Investigating the role of cathepsin S in the pathogenesis of cystic fibrosis-like lung disease

Elevated levels of the cysteine protease cathepsin S( catS) are found in cystic fibrosis (CF) lungsecretions, however, the role of catS in CF lungdisease is unclear. CatS is capable of maintaining its activity at a neutral pH allowing it to remain active outside of the cell. Consequently, catS has the capacity to promote remodelling of the extracellular matrix via its potent elastolytic activity. In addition, catS can cleave and inactivate key antimicrobials in the CF airways. On the basis of findings to date, we hypothesise that active catS contributes to the pathogenesis of CF lungdisease and represents a viable therapeutic target for the treatment of chronic lungdisease. The βENaC transgenic mouse model recapitulates essential features of chronic CF lungdisease such as airway mucusobstruction, inflammatory lungdamage and increased levels of catS activity in the lungswhen compared to wild-type controls. Pharmacological knockdown of catS activity was achieved in the βENaC mouse using the catS inhibitor VBY-999. Findings to date suggest that inhibition of catS reduces inflammatory cell infiltration into the lungas well as levels of pro-inflammatory cytokines in bronchoalveolar lavage fluid in both the early and late stage lungdisease in the βENaC mouse model. Furthermore, concomitant reductions in mucusplugging were also observed. Late treatment with the catS inhibitor had no effect on lungtissue damage, however, mucusplugging was reduced. These results support the hypothesis that active catS plays a role in the pathogenesis of chronic lungdisease and may be a viable and promising target in the treatment of diseases such as CF.