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1.
Am J Physiol Lung Cell Mol Physiol ; 308(11): L1168-77, 2015 Jun 01.
Article in English | MEDLINE | ID: mdl-25840999

ABSTRACT

Innate airway hyperresponsiveness (AHR) and augmented responses to ozone, an asthma trigger, are characteristics of obese mice. Systemic inflammation, a condition of increased circulating concentrations of inflammatory moieties, occurs in obesity. We hypothesized that TNF-α, via its effects as a master effector of this systemic inflammation, regulates innate AHR and augmented responses to ozone in obese mice. Therefore, we examined pulmonary inflammation and airway responsiveness in unexposed or ozone-exposed (2 ppm for 3 h) lean wild-type and obese Cpe(fat) mice that were TNF-α sufficient or deficient. Cpe(fat) mice lack carboxypeptidase E, which regulates satiety. Compared with wild type, Cpe(fat) mice had elevated serum IL-17A, G-CSF, KC, MCP-1, IL-9, MIG, and leptin, indicating systemic inflammation. Despite reductions in most of these moieties in TNF-α-deficient vs. -sufficient Cpe(fat) mice, we observed no substantial difference in airway responsiveness in these two groups of mice. Ozone-induced increases in bronchoalveolar lavage (BAL) neutrophils and macrophages were lower, but ozone-induced AHR and increases in BAL hyaluronan, osteopontin, IL-13, and protein carbonyls, a marker of oxidative stress, were augmented in TNF-α-deficient vs. -sufficient Cpe(fat) mice. Our data indicate that TNF-α has an important role in promoting the systemic inflammation but not the innate AHR of obesity, suggesting that the systemic inflammation of obesity is not the major driver of this AHR. TNF-α is required for the augmented effects of acute ozone exposure on pulmonary inflammatory cell recruitment in obese mice, whereas TNF-α protects against ozone-induced AHR in obese mice, possibly by suppressing ozone-induced oxidative stress.


Subject(s)
Asthma/immunology , Tumor Necrosis Factor-alpha/physiology , Animals , Asthma/chemically induced , Asthma/metabolism , Female , Gene Expression , Macrophages/immunology , Male , Mice, Inbred C57BL , Mice, Knockout , Mice, Obese , Neutrophil Infiltration , Oxidative Stress , Ozone
2.
Environ Health Perspect ; 121(5): 551-7, 2013 May.
Article in English | MEDLINE | ID: mdl-23434795

ABSTRACT

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.


Subject(s)
Interleukin-13/physiology , Lung/drug effects , Ozone/toxicity , Receptors, Tumor Necrosis Factor, Type II/physiology , Animals , Chemokine CCL20/biosynthesis , Female , Lung/immunology , Mice , Mice, Inbred C57BL , Mice, Obese
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