Potential Role of Inhibitors of Neutrophil Elastase in Treating Diseases of the Airway

The potential therapeutic use of inhibitors of neutrophil elastase (NE) is reviewed with emphasis on diseases of the airway. In addition to its proteolytic properties, NE is a potent secretagogue and may be pro-inflammatory. The properties of natural occurring inhibitors of NE such as alpha-one antitrypsin and secretory leukoprotease inhibitor are reviewed. In addition, recombinant versions of naturally occurring inhibitors and synthetic small molecule inhibitors are potential therapies for respiratory diseases. For recombinant proteins, aerosol administration has been the preferred method of delivery. The inhaled mode of delivery can complicate the determination of dose responsiveness and thus the evaluation of safety and efficacy of these agents. In addition to the aerosolization issue, there remain other significant barriers to the successful deployment of these agents in clinical trials. These include the need for high standards for purification of recombinant proteins, the lack of understanding of interaction with airway secretions, the controversy over role of NE in the pathogenesis of nonhereditary COPD, and asthma, while the need for the safety of new classes of systemically delivered small molecules will need to be established.