Regulation of Lung Macrophage Activation and Oxidative Stress Following Ozone Exposure by Farnesoid X Receptor.

Inflammatory macrophages are known to contribute to ozone toxicity. Farnesoid X receptor (FXR) is a nuclear receptor involved in regulating bile acid and lipid homeostasis; it also exerts anti-inflammatory activity by suppressing macrophage NF-κB. Herein, we analyzed the role of FXR in regulating macrophage activation in the lung following ozone exposure. Treatment of wild-type (WT) mice with ozone (0.8 ppm, 3 h) resulted in increases in proinflammatory (F4/80⁺CD11c⁺CD11b⁺Ly6C^Hi) and anti-inflammatory (F4/80⁺CD11c⁺CD11b⁺Ly6C^Lo) macrophages in the lung. The accumulation of proinflammatory macrophages was increased in FXR^−/− mice compared with WT mice; however, anti-inflammatory macrophage activation was blunted as reflected by reduced arginase and mannose receptor expression, a response correlated with decreased Nur77. This was associated with prolonged oxidative stress, as measured by 4-hydroxynonenal-modified proteins in the lung. Loss of FXR was accompanied by protracted increases in lung NF-κB activity and its target, inducible nitric oxide synthase in response to ozone. Levels of Tnf-α , Il-1β , Ccr2 , Ccl2 , Cx3cr1 , and Cx3cl1 were also increased in lungs of FXR^−/− relative to WT mice; conversely, genes regulating lipid homeostasis including Lxrα , Apoe , Vldlr , Abcg1 , and Abca1 were downregulated, irrespective of ozone exposure. In FXR^−/− mice, ozone caused an increase in total lung phospholipids, with no effect on SP-B or SP-D. Dyslipidemia was correlated with blunting of ozone-induced increases in positive end-expiratory pressure-dependent quasi-static pressure volume curves indicating a stiffer lung in FXR^−/− mice. These findings identify FXR as a regulator of macrophage activation following ozone exposure suggesting that FXR ligands may be useful in mitigating inflammation and oxidative stress induced by pulmonary irritants. [ABSTRACT FROM AUTHOR]