Docosahexaenoic Acid and Its Metabolites Protect against Ozone-induced Pulmonary Inflammation

Ozone (O₃) is an air pollutant that induces pulmonary inflammation and injury, leading to increased susceptibility and exacerbation of chronic lung diseases. Furthermore, ambient O₃ concentrations are expected to rise with increasing global temperatures. Docosahexaenoic acid (DHA) is an omega-3 polyunsaturated fatty acid found primarily in oily fish that reduces inflammation and enhances the resolution of inflammation. This is attributed partially to DHA-derived oxylipins termed specialized proresolving mediators that have antiinflammatory and/or proresolving properties. However, whether dietary DHA protects the lungs from O₃-induced inflammation and injury is unclear. We hypothesized that dietary DHA supplementation increases pulmonary specialized proresolving mediators and thereby decreases O₃-induced pulmonary inflammation. To test this, C57BL/6J mice were fed a control diet or a DHA-enriched diet (2% kcal from DHA) for 6 weeks, exposed to filtered air or 1 ppm O₃ for 3 hours (comparable with an O₃ action day for humans), and necropsied 24 or 48 hours after exposure. DHA supplementation reduced airspace neutrophilia, decreased cytokine production, and promoted transcriptomic signatures for leukocyte chemotaxis and fatty acid oxidation. Furthermore, dietary DHA increased pulmonary DHA and its oxylipins while decreasing proinflammatory omega-6 polyunsaturated fatty acids and their oxylipins. Oropharyngeal aspiration of DHA oxylipins monohydroxylated 14-hydroxy-DHA and maresin 1 decreased O₃-induced airspace neutrophilia and reduced bone marrow-derived macrophage production of neutrophil chemokines Cxcl1 and Cxcl2. These findings reveal that dietary DHA protects the lungs from O₃ exposure by driving monohydroxylated 14-hydroxy-DHA and maresin 1 production, which reduces neutrophil-recruiting chemokine production by macrophages. This pathway highlights a potential therapeutic dietary approach for mitigating air pollution-induced pulmonary inflammation.