| Summary: | The flaws of current methods of assessing disease severity in patients with COPD and emphysema are increasingly recognised, and new methods of assessing disease activity are urgently required. Although many potential biomarkers have been suggested to fulfil this role, few have been effectively validated, and furthermore any biomarker should be based on our current understanding of the pathophysiology the disease process. This is poorly understood, however it is apparent that neutrophil proteases (particularly neutrophil elastase (NE) and proteinase 3 (Pr3)) may represent a final common pathway leading to tissue destruction. The current thesis describes the development and validation of a new marker of NE activity (Aα-Val360), and the identification of a marker of Pr3 activity, as potential biomarkers of COPD and emphysema disease activity. Methods Following in vitro validation, the performance of Aα-Val360 was assessed in a series of patient populations. Mass spectrometry was used to identify a specific marker of Pr3 activity. Results and Conclusion Aα-Val360 demonstrated acceptable in vitro and in vivo variability; related to physiological, radiological and patient reported outcomes in subjects with (or at risk of developing) COPD and emphysema (both with and without A1AT deficiency); increased during acute exacerbations; decreased in response to treatment; and partly related to disease progression in some populations. Also, a Pr3 specific cleavage product was identified which could be used to develop a new specific assay of Pr3 activity. These potential biomarkers of disease activity may be important in the assessment of patients with COPD and emphysema (or who are at risk of developing these conditions), particularly in early phase clinical trials.
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