Lung-specific overexpression of constitutively active IKK2 induces pulmonary and systemic inflammations but not hypothalamic inflammation and glucose intolerance
PublisherOxford University Press
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AbstractThe lung is constantly exposed to ambient pollutants such as ambient fine particulate matter (PM2.5), making it one of the most frequent locations of inflammation in the body. Given the establishment of crucial role of inflammation in the pathogenesis of cardiometabolic diseases, pulmonary inflammation is thus widely believed to be an important risk factor for cardiometabolic diseases. However, the causality between them has not yet been well established. To determine if pulmonary inflammation is sufficient to cause adverse cardiometabolic effects, SFTPC-rtTA+/–tetO-cre+/–pROSA-inhibitor κB kinase 2(IKK2)ca+/– (LungIKK2ca) and littermate SFTPC-rtTA+/–tetO-cre–/–pROSA-IKK2ca+/– wildtype (WT) mice were fed with doxycycline diet to induce constitutively active Ikk2 (Ikk2ca) overexpression in the lung and their pulmonary, systemic, adipose, and hypothalamic inflammations, vascular function, and glucose homeostasis were assessed. Feeding with doxycycline diet resulted in IKK2ca overexpression in the lungs of LungIKK2ca but not WT mice. This induction of IKK2ca was accompanied by marked pulmonary inflammation as evidenced by significant increases in bronchoalveolar lavage fluid leukocytes, pulmonary macrophage infiltration, and pulmonary mRNA expression of tumor necrosis factor α (Tnfα) and interleukin-6 (Il-6). This pulmonary inflammation due to lung-specific overexpression of IKK2ca was sufficient to increase circulating TNFα and IL-6 levels, adipose expression of Tnfα and Il-6 mRNA, aortic endothelial dysfunction, and systemic insulin resistance. Unexpectedly, no significant alteration in hypothalamic expression of Tnfα and Il-6 mRNA and glucose intolerance were observed in these mice. Pulmonary inflammation is sufficient to induce systemic inflammation, endothelial dysfunction, and insulin resistance, but not hypothalamic inflammation and glucose intolerance. Copyright The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.
SponsorsNational Institutes of Health (R01ES024516 to Z.Y.); the American Heart Association (13SDG17070131 to Z.Y.); the National Natural Science Foundation of China (81270342 to Z.Y., 81500216 to M.C., and 81302452 to L.Q.); Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning (SSF201008) and Shanghai 3-Year Public Health Action Plan (GWTD2015S04) to Z.Y.
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85038036696&doi=10.1093%2ftoxsci%2fkfx154&partnerID=40&md5=f407aaafd50ebdc7ff9e18a6daa33a17; http://hdl.handle.net/10713/9952
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