also known as trappin-2, is an elastase-specific inhibitor that could be an ideal candidate for the treatment of neutrophil elastase-driven lung diseases. The inhibitory activity of pre-elafin resides in the COOH-terminal region that can be released as mature elafin. The NH(2)-terminal moiety of pre-elafin is characterized by the presence of a specific repeating sequence, termed cementoin, believed to immobilize the inhibitor to lung protein components and restrict its diffusion from the desired sites of action. This property should confer an advantage to pre-elafin compared to elafin in the treatment of neutrophil elastase-driven lung diseases.


METHODS
The inhibitory effect of recombinant human pre-elafin was assessed in a human neutrophil elastase-induced acute lung injury model in Golden Syrian hamsters. BAL fluid hemoglobin content was used as a marker of lung injury.


RESULTS
Recombinant human pre-elafin administered intratracheally 1 h prior to neutrophil elastase dose-dependently inhibited the lung hemorrhage with a calculated half-effective dose of 8.1 microg/kg (0.7 nmol/kg). Pre-elafin was equally efficient when administered 3 h before neutrophil elastase. In contrast to pre-elafin, commercial synthetic elafin was ineffective in inhibiting neutrophil elastase-induced lung hemorrhage even at a dose of 4.45 nmol/kg.


CONCLUSIONS
Our results suggest that pre-elafin may be eventually used in the treatment of neutrophil elastase-driven lung diseases.
Tremblay
Guy M
GM
Unité de recherche, Hôpital Laval, Institut universitaire de cardiologie et de pneumologie de l'Université Laval, Sainte-Foy, Quebec, Canada. guy.tremblay@med.ulaval.edu
Vachon
Eric
E
Larouche
Chantal
C
Bourbonnais
Yves
Y
D000208:Acute Disease; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D006224:Cricetinae; D006454:Hemoglobins / Q000032:analysis; D006470:Hemorrhage / Q000517:prevention & control*; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D008171:Lung Diseases / Q000517:prevention & control*; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use*
D006454:Hemoglobins; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D011994:Recombinant Proteins; D015842:Serine Proteinase Inhibitors; D019272:Leukocyte Elastase