[Therapy of lung diseases with antiproteases]

Neutrophil elastase (NE) is the most important protease of the human lung; if not inhibited NE is able to attack nearly all structural proteins and components of the immune system of the lung. In the normal human lung this is prevented by an excess of protease inhibitors. Based on quantitative and kinetic analyses alpha 1-antitrypsin (AAT) is the most important protease inhibitor of the human lung followed by the Secretory Leukoprotease Inhibitor (SLPI). As protease inhibitors may be inactivated by proteases and reactive oxygen metabolites released from polymorphonuclear cells, it is not surprising that some lung diseases--in particular lung emphysema caused by AAT deficiency, cystic fibrosis and ARDS--are characterized by an imbalance between proteases and protease inhibitors. Because uninhibited NE seems to play an important role in the pathogenesis of these diseases, it is obvious to use protease inhibitors as drugs. Up to now in most studies in men AAT purified from human plasma has been used: worldwide a substantial number of patients with lung emphysema caused by AAT deficiency is treated continuously; in addition AAT was aerosolized to patients with cystic fibrosis in a short term study with results suggesting that this therapy is efficient at least on a biochemical basis. We performed in vitro and in vivo animal studies with the recombinant form of SLPI (rSLPI). In these experiments we found that aerosolized rSLPI a) is not altered in its form or function in the first 13 h following aerosol; b) has a half-tie of 12 h in the lung; c) reaches the interstitium of the lung in intact form.(ABSTRACT TRUNCATED AT 250 WORDS)