Lung injury can result from an imbalance between proteinases (e.g. neutrophil elastase, cathepsin G, cathepsin L, cathepsin S) and their specific inhibitors. Neutrophil elastase and cathepsin G are elastolytic serine proteinases that are released from the azurophilic granules of activated neutrophils. In addition, the cysteine proteinases cathepsin L and S are contained in the lysosomal compartment of human lung macrophages. Cathepsin S and L are two of the most potent elastolytic enzymes found in humans. Alpha 1-antitrypsin and secretory leukoproteinase inhibitor are serine proteinase inhibitors that partially protect the lung from proteolytic degradation, however these enzymes are easily inactivated by the highly oxidative environment at the mucosal surface.

We have identified recently two new functional members of the high molecular weight serine proteinase inhibitor (serpin) family. These proteins, SCCA1 and SCCA2 (squamous cell carcinoma antigens 1 and 2), are 92% identical, but contain different reactive site loops. SCCA2 contains a leucine-serine at the critical P1-P1′ residues, whereas SCCA1 contains the novel serine-serine at these sites, respectively. Proteinase inhibitor assays showed that SCCA2 inhibits members of the chymotrypsin family of serine proteinases, cathepsin G and chymase. Surprisingly, SCCA1 is a potent inhibitor of the papain family of cysteine proteinases, cathepsin L, O and S. By immunoblotting and northern blot analysis, we detected the SCCA's in tracheal aspirates and total lung RNA, respectively. Immunohistochemistry showed dense staining in the pseudostratified columnar epithelium of the conducting airways. Furthermore, both molecules are resistant to oxidative inactivation due to the absence of cysteine and methionine residues in their reactive sites. We hypothesize that SCCA1 and SCCA2 are novel inhibitory-type serpins that protect the lung from proteinase mediated injury.