Nicholas, Benjamin L., Skipp, Paul, Barton, Sheila, Singh, Dave, Bagmane, Dinesh, Mould, Richard, Angco, Gilbert, Ward, Jon, Guha-Niyogi, Binita, Wilson, Susan, Howarth, Peter, Davies, Donna E., Rennard, Stephen, O'Connor, C. David and Djukanovic, Ratko
Identification of lipocalin and apolipoprotein A1 as biomarkers of chronic obstructive pulmonary disease
American Journal of Respiratory and Critical Care Medicine, 181, (10), . (doi:10.1164/rccm.200906-0857OC).
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Rationale: much effort is being made to discover non-invasive biomarkers of chronic airways disease that might enable better management, predict prognosis and provide new therapeutic targets.
Objectives: to undertake a comprehensive, unbiased proteomic analysis of induced sputum and identify novel non-invasive biomarkers for chronic obstructive pulmonary disease (COPD). Methods: Induced sputum was obtained from COPD patients with a spectrum of disease severity and control subjects. Two-dimensional gel electrophoresis and mass spectrometric identification of differentially expressed proteins was first applied to induced sputum from GOLD Stage 2 COPD patients and healthy smoker control subjects. Initial results thus obtained were validated by a combination of immunoassays (Western blotting and ELISA) applied to a large subject cohort. The biomarkers were localised to bronchial mucosa by immunohistochemistry.
Measurements and main results: of 1325 individual protein spots identified, 37 were quantitatively and 3 qualitatively different between the two groups (p<0.05%). 40 protein spots were subjected to tandem mass spectrometry, which identified 15 separate protein species. Seven of these were further quantified in induced sputum from 97 individuals. Using this sequential approach, two of these potential biomarkers (apolipoprotein A1 and lipocalin-1) were found to be significantly reduced in COPD patients when compared to healthy smokers. Their levels correlated with FEV1/FVC, indicating their relationship to disease severity.
Conclusions: a potential role for apolipoprotein A1 and lipocalin-1 in innate defence has been postulated previously; our discovery of their reduction in COPD indicates a deficient innate defence system in airways disease that could explain increased susceptibility to infectious exacerbations
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