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Impact of aging on pulmonary responses to acute ozone exposure in mice: role of TNFR1.

ABSTRACT: Chamber studies in adult humans indicate reduced responses to acute ozone with increasing age. Age-related changes in TNF? have been observed. TNF? induced inflammation is predominantly mediated through TNFR1.To examine the impact of aging on inflammatory responses to acute ozone exposure in mice and determine the role of TNFR1 in age-related differences.Wildtype and TNFR1 deficient (TNFR1(-/-)) mice aged 7 or 39 weeks were exposed to ozone (2?ppm for 3?h). Four hours after exposure, bronchoalveolar lavage (BAL) was performed and BAL cells, cytokines, chemokines, and protein were examined.Ozone-induced increases in BAL neutrophils and in neutrophil chemotactic factors were lower in 39- versus 7-week-old wildtype, but not (TNFR1(-/-)) mice. There was no effect of TNFR1 genotype in 7-week-old mice, but in 39-week-old mice, BAL neutrophils and BAL concentrations of MCP-1, KC, MIP-2, IL-6 and IP-10 were significantly greater following ozone exposure in TNFR1(-/-) versus wildtype mice. BAL concentrations of the soluble form of the TNFR1 receptor (sTNFR1) were substantially increased in 39-week-old versus 7-week-old mice, regardless of exposure.The data suggest that increased levels of sTNFR1 in the lungs of the 39-week-old mice may neutralize TNF? and protect these older mice against ozone-induced inflammation.

SUBMITTER: Shore SA

PROVIDER: S-EPMC3359651 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Impact of aging on pulmonary responses to acute ozone exposure in mice: role of TNFR1.

Shore Stephanie A SA Williams Erin S ES Chen Lucas L Benedito Leandro A P LA Kasahara David I DI Zhu Ming M

Inhalation toxicology 20111108 14

<h4>Context</h4>Chamber studies in adult humans indicate reduced responses to acute ozone with increasing age. Age-related changes in TNFα have been observed. TNFα induced inflammation is predominantly mediated through TNFR1.<h4>Objective</h4>To examine the impact of aging on inflammatory responses to acute ozone exposure in mice and determine the role of TNFR1 in age-related differences.<h4>Materials and methods</h4>Wildtype and TNFR1 deficient (TNFR1(-/-)) mice aged 7 or 39 weeks were exposed ...[more]

PMID: 22066571

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Project description:BackgroundInterleukin-33 is released in the airways following acute ozone exposure and has the ability to cause airway hyperresponsiveness, a defining feature of asthma. Ozone causes greater airway hyperresponsiveness in male than female mice. Moreover, sex differences in the gut microbiome account for sex differences in this response to ozone. The purpose of this study was to determine whether there were sex differences in the role of interleukin-33 in ozone-induced airway hyperresponsiveness and to examine the role of the microbiome in these events.MethodsWildtype mice and mice genetically deficient in ST2, the interleukin-33 receptor, were housed from weaning with either other mice of the same genotype and sex, or with mice of the same sex but opposite genotype. At 15 weeks of age, fecal pellets were harvested for 16S rRNA sequencing and the mice were then exposed to air or ozone. Airway responsiveness was measured and a bronchoalveolar lavage was performed 24 h after exposure.ResultsIn same-housed mice, ozone-induced airway hyperresponsiveness was greater in male than female wildtype mice. ST2 deficiency reduced ozone-induced airway hyperresponsiveness in male but not female mice and abolished sex differences in the response to ozone. However, sex differences in the role of interleukin-33 were unrelated to type 2 cytokine release: ozone-induced increases in bronchoalveolar lavage interleukin-5 were greater in females than males and ST2 deficiency virtually abolished interleukin-5 in both sexes. Since gut microbiota contribute to sex differences in ozone-induced airway hyperresponsiveness, we examined the role of the microbiome in these ST2-dependent sex differences. To do so, we cohoused wildtype and ST2 deficient mice, a situation that allows for transfer of microbiota among cage-mates. Cohousing altered the gut microbial community structure, as indicated by 16S rRNA gene sequencing of fecal DNA and reversed the effect of ST2 deficiency on pulmonary responses to ozone in male mice.ConclusionsThe data indicate that the interleukin-33 /ST2 pathway contributes to ozone-induced airway hyperresponsiveness in male mice and suggest that the role of interleukin-33 is mediated at the level of the gut microbiome.

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Impact of aging on pulmonary responses to acute ozone exposure in mice: role of TNFR1.

Publications

Impact of aging on pulmonary responses to acute ozone exposure in mice: role of TNFR1.

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