PROTEASES AND ANTIPROTEASES IN CYSTIC-FIBROSIS - PATHOGENETIC CONSIDERATIONS AND THERAPEUTIC STRATEGIES

The association between abnormal chloride transport, resulting from mu tations in the cystic fibrosis transmembrane regulator (CFTR) gene, an d the immunologic processes involved in the development of CF lung dis ease is poorly understood. However, neutrophil-dominated inflammation on the respiratory epithelial surface is a common finding in CF patien ts and suggests a mechanism for the immunologic abnormalities describe d in CF. Of particular importance for the pathophysiology of CF are pr oteases such as neutrophil elastase (NE) which are released from neutr ophils in CF airways and cause direct structural damage to respiratory tissue. In healthy individuals, the deleterious effects of excess pro tease activity in the respiratory system are inhibited by antiprotease s such as alpha(1)-antitrypsin (alpha(1)AT) and secretory leukoproteas e inhibitor (SLPI). However, in CF, antiproteases are outnumbered by p roteases and this protective mechanism is rendered ineffective. Restor ation of this protease/antiprotease balance through antiprotease repla cement therapy is currently under clinical investigation and prelimina ry results are promising.