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.
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