Inhibition of neutrophil elastase activity attenuates complement-mediated lung injury in the hamster

The role of neutrophil elastase in complement-mediated lung injury was examined in hamsters using a specific neutrophil elastase inhibitor, sodium N-[2-[4-(2,2 dimethylpropionyloxy)phenylsulfonylamino]benzoyl]aminoacetate tetrahydrate (sivelestat). Intravenous injection with cobra venom factor (CVF) into hamsters transiently increased plasma neutrophil elastase activity by about 10-fold. This increase was followed by a sustained increase in lung vascular [I-125]bovine serum albumin permeability peaking 30 min after CVF injection. The increase in lung vascular permeability was associated with neutrophil accumulation in lung tissue and an increase in protein concentration in the bronchoalveolar lavage fluid. Inhibition of the elevated plasma neutrophil elastase activity (36.5%, 66.9% and 104.3%) by continuous i.v. infusion with sivelestat (0.1, 0.3 and 1 mg/kg/h), dose-dependently attenuated the increase in lung vascular permeability 30 min after CVF injection. Furthermore, sivelestat at 1 mg/kg/h almost totally prevented the increase in protein concentration in the bronchoalveolar lavage fluid without affecting lung neutrophil accumulation. These results suggest that neutrophil elastase is an important mediator in complement-mediated acute lung injury. (C) 2001 Elsevier Science B.V. All rights reserved.