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

Abstract

Background: Acute ozone (O3) exposure results in greater inflammation and airway hyperresponsiveness (AHR) in obese versus lean mice.Objectives: We examined the hypothesis that these augmented responses to O3 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 Cpefat and TNFR2-deficient Cpefat mice (Cpefat/TNFR2–/–), to O3 (2 ppm for 3 hr) either with or without treatment with anti–IL-13 or left them unexposed.Results: O3-induced increases in baseline pulmonary mechanics, airway responsiveness, and cellular inflammation were greater in Cpefat than in WT mice. In lean mice, TNFR2 deficiency ablated O3-induced AHR without affecting pulmonary inflammation; whereas in obese mice, TNFR2 deficiency augmented O3-induced AHR but reduced inflammatory cell recruitment. O3 increased pulmonary expression of IL-13 in Cpefat but not WT mice. Flow cytometry analysis of lung cells indicated greater IL-13–expressing CD4+ cells in Cpefat versus WT mice after O3 exposure. In Cpefat mice, anti–IL-13 treatment attenuated O3-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 Cpefat/TNFR2–/– mice. There was no effect of anti–IL-13 treatment in WT mice.Conclusions: Pulmonary responses to O3 are not just greater, but qualitatively different, in obese versus lean mice. In particular, in obese mice, O3 induces IL-13 and IL-13 synergizes with TNF via TNFR2 to exacerbate O3-induced changes in pulmonary mechanics and inflammatory cell recruitment but not AHR.

Innate and ozone-induced airway hyperresponsiveness in obese mice: role of TNF-α

“…These data suggest that exposure to this common air pollutant may be a particular problem for the obese person with asthma. Obese mice also exhibit innate AHR and have greater airway responsiveness after acute exposure to O 3 than lean mice (32,50,58,59,62).…”

“…Studies in obese mice suggest a complex role for TNF-␣ in obesity-related AHR (58,59,62). TNF-␣ can bind to either of two receptors, TNFR1 and TNFR2.…”

“…The role of TNFR2 in pulmonary responses to acute O 3 exposure also differs in lean and obese mice (10,51,59). In lean mice, TNFR2 deficiency reduces O 3 -induced AHR but does not affect O 3 -induced inflammation (10,51,59), whereas in obese mice TNFR2 deficiency augments O 3 -induced AHR but reduces O 3 -induced changes in baseline pulmonary mechanics and O 3 -induced recruitment of neutrophils and macrophages to lungs (59).…”

“…In lean mice, TNFR2 deficiency reduces O 3 -induced AHR but does not affect O 3 -induced inflammation (10,51,59), whereas in obese mice TNFR2 deficiency augments O 3 -induced AHR but reduces O 3 -induced changes in baseline pulmonary mechanics and O 3 -induced recruitment of neutrophils and macrophages to lungs (59). The impact of overall TNF-␣ deficiency on obesity-related changes in the response to O 3 has not yet been assessed but could differ from the impact of TNFR2 deficiency because of differences in TNFR1 and TNFR2 signaling described above.…”

“…A parameter-estimation model (19) was used to partition ZL into components representing Newtonian resistance (R n), which mainly reflects changes in the mechanical properties of the airways, and the coefficients of lung tissue damping (G) and lung tissue elastance (H), measures of changes in the lung periphery, including airway closure. Measurements of Rn, G, H were then obtained after inhalation of aerosols containing PBS and increasing concentrations of methacholine from 1 to 100 mg/ml, as previously described (58,59).…”