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Title: Defining the role of cathepsin S as a mediator of acute lung inflammation
Author: Abladey, Anthony Abladey
ISNI:       0000 0004 6062 3728
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2016
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A major feature of acutely inflamed airways is the presence of free and active proteases which are responsible for the degradation of lung tissue and other soluble proteins in the respiratory tract. There is strong evidence in literature that suggests that cathepsin S (cat S) is implicated in the pathogenesis of pulmonary conditions such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). However, very little data exists on its role in acute respiratory distress syndrome (ARDS). Unlike other cathepsins, cat S maintains its proteolytic activity at a neutral pH, and has the ability to promote extracellular matrix remodelling through its potent elastolytlc activity. Based on findings to date, we hypothesized that cat S plays a key role in the pathogenesis of ARDS and represents a viable therapeutic target for the management of acute Inflammatory lung diseases. Intratracheal (i.t.) instillation of endotoxin such as lipopolysaccharide (LPS) and proteases such as neutrophil elastase (NE) in murine species is a very reproducible technique which models many of the classical features of human acute lung injury, typified by significant pulmonary neutrophil infiltration, alveolar-capillary permeability and the increased expression of pro-inflammatory cytokines. In this thesis, we have demonstrated that cat S is elevated in the lungs of ARDS patients and ARDS models, whilst Lt. instillation of cat S produces typical symptoms of AROS in mice. Of note, we report that cat S instillation significantly upregulates the levels of MIP-1y, a potent neutrophil chemoattractant with no previously reported association with AROS. We also show that, our in vivo findings are complimented by our in vitro studies where we report that treatment of epithelial cells with cat S upregulates pro-inflammatory cytoklne secretion. We have also demonstrated that pharmacological inhibition of cat S, achieved using the cat S inhibitors VBY -999 and 1.6, reduces inflammatory cell infiltration into the lung and alveolar capillary permeability, as well as levels of pro-inflammatory cytokines in bronchoalveolar lavage fluid In the LPS-induced acute lung injury model, albeit to varying degrees. The use of cat S knockout (cat S -1-) mice validated the results of our inhibitor studies. Furthermore, we show that, cat S may be considered an agonist of the EGFR, PAR-1 and PAR-2 signalling pathways as antagonism of these pathways significantly abrogated cat S-induced symptoms of ARDS in mice, albeit to varying degrees. These findings support the hypothesis that cat S plays a role in tissue damage in acute lung inflammation and may represent a potential therapeutic target in the management of lung diseases including ARDS.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available