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Title: Obesity and airway responsiveness: role of TNFR2.

Authors: Williams, Alison S; Chen, Lucas; Kasahara, David I; Si, Huiqing; Wurmbrand, Allison P; Shore, Stephanie A

Published In Pulm Pharmacol Ther, (2013 Aug)

Abstract: Obese mice exhibit innate airway hyperresponsiveness (AHR), a feature of asthma. Tumor necrosis factor alpha (TNFα) is implicated in the disease progression and chronic inflammatory status of both obesity and asthma. TNF acts via two TNF receptors, TNFR1 and TNFR2. To examine the role of TNFR2 in the AHR observed in obese mice, we generated obese Cpe(fat) mice that were either sufficient or deficient in TNFR2 (Cpe(fat) and Cpe(fat)/TNFR2(-/-) mice, respectively) and compared them with their lean controls (WT and TNFR2(-/-) mice). Compared to WT mice, Cpe(fat) mice exhibited AHR to aerosolized methacholine (measured using the forced oscillation technique) which was ablated in Cpe(fat)/TNFR2(-/-) mice. Bioplex or ELISA assay indicated significant increases in serum leptin, G-CSF, IL-7, IL-17A, TNFα, and KC in obese versus lean mice, as well as significant obesity-related increases in bronchoalveolar lavage fluid (BALF) G-CSF and IP-10, regardless of TNFR2 status. Importantly, BALF IL-17A was significantly increased over lean controls in Cpe(fat) but not Cpe(fat)/TNFR2(-/-) mice. Functional annotation clustering of significantly affected genes identified from microarray analysis comparing gene expression in lungs of Cpe(fat) and WT mice, identified blood vessel morphogenesis as the gene ontology category most affected by obesity. This category included several genes associated with AHR, including endothelin and trkB. Obesity increased pulmonary mRNA expression of endothelin and trkB in TNFR2 sufficient but not deficient mice. Our results indicate that TNFR2 signaling is required for the innate AHR that develops in obese mice, and suggest that TNFR2 may act by promoting IL-17A, endothelin, and/or trkB expression.

PubMed ID: 22584291 Exiting the NIEHS site

MeSH Terms: Animals; Bronchial Hyperreactivity/physiopathology*; Bronchoalveolar Lavage Fluid/chemistry; Endothelins/genetics; Female; Gene Expression Regulation; Interleukin-17/genetics; Lung/metabolism*; Methacholine Chloride/pharmacology; Mice; Mice, Inbred C57BL; Mice, Knockout; Microarray Analysis; Obesity/physiopathology*; RNA, Messenger/metabolism; Receptor, trkB/genetics; Receptors, Tumor Necrosis Factor, Type II/genetics*; Signal Transduction/physiology

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