Augmented Pulmonary Responses to Acute Ozone Exposure in Obese Mice: Roles of TNFR2 and IL-13

BACKGROUND: Acute ozone (O-3) exposure results in greater inflammation and airway hyperresponsiveness (AHR) in obese versus lean mice. OBJECTIVES: We examined the hypothesis that these augmented responses to O-3 are the result of greater signaling through tumor necrosis factor receptor 2 (TNFR2) and/or interleukin (IL)-13. METHODS: We exposed lean wild-type (WT) and TNFR2-deficient (TNFR2(-/-)) mice, and obese Cpe(fat) and TNFR2-deficient Cpe(fat) mice (Cpe(fat)/TNFR2(-/-)), to O-3 (2 ppm for 3 hr) either with or without treatment with anti-IL-13 or left them unexposed. RESULTS: O-3-induced increases in baseline pulmonary mechanics, airway responsiveness, and cellular inflammation were greater in Cpe(fat) than in WT mice. In lean mice, TNFR2 deficiency ablated O-3-induced AHR without affecting pulmonary inflammation; whereas in obese mice, TNFR2 deficiency augmented O-3-induced AHR but reduced inflammatory cell recruitment. O-3 increased pulmonary expression of IL-13 in Cpe(fat) but not WT mice. Flow cytometry analysis of lung cells indicated greater IL-13-expressing CD4(+) cells in Cpe(fat) versus WT mice after O-3 exposure. In Cpe(fat) mice, anti-IL-13 treatment attenuated O-3-induced increases in pulmonary mechanics and inflammatory cell recruitment, but did not affect AHR. These effects of anti-IL-13 treatment were not observed in Cpe(fat)/TNFR2(-/-) mice. There was no effect of anti-IL-13 treatment in WT mice. CONCLUSIONS: Pulmonary responses to O-3 are not just greater, but qualitatively different, in obese versus lean mice. In particular, in obese mice, O-3 induces IL-13 and IL-13 synergizes with TNF via TNFR2 to exacerbate O-3-induced changes in pulmonary mechanics and inflammatory cell recruitment but not AHR.