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

Abstract

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