Chronic Obstructive Pulmonary Disease (COPD) is a disease with a major unmet medical need, for which at present there is no effective treatment that will halt the decline in lung function. Development of new therapies is hampered by the lack of well defined clinical biomarkers to both characterize patients and assess drug efficacy. Oxidative stress and the associated inflammatory responses in the lungs are key elements in the pathogenesis of COPD. However, there have been no longitudinal studies to assess the utility of representative markers of oxidative stress and inflammation as biomarkers of disease severity and hence their potential as surrogate endpoints for assessment of the effectiveness of new therapeutic agents. The purpose of this project is to identify and characterize candidate markers of oxidative stress and inflammation in both cross sectional and longitudinal studies. The proposed biomarkers for these studies are the lipid peroxidation products 4-hydroxy-2-nonenal, F2alpha-isoprostanes, and cytokines such as interleukin (IL) IL-8, IL-6, IL-1, tumor necrosis factor-alpha (TNF-alpha) and vascular endothelial growth factor in a well characterized cohort of COPD patients in both cross sectional and longitudinal studies. A further aim is to relate the levels of these markers of oxidative stress to inflammatory mediators and differential cell counts in induced sputum. In addition, a population of COPD patients will be characterized according to the levels of surrogate markers of airway inflammation and oxidative stress, which will be related to disease severity and to the clinical phenotype of COPD. Sophisticated techniques such gas chromatography/mass spectrometry (GC/MS) will be used to measure specific and stable lipid peroxidation products in peripheral blood, induced sputum and exhaled breath condensate. Moreover, mindful of the possibility that no single molecule will be a biomarker which is applicable to all patients with COPD, metabonomic and genomic technologies will be exploited to assess a spectrum of potential biomarkers, thus generating a 'finger print' characteristic of the disease. Such information will allow the identification of novel biomarkers and the fingerprints themselves may represent a mechanism to stratify COPD patients and allow the assessment of novel therapies.
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