Persistence of alveolar neutrophil influx and activation may enhance the fibrotic process after
acute lung injury. On the other hand,
elastase has an antimicrobial activity and could participate in neutrophil migration, both events being critically important in host defense, explaining the controversial issue of therapeutic
elastase inhibition in the setting of
acute lung injury. We assessed the effect of a
neutrophil elastase inhibitor, EPI-hNE-4, in single (
bleomycin, 1.2 mg/rat intratracheally) and repeated (
bleomycin, 1.2 mg/rat plus
endotoxin and 1 mg/kg intratracheally 24 h later)
lung injuries to assess the role of neutrophil in
fibrosis. Subsequently, the effect of EPI-hNE-4 on bacterial clearance was evaluated during Pseudomonas aeruginosa-induced
pneumonia. In the single injury model, despite a dramatic reduction of alveolar neutrophil influx with EPI-hNE-4 treatment, no significant inhibition of the decrease in respiratory system compliance, an index of lung
fibrosis, was demonstrated at day 14. In the
repeated injury model, EPI-hNE-4 treatment afforded a significant protective effect on compliance and alveolar
inflammation at day 14. During
bacterial pneumonia,
EPI-hNE4 did not modify alveolar neutrophil recruitment or bacterial clearance from bronchoalveolar lavage fluid and lung homogenate. In conclusion, EPI-hNE-4, a specific inhibitor of
leukocyte elastase, afforded a partial protective effect on the respiratory system compliance during repeated
lung injuries, and had no detrimental effect during a gram-negative
bacterial pneumonia.