Lipids potentially contribute to exacerbated inflammatory markers in Metabolic Syndrome mice acutely following pulmonary nanoparticle exposure

Abstract

Metabolic Syndrome (MetS) is a combination of disturbances including dyslipidemia. Epidemiological assessments demonstrated that individuals with MetS exhibit exacerbated inflammation following particulate inhalation. The mechanisms underlying these inflammatory responses remain to be elucidated, preventing the development of strategies to protect vulnerable and prevalent populations. Lipids dysregulated in MetS are intricately involved in inflammatory regulation. Particulate exposure-induced modifications in bioactive lipids were suggested to mediate inflammation in MetS susceptible mice. To assess this hypothesis, mice were fed a control diet or a high-fat western diet for 14-weeks to generate healthy or MetS models. Mice were exposed to silver nanoparticles (AgNPs) via oropharyngeal aspiration and acute toxicity endpoints determined 4-h post-exposure. Analysis of bronchoalveolar lavage fluid demonstrated that the AgNP exposure produced neutrophilia in both healthy and MetS mouse models, which was exacerbated in MetS mice. Gene expression of chemokine ligand-1 and macrophage inflammatory protein-2 were upregulated equally in both healthy and MetS mice. Pulmonary lipids were measured utilizing an MRM profiling approach, which noted induction of pro-inflammatory lipids in MetS following AgNP exposure compared to healthy mice. Specifically, arachidonic acid, prostaglandin-E2, prostaglandin-D2, 12-hydroxyeicosatetraenoic acid, and leukotriene-B4 were elevated in MetS mice following exposure, supporting the contribution of lipids to exacerbated inflammation. Further, pulmonary gene expression demonstrated upregulation of lipid metabolism enzymes arachidonate 15-lipoxygenase and prostaglandin-endoperoxide synthase 2 in MetS mice following AgNP exposure. Overall, data suggest dysregulation of pro-inflammatory lipid mediators contributes to early exacerbations in inflammatory responses observed in MetS animals following particulate exposures that might be targeted for therapeutic interventions.