Transient and Persistent Metabolomic Changes in Plasma following Chronic Cigarette Smoke Exposure in a Mouse Model

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.

Metabolomics screening identifies reducedL-carnitine to be associated with progressive emphysema

“…This is substantiated by the rapid increase in studies over the last 5 years assessing metabolomic changes in COPD patients and animal models of disease [10][11][12][13][14][15][16][17]. These studies, however, lack a thorough analysis of metabolomic changes occurring in the lung tissue during the progression of emphysema.…”

“…In their combined approach, Bowler et al [15] reported a strong inverse association between the level of some plasma sphingomyelins (SMs) and emphysema in COPD patients. In addition to these clinical studies, one animal study used an untargeted approach to examine metabolomic changes in plasma following chronic exposure to cigarette smoke in a mouse model that resulted in emphysema [16] and a very recent study examining the effect of traditional Chinese medicine on a cigarette-smoke-induced rat model of COPD examined metabolite levels in lung tissue [17]. However, to the best of our knowledge, no study has yet assessed the metabolomic changes occurring in the emphysematous lung during disease progression.…”

Resolvin E1 derived from eicosapentaenoic acid prevents hyperinsulinemia and hyperglycemia in a host genetic manner

“…Samples were analyzed using liquid chromatography mass spectrometry (LCMS) and raw data were extracted and processed using Agilent Technologies Mass Hunter Profinder Version B.08.00 (Profinder) software in combination with Agilent Technologies Mass Profiler Professional Version 14 (MPP) as previously described [56][57][58] To visualize clustering between the dietary groups we ran a principal component analysis (PCA) using all metabolites. We then determined statistically significant metabolites between obese mice and obese mice supplemented with EPA.…”

Dysregulation of metabolic pathways in a mouse model of allergic asthma

“…For example, dysregulated arginine‐proline and arginine‐creatine metabolisms have been identified in ischemic retinopathy and chronic kidney disease . Combining clinical outcomes with untargeted small molecule analysis has identified novel disease‐related mechanisms including the progression of nonalcoholic fatty liver disease and chronic obstructive pulmonary disease (COPD) . Amino acids have been implicated in asthma; for example, arginine acts as a substrate for nitric oxide (NO) production, which plays a role in airway responsiveness.…”

“…12 Combining clinical outcomes with untargeted small molecule analysis has identified novel disease-related mechanisms including the progression of nonalcoholic fatty liver disease and chronic obstructive pulmonary disease (COPD). 13,14 Amino acids have been implicated in asthma; for example, arginine acts as a substrate for nitric oxide (NO) production, 15 which plays a role in airway responsiveness. The regulation of sphingolipid homeostasis has been correlated with the ORMDL3 gene 16 which is located within the most replicated asthma-susceptibility locus.…”