Bile acid profiles are altered in obese individuals with asthma. Thus, we sought to better understand how obesity-related systemic changes contribute to lung pathophysiology. We also test the therapeutic potential of nitro-oleic acid (NO2-OA), a regulator of metabolic and inflammatory signaling pathways, to mitigate allergen and obesity-induced lung function decline in a murine model of asthma. Bile acids were measured in the plasma of healthy subjects and individuals with asthma and serum and lung tissue of mice with and without allergic airway disease (AAD). Lung function, indices of inflammation and hepatic bile acid enzyme expression were measured in obese mice with house dust mite-induced AAD treated with vehicle or NO2-OA. Serum levels of glycocholic acid and glycoursodeoxycholic acid clinically correlate with body mass index and airway hyperreactivity whereas murine levels of β-muricholic acid and tauro-β-muricholic acid were significantly increased and positively correlated with impaired lung function in obese mice with AAD. NO2-OA reduced murine bile acid levels by modulating hepatic expression of bile acid synthesis enzymes, with a concomitant reduction in small airway resistance and tissue elastance. Bile acids correlate to body mass index and lung function decline and the signaling actions of nitroalkenes can limit AAD by modulating bile acid metabolism, revealing a potential pharmacologic approach to improving the current standard of care.

Department of Cell Biology and Radiobiology Institute of Biophysics Czech Academy of Sciences 61265 Brno Czech Republic

Department of Clinical and Translational Science University of Pittsburgh Pittsburgh PA 15261 USA

Department of Environmental and Occupational Health Graduate School of Public Health University of Pittsburgh Pittsburgh PA 15261 USA

Department of Pathology School of Medicine University of Pittsburgh Pittsburgh PA 15261 USA

Department of Pharmacology and Chemical Biology School of Medicine University of Pittsburgh 200 Lothrop Street E1345 Pittsburgh PA 15261 USA

Division of Pulmonary Allergy and Critical Care Medicine Department of Medicine University of Pittsburgh Pittsburgh PA 15261 USA

Division of Pulmonary Medicine Department of Pediatrics UPMC Children's Hospital of Pittsburgh Pittsburgh PA 15224 USA

Division of Pulmonary Sciences and Critical Care School of Medicine University of Colorado Denver Aurora CO 80045 USA

Health Sciences Metabolomics and Lipidomics Core University of Pittsburgh Pittsburgh PA 15261 USA

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