Does traffic-related air pollution accelerate the development of the metabolic syndrome by impairing the resolution of neurogenic inflammation? - PROJECT SUMMARY Metabolic disorders, including obesity and diabetes affect 1 in 3 individuals in the United States exacting a huge cost on individuals and society. Epidemiologic studies have reported a positive correlation between exposure to traffic-related air pollution (TRAP) and increased risk of metabolic disorders. Preclinical studies support this association, but many of these studies used acute exposure to concentrated ambient particles or diesel exhaust that do not recapitulate the complexity of chronic real-world human exposures to TRAP. Moreover, the mechanism(s) by which TRAP increases individual risk for metabolic disorders remain speculative. We have designed a unique exposure model in which rats are exposed in real-time to TRAP collected from a major freeway tunnel system, which preserves the gaseous and particulate components of real-world TRAP and captures daily fluctuations in pollutant levels. We will leverage this model to test our central hypothesis that chronic TRAP exposure exacerbates metabolic disease by interfering with the resolution of neurogenic inflammation. Using an established high-fat diet rat model of the metabolic syndrome, we will test whether chronic TRAP exposure activates neurogenic inflammation in peripheral organs, initially in the lungs and subsequently in organs involved in metabolic disease, such as the liver and adipose tissue. We hypothesize that chronic activation of neurogenic inflammation tips the balance towards pro-inflammatory pathways and away from inflammation resolution. In Aim 1, we will determine whether chronic TRAP exposure causes neurogenic inflammation leading to increased pro-inflammatory (M1) and decreased inflammation resolving (M2) macrophage phenotypes. Further we will characterize changes in the turnover of pro-inflammatory and pro- resolving lipid mediators using deuterated tracers. In addition to examining the temporal relationships between these outcomes, we will determine whether TRAP exacerbates metabolic disease, evidenced as a decreased time to onset and/or increased severity of symptoms. In Aim 2, we will use a drug that blocks neurogenic inflammation, and a drug that promotes inflammation resolution, to assess the causal relationship of TRAP- induced neurogenic inflammation to both impaired inflammation resolution and symptoms of metabolic disease. This will be determined by M1/M2 macrophage phenotypes and relative balance of pro-inflammatory and pro- resolving lipid synthesis. Our broad long-term objectives are to understand how chronic exposure to TRAP exacerbates the burden of metabolic disease, to inform regulatory and health interventions aimed at reducing metabolic risk for individuals living, working, or attending school near busy roadways. This proposal is directly aligned with the Notice of Special Interest (NOT-ES-20-018) goals of characterizing “cell and tissue specific resolution phenotype in normal and disease models and the impact of exposure to environmental agents”.
