Leukocyte-mediated degradation of lung extracellular matrix & serum molecules in chronic inflammatory disease, as discerned through urinary biomarkers

Chronic Obstructive Pulmonary disease (COPD) is an irreversible inflammatory disease of the lung, characterised by abnormal inflammation of the lungs in response to inhalation of noxious particles or toxic gases, especially cigarette smoke. COPD exacerbations, defined as acute sustained worsening of symptoms from usual stable state, accounts for significant morbidity and mortality. Improved diagnostics which give advanced warning of an exacerbation could help prevent further declines in lung function. The quest to identify a marker or a combination of markers associated with COPD exacerbations has been pursued for some time. Many groups have studied biomarkers in plasma, serum, sputum and bronchoalveolar lavage (BAL) fluid and uncovered useful markers for prediction of exacerbations, disease severity and mortality. However, there is limited research on urine biomarkers. Profiling inflammatory mediators in urine samples presents a simple, convenient, non-invasive measure of inflammation in COPD patients and can be done repeatedly within their own home or in the clinic, allowing easier monitoring of time-dependent changes in biomarker levels. The research described in this thesis is the first investigation where a large panel of biomarkers has been evaluated in urine samples from subjects in various stages of COPD. This has provided new insights into the relevance and origin of the biomarkers. Prototype point-of-care tests were developed that could be used routinely by patients in their own homes to monitor their inflammation status and predict pulmonary exacerbations. This was evaluated in a prospective observational study, results of which were used to develop a simple algorithm that showed the potential for differentiating between stable state and exacerbation events. The research described here is part of a major research initiative carried out within the Mologic R&D group and constitutes investigations designed and directed by the author, and conclusions derived from the author’s analysis of the data collected by the biomarker immunoassays. The findings constitute a key scientific foundation for a new approach to personalised medicine for COPD sufferers.