Docosahexaenoic Acid Protects the Lungs from Ozone-Induce Inflammation Via its Oxylipins

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 levels are expected to rise with increasing global temperatures. Docosahexaenoic acid (DHA) is an omega-3 (n-3) polyunsaturated fatty acid (PUFA) primarily found in oily fish that reduces inflammation and enhances the resolution of inflammation. This is partially attributed to DHA-derived oxylipins termed specialized pro-resolving mediators (SPMs) that have anti-inflammatory/pro-resolving properties. However, whether dietary DHA protects the lungs from O3-induced inflammation and injury is unclear. We hypothesized that dietary DHA supplementation increases pulmonary SPMs and thereby decreases O3-induced pulmonary inflammation. To test this, C57BL/6J mice were fed control diet or DHA-enriched diet (2% kcal from DHA) for 6 weeks, exposed to filtered air (FA) or 1 ppm O3 for 3h (comparable to an O3 Action Day for humans), and necropsied 24h or 48h following 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 pro-inflammatory n-6 PUFAs and their oxylipins. Oropharyngeal aspiration of DHA-oxylipins 14-HDHA or maresin 1 (MaR1) 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 14-HDHA and MaR1 production, which reduces neutrophil recruiting chemokine production by macrophages. This pathway highlights a potential therapeutic dietary approach for mitigating air pollution-induced pulmonary inflammation. Overall design: Gene expression of RNA isolated from lung tissue of mice fed a control diet or docosahexanoic acid rich diet prior to a filtered air or ozone exposure