Abstract
COPD (chronic obstructive pulmonary disease) is defined by a fixed expiratory airflow obstruction associated with disordered airways and alveolar destruction. COPD is caused by cigarette smoking and is the third greatest cause of mortality in the US. Forced expiratory volume in 1 second (FEV1) is the only validated clinical marker of COPD, but it correlates poorly with clinical features and is not sensitive enough to predict the early onset of disease. Using LC/MS global untargeted metabolite profiling of serum samples from a well-defined cohort of healthy smokers (n = 37), COPD smokers (n = 41) and non-smokers (n = 37), we sought to discover serum metabolic markers with known and/or unknown molecular identities that are associated with early-onset COPD. A total of 1,181 distinct molecular ions were detected in 95% of sera from all study subjects and 23 were found to be differentially-expressed in COPD-smokers vs. healthy-smokers. These 23 putative biomarkers were differentially-correlated with lung function parameters and used to generate a COPD prediction model possessing 87.8% sensitivity and 86.5% specificity. In an independent validation set, this model correctly predicted COPD in 8/10 individuals. These serum biomarkers included myoinositol, glycerophopshoinositol, fumarate, cysteinesulfonic acid, a modified version of fibrinogen peptide B (mFBP), and three doubly-charged peptides with undefined sequence that significantly and positively correlate with mFBP levels. Together, elevated levels of serum mFBP and additional disease-associated biomarkers point to a role for chronic inflammation, thrombosis, and oxidative stress in remodeling of the COPD airways. Serum metabolite biomarkers offer a promising and accessible window for recognition of early-stage COPD.
Highlights
Chronic obstructive pulmonary disease (COPD) is a debilitating cigarette smoking-associated disease and the third most common cause of death in the US
Baseline parameters were similar in BMI and Number of subjects Gender Ethnicity Packs per year Packs per day Age of initiation Age BMI forced expiratory volume in 1 second (FEV1)% forced vital capacity (FVC)% FEV1/FVC% total lung function (TLC) DLCO COHb Urine cotinine
One biomarker identified in serum distinguishing COPD smokers from smokers was a modified form of the fibrinogen-derived peptide, fibrinogen peptide B (FPB)
Summary
Chronic obstructive pulmonary disease (COPD) is a debilitating cigarette smoking-associated disease and the third most common cause of death in the US. A variety of promising biomarkers have been reported for COPD [7], including blood proteins [8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39], miRNAs [40, 41], and small molecule metabolites [42,43,44,45,46,47,48,49,50]. Notwithstanding rapidly expanding efforts to identify COPD biomarkers, especially blood proteins, no single marker has been adopted for routine clinical use to date
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