Proteinase 3 activity as a biomarker for disease severity in Chronic Obstructive Pulmonary Disease

Crisford, Helena Anne (2022). Proteinase 3 activity as a biomarker for disease severity in Chronic Obstructive Pulmonary Disease. University of Birmingham. Ph.D.

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Abstract

Background
Alpha-1 antitrypsin (AAT) deficiency (AATD) represents a subset of chronic obstructive pulmonary disease (COPD) which is a progressive, inflammatory disease of the lungs. COPD presents a significant global health burden; however, its heterogeneity means its pathogenesis remains poorly understood. AATD is caused by mutation in the anti-proteinase AAT, which results in little/no production of AAT and consequently uninhibited action of destructive proteinases, including proteinase 3 (PR3) and neutrophil elastase (NE). PR3 and NE are implicated in the pathophysiological development of emphysema and biomarkers of their activity (Aα-Val541 and Aα-Val360 respectively) correlate to disease severity and progression.

Methods
A novel in vitro neutrophil/fibrinogen-buffer model of the proteinase/anti-proteinase balance observed in AATD was validated for use within in-house PR3 and NE proteinase activity immunoassays to determine whether proteinase activity footprints (Aα-Val541 and Aα-Val360) could be used as pharmaceutical biomarkers in disease.

Results and Conclusions
A reduction in proteinase activity within the model following AAT treatment was observed which supported the significance of the putative 11 μM AAT clinical threshold. The model was also validated to assess drug efficacy. For the first time, AZD9668 was demonstrated to reduce NE activity in vitro and evidence was presented to suggest it worked synergistically with AAT. These data support the application of the novel model presented in this thesis as a method to determine the effect of inhibitors on proteinase activity footprints and as a biomarker of pharmaceutical efficacy.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):