Fatty acids metabolism in ozone-induced pulmonary inflammatory injury: Evidence, mechanism and prevention

Abstract

Ozone (O₃) is a major air pollutant that directly threatens the respiratory system, lung fatty acid metabolism disorder is an important molecular event in pulmonary inflammatory diseases. Liver kinase B1 (LKB1) and nucleotide-binding domain leucine-rich repeat-containing protein 3 (NLRP3) inflammasome not only regulate inflammation, but also have close relationship with fatty acid metabolism. However, the role and mechanism of LKB1 and NLRP3 inflammasome in lung fatty acid metabolism, which may contribute to ozone-induced lung inflammation, remain unclear, and effective strategy for preventing O₃-induced pulmonary inflammatory injury is lacking. To explore these, mice were exposed to 1.00 ppm O₃ (3 h/d, 5 days), and pulmonary inflammation was determined by airway hyperresponsiveness, histopathological examination, total cells and cytokines in bronchoalveolar lavage fluid (BALF). Targeted fatty acids metabolomics was used to detect medium and long fatty acid in lung tissue. Then, using LKB1-overexpressing adenovirus and NLRP3 knockout (NLRP3-/-) mice to explore the mechanism of O₃-induced lung fatty acid metabolism disorder. Results demonstrated that O₃ exposure caused pulmonary inflammatory injury and lung medium and long chain fatty acids metabolism disorder, especially decreased dihomo-γ-linolenic acid (DGLA). Meanwhile, LKB1 expression was decreased, and NLRP3 inflammasome was activated in lung of mice after O₃ exposure. Additionally, LKB1 overexpression alleviated O₃-induced lung inflammation and inhibited the activation of NLRP3 inflammasome. And we found that pulmonary fatty acid metabolism disorder was ameliorated of NLRP3 -/- mice compared with those in wide type mice after O₃ exposure. Furthermore, administrating DGLA intratracheally prior to O₃ exposure significantly attenuated O₃-induced pulmonary inflammatory injury. Taken together, these findings suggest that fatty acids metabolism disorder is involved in O₃-induced pulmonary inflammation, which is regulated by LKB1-mediated NLRP3 pathway, DGLA supplement could be a useful preventive strategy to ameliorate ozone-associated lung inflammatory injury.

Keywords: Dihomo-γ-linolenic acid; Fatty acids disorder; LKB1; Lung stem cells; NLRP3 inflammasome; Ozone.