Pneumologie 2016; 70 - P33
DOI: 10.1055/s-0036-1584637

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

RR Brown 1, DM Small 1, AA Abladey 1, LJ Holsinger 2, R Booth 2, CJ Scott 1, JS Elborn 1, MA Mall 3, S Weldon 1, CC Taggart 1
  • 1Queens University Belfast
  • 2Virobay Inc.
  • 3University Hospital Heidelberg

Introduction: 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.

Methods: Pharmacological knockdown of cat S activity was achieved in the βENaC-Tg mouse, a mouse model recapitulating features of chronic CF lung disease such as airway mucus obstruction and inflammatory lung damage using the cat S inhibitor VBY-999 or via the genetic knockout of cat S. Mice were injected daily from birth for 14 days with VBY-999/Dextrose control. Mice were culled, BAL was performed and lungs were collected for histology or protein/RNA analysis.

Results: 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 and lung tissue destruction with the genetic knockout and pharmacological inhibition of cat S in the βENaC mouse model. Furthermore, concomitant reductions in mucus plugging were also observed.

Discussion: 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. Further work will be directed toward determining a mechanism through which cat S exerts these effects.