Novel neutrophil elastase inhibitors as a treatment for neutrophil-predominant inflammatory lung diseases

Acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) are progressive and frequently fatal disorders, which have, at present, few effective therapeutic methods. The pathogenesis of these lung diseases is characterized by a neutrophil-predominant inflammation associated with excessive release of neutrophil proteases, including neutrophil elastase (NE), a terminal pulmonary tissue destroyer. Although precise pathogenic mechanisms have been under debate, the NE-mediated severe pulmonary tissue damage, based upon the protease-antiprotease imbalance hypothesis, may be a major pathogenic determinant of these diseases, in particular COPD. Novel aggressive therapeutic approaches to these lung disorders are required, and prevention of NE release may be considered as a promising strategy for disease outcome. This review mainly focuses upon the pathogenic contribution of NE to these neutrophil-predominant inflammatory lung diseases, and evaluates the experimental and clinical efficacies of the two-types of appropriate small molecular weight human neutrophil elastase (HNE) inhibitors: acyl-enzyme inhibitors and transition-state inhibitors. While much progress has been made in the investigation of these disorders and the contribution of HNE inhibitors, several fundamental questions remain to be answered, and so further studies are required.