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 CD(4+) 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.