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

The role of neutrophil elastase in complement-mediated lung injury was exam ined in hamsters using a specific neutrophil elastase inhibitor, sodium N-[ 2-[4-(2,2 dimethylpropionyloxy)phenylsulfonylamino]benzoyl]aminoacetate tet rahydrate (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 n eutrophil accumulation in lung tissue and an increase in protein concentrat ion in the bronchoalveolar lavage fluid. Inhibition of the elevated plasma neutrophil elastase activity (36.5%, 66.9% and 104.3%) by continuous i.v. i nfusion with sivelestat (0.1, 0.3 and 1 mg/kg/h), dose-dependently attenuat ed the increase in lung vascular permeability 30 min after CVF injection. F urthermore, sivelestat at 1 mg/kg/h almost totally prevented the increase i n protein concentration in the bronchoalveolar lavage fluid without affecti ng lung neutrophil accumulation. These results suggest that neutrophil elas tase is an important mediator in complement-mediated acute lung injury. (C) 2001 Elsevier Science B.V. All rights reserved.