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Title: A role for Cathepsin S in the pathogenesis of cystic fibrosis-like lung disease
Author: Brown, Ryan
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2016
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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 of the βENaC transgenic mouse compared to wild-type controls. Pharmacological knockdown of cat S activity was achieved in the βENaC mouse using the cat S inhibitor VBY-999. In this thesis we have demonstrated 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. We generated a βENaC mouse in which cat S was genetically deleted, the results from which supported our findings from the inhibitor study. 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 chronic lung diseases such as CF and COPD.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available