(P18-018-25) Pulmonary Inflammation Is Exacerbated by Diet-Induced Obesity and Mitigated by Docosahexaenoic Acid

Objectives: Obesity promotes pulmonary inflammation and thereby increases susceptibility and severity of lung diseases, which are a significant public health burden. Thus, there is a critical need to develop therapeutic approaches for preventing the impact of obesity on pulmonary inflammation.

Methods: Herein, we first established that diet-induced obesity in C57BL/6J mice exacerbates pulmonary inflammation at the transcriptomic, lipidomic, and cellular level. Next, we tested if dietary supplementation with docosahexaenoic acid (DHA), modeling pharmacological intake in humans, could improve the immune cell repertoire and lipidomic profile of obese mice in a model of acute lung injury driven by lipopolysaccharide (LPS). Select molecular studies were also conducted with DHA in cell culture.

Results: DHA in the diet specifically decreases the number of select immune cell populations such as interstitial macrophages, CD11b^- dendritic cells, and eosinophils in bronchoalveolar lavage fluid. Mass spectrometry-based studies show DHA lowers select pro-inflammatory oxylipins. Supporting in vitro studies with an alveolar macrophage cell line reveal that DHA treatment decreases the concentration of pro-inflammatory oxylipins and IL-6 secretion upon LPS stimulation while increasing anti-inflammatory oxylipins accompanied by significant upstream remodeling of lipid raft signaling domains. Finally, myeloid specific deletion of ELOVL2 in mice to lower DHA levels increases the number of monocyte-derived macrophages, dendritic cells, and natural killer cells upon LPS activation.

Conclusions: Collectively, these results reveal a therapeutic role for DHA in mitigating pulmonary inflammation in obesity through pleiotropic mechanisms.

Funding Sources: NIH P30DK056350 (SRS), R01ES031378 (SRS,KG), F31HL176155(RV)