Role of PPARγ in dyslipidemia and altered pulmonary functioning in mice following ozone exposure

• Published in: Toxicological sciences 2023-06, Vol.194 (1), p.109-119
• Main Authors: Smith, Ley Cody, Gow, Andrew J, Abramova, Elena, Vayas, Kinal, Guo, Changjiang, Noto, Jack, Lyman, Jack, Rodriquez, Jessica, Gelfand-Titiyevskiy, Benjamin, Malcolm, Callum, Laskin, Jeffrey D, Laskin, Debra L
• Format: Article
• Language: English
• Subjects: Animals; Dyslipidemias - chemically induced; Dyslipidemias - metabolism; Lung - metabolism; Macrophages, Alveolar - metabolism; Mice; Organ Specific Toxicology; Ozone - toxicity; Phospholipids - metabolism; PPAR gamma - metabolism; Surface-Active Agents
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kfad048

Abstract Exposure to ozone causes decrements in pulmonary function, a response associated with alterations in lung lipids. Pulmonary lipid homeostasis is dependent on the activity of peroxisome proliferator activated receptor gamma (PPARγ), a nuclear receptor that regulates lipid uptake and catabolism by alveolar macrophages (AMs). Herein, we assessed the role of PPARγ in ozone-induced dyslipidemia and aberrant lung function in mice. Exposure of mice to ozone (0.8 ppm, 3 h) resulted in a significant reduction in lung hysteresivity at 72 h post exposure; this correlated with increases in levels of total phospholipids, specifically cholesteryl esters, ceramides, phosphatidylcholines, phosphorylethanolamines, sphingomyelins, and di- and triacylglycerols in lung lining fluid. This was accompanied by a reduction in relative surfactant protein-B (SP-B) content, consistent with surfactant dysfunction. Administration of the PPARγ agonist, rosiglitazone (5 mg/kg/day, i.p.) reduced total lung lipids, increased relative amounts of SP-B, and normalized pulmonary function in ozone-exposed mice. This was associated with increases in lung macrophage expression of CD36, a scavenger receptor important in lipid uptake and a transcriptional target of PPARγ. These findings highlight the role of alveolar lipids as regulators of surfactant activity and pulmonary function following ozone exposure and suggest that targeting lipid uptake by lung macrophages may be an efficacious approach for treating altered respiratory mechanics.