NCT01974154

COPD Metabolome, Smoking Oxidants and Aberrant Ciliated Cell Function

• Status: Terminated
• Phase: —
• Study type: Observational
• Enrollment: 206 (actual)
• Sponsor: Weill Medical College of Cornell University · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Accepted

Summary

Cigarette smoking is the major cause of chronic obstructive pulmonary disease (COPD), the 4th cause of mortality in the US. Central to COPD pathogenesis is "ciliopathy", dysfunction of the airway ciliated cells that mediate transport of mucus to remove inhaled pathogens. The focus of this study is to carry out metabolic profiling of banked biologic samples and assess the hypothesis that COPD is associated with a unique metabolome in serum and lung epithelial lining fluid, and that subsets of the COPD metabolome are linked to the ciliopathy of COPD.

Detailed description

Cigarette smoking is the major cause of chronic obstructive pulmonary disease (COPD), the 4th cause of mortality in the US. Central to COPD pathogenesis is "ciliopathy", dysfunction of the airway ciliated cells that mediate transport of mucus to remove inhaled pathogens. The COPD ciliopathy leads to mucus accumulation, impaired host defense and recurrent infections. Using a state-of-the-art platform for global metabolite profiling and unique cohorts with serum and lung biologic samples, our deliverables are to identify a metabolome focused on biomarkers related to airway ciliopathy in COPD, and use the observed metabolic changes to: (1) direct mechanistic studies to define ciliopathy at a molecular level; (2) identify novel targets for therapeutic intervention in COPD; and (3) identify smokers at high risk for COPD. Preliminary metabolic data led to our first clues - COPD smokers have decreased serum citrulline levels, consistent with a deficiency in lung nitric oxide synthase (NOS) activity, and thus lung nitric oxide (NO) deficiency. This, together with supporting data of a smoking-induced NOS/NO-related ciliopathy, and knowledge that smokers have significant oxidant-related changes in the airway epithelial transcriptome, led to our aims, combining metabolomics of defined cohorts, murine and human mechanistic studies and computational / statistical integration. Aim 1. To carry out metabolic profiling of banked biologic samples of our characterized cohorts to assess the hypothesis that COPD is associated with a unique metabolome in serum and lung epithelial lining fluid, and that subsets of the COPD metabolome are linked to the ciliopathy of COPD. Aim 2. To combine metabolic profiling and in vitro studies of human and murine airway epithelium to evaluate the hypothesis that there is a link between the COPD metabolome (focusing on the inferred NO deficiency) and mechanisms underlying the ciliopathy of COPD. Aim 3. Characterize and quantify the cigarette smoke induced "redoxome" in lung and serum and assess its role in ciliated cell dysfunction. Studies seek to identify a link between smoking, a burden of oxidants to the lung epithelium and the pathogenesis of COPD - potentially providing biomarker(s) that predict which smokers will develop COPD and identifying new targets for therapy of COPD.

Conditions

• COPD
• Smoking

Interventions

Type	Name	Description
OTHER	Cohort I	We will evaluate serum and lung ELF obtained by bronchoalveolar lavage, under previous protocols, from 159 individuals at baseline and at 0, 3, 6 and 12 months.
OTHER	Cohort II	Quantify the cilia length on prepared slides from 67 cohort II samples of airway epithelium from biological samples were already obtained from subjects who were consented to participate in prior WCMC IRB approved protocols.

Timeline

• Start date: 2013-12-01
• Primary completion: 2019-05-01
• Completion: 2019-05-01
• First posted: 2013-11-01
• Last updated: 2020-07-30

Locations

1 site across 1 country: United States