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(Chest. 2002;121:582-588.)
© 2002 American College of Chest Physicians

Inhibition of Human Neutrophil Elastase-Induced Acute Lung Injury in Hamsters by Recombinant Human Pre-elafin (Trappin-2)*

Guy M. Tremblay, PhD; Eric Vachon, BSc; Chantal Larouche, BSc and Yves Bourbonnais, PhD

* From Unité de recherche (Dr. Tremblay and Mr. Vachon), Hôpital Laval, Institut universitaire de cardiologie et de pneumologie de l’Université Laval; and Département de biochimie et de microbiologie (Ms. Larouche and Dr. Bourbonnais) and Centre de Recherche sur la Fonction, la Structure et l’Ingénierie des Protéines, Université Laval, Quebec City, Canada.

Correspondence to: Guy M. Tremblay, PhD, Hôpital Laval, Bureau M2691, 2725 chemin Sainte-Foy, Sainte-Foy, Quebec, Canada G1V 4G5; e-mail: guy.tremblay{at}med.ulaval.ca

Study objectives: 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 NH2-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.

Measurements: 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 µg/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.

Key Words: BAL fluid • hamsters • leukocyte elastase • lung • pulmonary emphysema • recombinant fusion proteins • serine proteinase inhibitors






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