IN-VIVO SUPPRESSION OF IMMUNE COMPLEX-INDUCED ALVEOLITIS BY SECRETORYLEUKOPROTEINASE INHIBITOR AND TISSUE INHIBITOR OF METALLOPROTEINASES-2

The pulmonary tree is exposed to neutrophil-derived serine proteinases and matrix metalloproteinases in inflammatory lung diseases, but the degree to which these enzymes participate in tissue injury remains und efined, as does the therapeutic utility of antiproteinase-based interv entions. To address these issues, an in vivo rat model was examined in which the intrapulmonary deposition of immune complexes initiates a n eutrophil-mediated acute alveolitis. In vitro studies demonstrated tha t rat neutrophils can release neutrophil elastase and cathepsin G as w ell as a neutrophil progelatinase, which was subsequently activated by either chlorinated oxidants or serine proteinases. Based on structura l homologies that exist between rat and human neutrophil proteinases, rat neutrophil elastase and cathepsin G activities could be specifical ly regulated in vitro by recombinant human secretory leukoproteinase i nhibitor, and rat neutrophil gelatinase activity proved sensitive to i nhibition by recombinant human tissue inhibitor of metalloproteinases 2. When either of the recombinant antiproteinases were instilled intra tracheally, in vivo lung damage as assessed by increased permeability or hemorrhage was significantly reduced. Furthermore, the coadministra tion of the serine and matrix metalloproteinase inhibitors almost comp letely prevented pulmonary damage while effecting only a modest decrea se in neutrophil influx. These data support a critical role for neutro phil-derived proteinases in acute lung damage in vivo and identify rec ombinant human secretory leukoproteinase and recombinant human tissue, inhibitor of metalloproteinases 2 as potentially efficacious interven tions in inflammatory disease states.