title: Repeated ozone exposure exacerbates insulin resistance and activates innate immune response in genetically susceptible mice.
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.
  
  
  
  To investigate the effect of O3 exposure on glucose intolerance, immune activation and underlying mechanisms in a genetically susceptible mouse model.
  
  
  
  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.
  
  
  
  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.
  
  
  
  Repeated O3 inhalation induces oxidative stress, adipose inflammation and insulin resistance.
authors.affiliation: a Division of Cardiovascular Medicine , Department of Medicine, University of Maryland School of Medicine , Baltimore , MD , USA .
authors.forename: Jixin
authors.initials: J
authors.lastname: Zhong
authors.affiliation: b EPA Great Lakes Clean Air Research Center, Michigan State University , East Lansing , MI , USA .
authors.forename: Katryn
authors.initials: K
authors.lastname: Allen
authors.affiliation: a Division of Cardiovascular Medicine , Department of Medicine, University of Maryland School of Medicine , Baltimore , MD , USA .
authors.forename: Xiaoquan
authors.initials: X
authors.lastname: Rao
authors.affiliation: a Division of Cardiovascular Medicine , Department of Medicine, University of Maryland School of Medicine , Baltimore , MD , USA .
authors.forename: Zhekang
authors.initials: Z
authors.lastname: Ying
authors.affiliation: c Boonshoft School of Medicine, Wright State University , Dayton , OH , USA , and.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Braunstein
authors.affiliation: a Division of Cardiovascular Medicine , Department of Medicine, University of Maryland School of Medicine , Baltimore , MD , USA .
authors.forename: Saumya R
authors.initials: SR
authors.lastname: Kankanala
authors.affiliation: a Division of Cardiovascular Medicine , Department of Medicine, University of Maryland School of Medicine , Baltimore , MD , USA .
authors.forename: Chang
authors.initials: C
authors.lastname: Xia
authors.affiliation: a Division of Cardiovascular Medicine , Department of Medicine, University of Maryland School of Medicine , Baltimore , MD , USA .
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Wang
authors.affiliation: b EPA Great Lakes Clean Air Research Center, Michigan State University , East Lansing , MI , USA .
authors.forename: Lori A
authors.initials: LA
authors.lastname: Bramble
authors.affiliation: b EPA Great Lakes Clean Air Research Center, Michigan State University , East Lansing , MI , USA .
authors.forename: James G
authors.initials: JG
authors.lastname: Wagner
authors.affiliation: b EPA Great Lakes Clean Air Research Center, Michigan State University , East Lansing , MI , USA .
authors.forename: Ryan
authors.initials: R
authors.lastname: Lewandowski
authors.affiliation: d Davis Heart & Lung Research Institute, Department of Internal Medicine, the Ohio State University , Columbus , OH , USA.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Sun
authors.affiliation: b EPA Great Lakes Clean Air Research Center, Michigan State University , East Lansing , MI , USA .
authors.forename: Jack R
authors.initials: JR
authors.lastname: Harkema
authors.affiliation: a Division of Cardiovascular Medicine , Department of Medicine, University of Maryland School of Medicine , Baltimore , MD , USA .
authors.forename: Sanjay
authors.initials: S
authors.lastname: Rajagopalan
mesh_terms: D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D015870:Gene Expression / Q000187:drug effects; D007113:Immunity, Innate / Q000187:drug effects* / Q000235:genetics; D019570:Inhalation Exposure / Q000009:adverse effects*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics*; D020738:Leptin / Q000097:blood; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008815:Mice, Inbred Strains; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D010126:Ozone / Q000633:toxicity*
chemical_list: D000393:Air Pollutants; D007328:Insulin; D020738:Leptin; D010126:Ozone
keywords: Air pollution; inflammation; insulin resistance; oxidative stress; ozone exposure