Specialized pro-resolving lipid mediators regulate ozone-induced pulmonary and systemic inflammation

Abstract

Exposure to ozone (O 3 ) induces lung injury, pulmonary inflammation, and alters lipid metabolism. During tissue inflammation, specialized pro-resolving lipid mediators (SPMs) facilitate the resolution of inflammation. SPMs regulate the pulmonary immune response during infection and allergic asthma; however, the role of SPMs in O 3 -induced pulmonary injury and inflammation is unknown. We hypothesize that O 3 exposure induces pulmonary inflammation by reducing SPMs. To evaluate this, male C57Bl/6J mice were exposed to filtered air (FA) or 1ppm O 3 for 3h and necropsied 24h after exposure. Pulmonary injury/inflammation was determined by bronchoalveolar lavage (BAL) differentials, protein, and lung tissue cytokine expression. SPMs were quantified by liquid chromatography tandem mass spectrometry and SPM receptors leukotriene B 4 receptor 1 (BLT-1), formyl peptide receptor 2 (ALX/FPR2), chemokine-like receptor 1 (ChemR23), and SPMgenerating enzyme (5-LOX and 12/15-LOX) expression were measured by real time PCR. 24h post-O 3 exposure, BAL PMNs and protein content were significantly increased compared to FA controls. O 3 -induced lung inflammation was associated with significant decreases in pulmonary SPM precursors (14-HDHA, 17-HDHA), the SPM PDX, and in pulmonary ALX/FPR2, ChemR23, and 12/15-LOX expression. Exogenous administration of 14-HDHA, 17-HDHA, and PDX 1h prior to O 3 exposure rescued pulmonary SPM precursors/SPMs, decreased proinflammatory cytokine and chemokine expression, and decreased BAL macrophages and PMNs. Taken together, these data indicate that O 3 -mediated SPM reductions may drive O 3 -induced pulmonary inflammation.