The role of obesity driven oxLAM production following ozone

Air pollution is responsible for approximately 9 million premature deaths and more than $4 trillion in annual economic losses. Ozone (O3), a criteria air pollutant, contributes to this mortality by causing lung inflammation and injury, which is augmented in susceptible populations. One such susceptible population are invididuals who have obesity. This is significant given that >10% of the global population, including 42% of the U.S. population, is obese (BMI>30), thereby representing a large population that can exhibit enhanced O3 sensitivity. A hallmark of obesity is increased circulating n-6 polyunsaturated fatty acids (PUFA). One of the n-6 PUFAs known to be elevated in obesity is linoleic acid (LA). LA is highly abundant in the western obesogenic diet but largely understudied in the context of lung inflammation. Once ingested, LA can be metabolized into hydroxyoctadecadienoic acids which are further metabolized by enzymes including soluble epoxide hydrolase (sEH) into distinct OXLAMs (oxidized linoleic acid metabolites) that drive inflammation. EpOMEs and DiHOMEs are sEH driven OXLAMs that have been shown to both drive and dampen tissue inflammation. Presently, it is unknown if high LA intake in an obesogenic diet drives increased OXLAM production, including EpOMEs and DiHOMEs, and if this augments O3-induced lung inflammation. Based on strong preliminary data, we hypothesize that decreasing dietary consumption of LA will reduce lung LA and subsequent production of EpOMEs and DiHOMEs, which will mitigate obesity-exacerbated lung inflammation and injury following O3 exposure. This hypothesis is conceptually innovative as it defines how dietary LA intake in obesity drives susceptibility to O3 and offers a precision nutrition strategy to mitigate this impact in a vulnerable population. The approach to test this hypothesis will rely on mouse models and human bronchoalveolar lavage and plasma samples from individuals with a differential body mass indexes (BMI). In Aim 1, we will establish that decreased dietary LA consumption mitigates obesity-induced augmentation of O3 lung inflammation by decreasing lung LA accumulation and production of OXLAMs. In Aim 2, we will dissect the contribution of individual sEH driven OXLAMs on O3-induced pulmonary inflammation. Impact: This study will open an entirely new avenue of air pollution research, focused on how dietary LA intake in obesity leads to generation of pulmonary OXLAMs and drives inflammation following O3 exposure. The results of this proposal could support future targeted dietary interventions in obesity that could mitigate O3-induced pulmonary inflammation and injury and more broadly impact other types of lung injury. Thus, these studies will directly pave the way for innovative precision nutrition approaches in susceptible individuals that will combat the adverse health effects of air pollution. Project Number: 1R21ES037201-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Environmental Health Sciences (NIEHS) | Principal Investigator: Kymberly Gowdy (+1 co-PI) | Institution: OHIO STATE UNIVERSITY, Columbus, OH | Award Amount: $437,162 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 RCCS-Y (03)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11389011