Abstract
Cigarette smoke exposure is linked to the development of a variety of chronic lung and systemic diseases in susceptible individuals. Metabolomics approaches may aid in defining disease phenotypes, may help predict responses to treatment, and could identify biomarkers of risk for developing disease. Using a mouse model of chronic cigarette smoke exposure sufficient to cause mild emphysema, we investigated whether cigarette smoke induces distinct metabolic profiles and determined their persistence following smoking cessation. Metabolites were extracted from plasma and fractionated based on chemical class using liquid-liquid and solid-phase extraction prior to performing liquid chromatography mass spectrometry-based metabolomics. Metabolites were evaluated for statistically significant differences among group means (p-value≤0.05) and fold change ≥1.5). Cigarette smoke exposure was associated with significant differences in amino acid, purine, lipid, fatty acid, and steroid metabolite levels compared to air exposed animals. Whereas 60% of the metabolite changes were reversible, 40% of metabolites remained persistently altered even following 2 months of smoking cessation, including nicotine metabolites. Validation of metabolite species and translation of these findings to human plasma metabolite signatures induced by cigarette smoking may lead to the discovery of biomarkers or pathogenic pathways of smoking-induced disease.
Highlights
A biological marker is a characteristic that is objectively measured and evaluated as an indicator of normal or pathogenic biological processes, or of pharmacologic responses to a therapeutic intervention [1]
The respiratory tract is the first target of cigarette smoke inhalation and cigarette smoking is a major risk factor for diseases of the airways such as chronic obstructive pulmonary disease (COPD) [6] and head, neck, and lung cancers [7]
The levels of nicotine glucuronide paralleled smoking exposure history and were highly elevated in CS-6mo samples compared to AC-6mo samples (p = 0.00043), but were elevated in CS-cessation compared to AC-6mo (p = 0.027)
Summary
A biological marker (biomarker) is a characteristic that is objectively measured and evaluated as an indicator of normal or pathogenic biological processes, or of pharmacologic responses to a therapeutic intervention [1]. Biomarkers identified in biological fluids such as plasma can be used for early disease diagnoses or to identify those at risk for disease development, which could lead to behavior modification or clinical interventions that may impact disease prognosis. It is well established that cigarette smoking is a risk factor for many systemic diseases, including cardiovascular disease and numerous cancers (e.g. bladder or pancreas), suggesting significant pathogenicity of circulating toxic components or metabolites of absorbed cigarette smoke. Not all smokers develop disease and progression of diseases such as COPD may persist despite smoking cessation. These observations suggest a critical need for determining pathways through which smoking can lead to disease and for the discovery of useful biomarkers of disease phenotype, severity, and progression
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