COPD Metabolome, Smoking Oxidants and Aberrant Ciliated Cell Function
Principal Investigator: Ronald Crystal
Funding Mechanism: National Institutes of Health- Grant
ID number: 1P20HL113443-01
Award Date: 4/15/2012
Institution: Weill Medical College of Cornell University
Cigarette smoking is the major cause of chronic obstructive pulmonary disease (COPD), the fourth leading cause of mortality in the U.S. Central to COPD pathogenesis is ciliopathy, a dysfunction of the airway ciliated cells that mediate transport of mucus to remove inhaled pathogens; ciliopathy leads to mucus accumulation, impaired host defense and recurrent infections. While cigarette smoking is known to be the major cause of ciliopathy, the molecular mechanisms underlying smoking-induced airway ciliopathy are unknown. The goal of this five-year investigation is to examine metabolomic changes in smoking-related airway ciliopathy in order to identify a link between smoking, burden of oxidants to the lung epithelium and COPD pathogenesis. Study aims are: (1) to perform global metabolic profiling of banked biologic samples from two existing patient cohorts to assess the hypothesis that smoking-induced COPD is associated with a unique serum and lung metabolome and that subsets of this metabolome are linked to COPD ciliopathy; (2) to combine metabolic profiling and in vitro studies of human and murine airway epithelial cells to evaluate the link between the COPD metabolome and mechanisms underlying COPD ciliopathy; and (3) to characterize and quantify the cigarette smoke-induced "redoxome" of redox-prone metabolites in lung and serum that could be affected by the oxidants in cigarette smoke, and to assess its role in ciliopathy. The two existing cohorts include (1) 159 individuals in five groups (30 healthy nonsmokers, 12 healthy smokers, 61 healthy smokers undergoing smoking cessation, 10 COPD smokers and 46 COPD smokers undergoing smoking cessation) who provided serum, bronchoalveolar lavage (lung epithelial lining fluid) and airway epithelium samples at 0, 3, 6 and 12 months, and (2) 67 smokers (34 active smokers with normal spirometry and low diffusing capacity of whom 24% developed COPD and 33 normal smoking controls of whom 3% developed COPD) who were followed with lung function studies for up to six years. The investigators will recruit 50 new subjects (healthy nonsmokers, healthy smokers and COPD smokers) who will provide live airway epithelial cells for the human mechanistic studies.