title: Innate and ozone-induced airway hyperresponsiveness in obese mice: role of TNF-α.
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.
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Alison Suzanne
authors.initials: AS
authors.lastname: Williams
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Joel Andrew
authors.initials: JA
authors.lastname: Mathews
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts.
authors.forename: David Itiro
authors.initials: DI
authors.lastname: Kasahara
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Allison Patricia
authors.initials: AP
authors.lastname: Wurmbrand
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Lucas
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts sshore@hsph.harvard.edu.
authors.forename: Stephanie Ann
authors.initials: SA
authors.lastname: Shore
mesh_terms: D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D008264:Macrophages / Q000276:immunology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D020556:Neutrophil Infiltration; D018384:Oxidative Stress; D010126:Ozone; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D010126:Ozone
keywords: IL-13; bronchoalveolar lavage; hyaluronan; osteopontin; systemic inflammation
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