Repeated ozone exposure exacerbates insulin resistance and activates innate immune response in genetically susceptible mice

Jixin Zhong, Katryn Allen, Xiaoquan Rao, Zhekang Ying, Zachary Braunstein, Saumya R. Kankanala, Chang Xia, Xiaoke Wang, Lori A. Bramble, James G. Wagner, Ryan Lewandowski, Qinghua Sun, Jack R. Harkema, Sanjay Rajagopalan

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Inhaled ozone (O3) has been demonstrated as a harmful pollutant and associated with chronic inflammatory diseases such as diabetes and vascular disorders. However, the underlying mechanisms by which O3 mediates harmful effects are poorly understood. Objectives: To investigate the effect of O3 exposure on glucose intolerance, immune activation and underlying mechanisms in a genetically susceptible mouse model. Methods: Diabetes-prone KK mice were exposed to filtered air (FA), or O3 (0.5 ppm) for 13 consecutive weekdays (4 h/day). Insulin tolerance test (ITT) was performed following the last exposure. Plasma insulin, adiponectin, and leptin were measured by ELISA. Pathologic changes were examined by H&E and Oil-Red-O staining. Inflammatory responses were detected using flow cytometry and real-time PCR. Results: KK mice exposed to O3 displayed an impaired insulin response. Plasma insulin and leptin levels were reduced in O3-exposed mice. Three-week exposure to O3 induced lung inflammation and increased monocytes/macrophages in both blood and visceral adipose tissue. Inflammatory monocytes/macrophages increased both systemically and locally. CD4 + T cell activation was also enhanced by the exposure of O3 although the relative percentage of CD4 + T cell decreased in blood and adipose tissue. Multiple inflammatory genes including CXCL-11, IFN-γ, TNFα, IL-12, and iNOS were up-regulated in visceral adipose tissue. Furthermore, the expression of oxidative stress-related genes such as Cox4, Cox5a, Scd1, Nrf1, and Nrf2, increased in visceral adipose tissue of O3-exposed mice. Conclusions: Repeated O3 inhalation induces oxidative stress, adipose inflammation and insulin resistance.

Original languageEnglish (US)
Pages (from-to)383-392
Number of pages10
JournalInhalation Toxicology
Volume28
Issue number9
DOIs
StatePublished - Jul 28 2016
Externally publishedYes

Keywords

  • Air pollution
  • inflammation
  • insulin resistance
  • oxidative stress
  • ozone exposure

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

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    Zhong, J., Allen, K., Rao, X., Ying, Z., Braunstein, Z., Kankanala, S. R., Xia, C., Wang, X., Bramble, L. A., Wagner, J. G., Lewandowski, R., Sun, Q., Harkema, J. R., & Rajagopalan, S. (2016). Repeated ozone exposure exacerbates insulin resistance and activates innate immune response in genetically susceptible mice. Inhalation Toxicology, 28(9), 383-392. https://doi.org/10.1080/08958378.2016.1179373