A COMPARISON OF ALPHA-1-PROTEINASE INHIBITOR METHOXYSUCCINYL-ALA-ALA-PRO-VAL-CHLOROMETHYLKETONE AND SPECIFIC BETA-LACTAM INHIBITORS IN AN ACUTE MODEL OF HUMAN POLYMORPHONUCLEAR LEUKOCYTE ELASTASE-INDUCED LUNG HEMORRHAGE IN THE HAMSTER

A pharmacokinetic model is described for testing of polymorphonuclear leukocyte (PMN) elastase inhibitors administered by intratracheal or aerosol dosing of hamsters. Acute lung injury, measured as hemorrhage occurring within hours after intratracheal instillation of human PMN elastase, correlated directly with the amount of active enzyme instilled. Hemorrhage began within minutes of elastase instillation, was maximal within 1 h, and remained constant for up to 5 h subsequently. Therefore, inhibition of hemorrhage was used as an assay of the effectiveness of various PMN elastase inhibitors given by the intratracheal route. Lung hemorrhage could also be induced by intratracheal instillation of other elastolytic enzymes, such as thermolysin, and inhibition of hemorrhage was seen only with inhibitors active against the type of elastase used. Methoxysuccinyl-alanyl-alanyl-prolyl-valine-chloromethylketone (MeOSuc-AAPV-CMK), as well as α1-proteinase inhibitor (α1PI) but not tosyl-lysine-chloromethylketone (tosyl-lysine-CMK), inhibited the hemorrhage caused by human PMN elastase, but the specific inhibitors of this enzyme had no effect on thermolysin-induced lung hemorrhage. The duration of activity of these compounds as elastase inhibitors in this model correlated directly with the extent of their persistence in lung lavage fluid as determined by HPLC analysis of compound recovered by bronchoalveolar lavage. Both MeOSuc-AAPV-CMK and α1PI suppressed further development of an ongoing hemorrhage when given 20 min after instillation of PMN elastase. A series of newly discovered cephalosporin inhibitors of PMN elastase inhibit hemorrhage in this model, their activity persisting for several hours in concert with their presence in bronchoalveolar lavage fluid. These low-molecular-weight inhibitors of PMN elastase may be of therapeutic value in treatment of diseases, such as emphysema, thought to be due to a proteinase-antiproteinase imbalance.