Proteases, antiproteases and other inflammatory mediators associated with Chronic Obstructive Pulmonary Disease (COPD)

Chronic obstructive pulmonary disease (COPD) is a complex heterogeneous lung condition characterised by chronic inflammation and a reduction in airflow. COPD is diagnosed by measuring patient airflow obstruction, a late developing symptom, by which time irreversible lung damage has already occurred. A wider range of investigations leading to a greater understanding of the molecular mechanisms underpinning the development and progression of COPD are required to identify earlier and better methods of diagnosis. The presence of a protease-antiprotease imbalance within the airways contributes to the chronic inflammation and proteolytic destruction of the lung tissue observed in COPD. The most defined example of the protease-antiprotease imbalance within COPD occurs between the neutrophil serine protease, neutrophil elastase, and its endogenous serine protease inhibitor (serpin), alpha1 anti-trypsin. This protease-antiprotease imbalance can be a result of a genetic deficiency of alpha1 anti-trypsin, however, less than 5% of COPD patients possess the deficiency suggesting that other protease-antiprotease imbalances may be at play. The overarching aim of this research project was to identify novel proteins that may contribute to the protease-antiprotease imbalance within COPD.<br/><br/>Both preliminary and validation investigations identified a reduction in the protein and gene levels of another serpin, serpin A5, within COPD airway samples relative to healthy counterparts. As serpin A5 has never been reported within the lung environment initial characterisation studies successfully confirmed the presence of the protein using a variety of techniques including immunohistochemistry, western blotting and immunofluorescence microscopy. Investigations into the potential function and role of serpin A5 within the airways were also conducted. Identification of novel target proteases of serpin A5 confirmed that the inhibitor could potently inhibit a variety of protease activities documented to have a role within the lungs and/or lung pathobiology. <br/> <br/>Overall, the identification of serpin A5 as a novel antiprotease which appears to have some importance in the pathogenesis of COPD warrants further investigation to determine if it has any potential as a means of aiding earlier diagnosis, similar to alpha1 anti-trypsin. Serpin A5 holds the potential to contribute to better patient stratification and disease diagnosis in the future leading to a more efficacious and targeted approach to the therapeutic management of COPD.<br/>

Name dc:type.qualificationname

Doctor of Philosophy

Level dc:type.qualificationlevel

Doctoral Thesis

Grantor dc:publisher.institution

Queen's University Belfast

Year dc:date.issued

2022

Author dc:creator

• Kelly-Robinson, Gillian

Advisors dc:contributor.advisor

• Martin, Lorraine
• McGarvey, Lorcan

• Proteases
• antiproteases
• serpin
• serpin A5
• COPD

Language dc:language

eng

Identifier

oai:pure.qub.ac.uk/portal:studenttheses/d40ce8fa-d0ab-48aa-9eca-3b204cd76d20

OAI identifier oai:identifier

oai:pure.qub.ac.uk/portal:studenttheses/d40ce8fa-d0ab-48aa-9eca-3b204cd76d20