TY - JOUR
T1 - Repeated ozone exposure exacerbates insulin resistance and activates innate immune response in genetically susceptible mice
AU - Zhong, Jixin
AU - Allen, Katryn
AU - Rao, Xiaoquan
AU - Ying, Zhekang
AU - Braunstein, Zachary
AU - Kankanala, Saumya R.
AU - Xia, Chang
AU - Wang, Xiaoke
AU - Bramble, Lori A.
AU - Wagner, James G.
AU - Lewandowski, Ryan
AU - Sun, Qinghua
AU - Harkema, Jack R.
AU - Rajagopalan, Sanjay
N1 - Publisher Copyright:
© 2016 Informa UK Limited, trading as Taylor & Francis Group.
PY - 2016/7/28
Y1 - 2016/7/28
N2 - 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.
AB - 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.
KW - Air pollution
KW - inflammation
KW - insulin resistance
KW - oxidative stress
KW - ozone exposure
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U2 - 10.1080/08958378.2016.1179373
DO - 10.1080/08958378.2016.1179373
M3 - Article
C2 - 27240593
AN - SCOPUS:84973103440
SN - 0895-8378
VL - 28
SP - 383
EP - 392
JO - Inhalation Toxicology
JF - Inhalation Toxicology
IS - 9
ER -