TY - JOUR T1 - Fibroblast Growth Factor 23 and Klotho Contribute to Airway Inflammation JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/13993003.00236-2018 SP - 1800236 AU - Stefanie Krick AU - Alexander Grabner AU - Nathalie Baumlin AU - Christopher Yanucil AU - Scott Helton AU - Astrid Grosche AU - Juliette Sailland AU - Patrick Geraghty AU - Liliana Viera AU - Derek W. Russell AU - J. Michael Wells AU - Xin Xu AU - Amit Gaggar AU - Jarrod Barnes AU - Gwendalyn D. King AU - Michael Campos AU - Christian Faul AU - Matthias Salathe Y1 - 2018/01/01 UR - http://erj.ersjournals.com/content/early/2018/05/03/13993003.00236-2018.abstract N2 - Circulating levels of fibroblast growth factor (FGF) 23 are associated with systemic inflammation and increased mortality in chronic kidney disease. α-klotho, a co-receptor for FGF23, is downregulated in chronic obstructive pulmonary disease (COPD). However, whether FGF23 and klotho-mediated FGFR activation delineates a pathophysiologic mechanism in COPD remains unclear. We hypothesized that FGF23 can potentiate airway inflammation via klotho independent FGFR4 activation. FGF23 and its effect were studied using plasma and transbronchial biopsies from COPD and control patients and primary human bronchial epithelial cells isolated from COPD patients as well as a murine COPD model.Plasma FGF23 levels were significantly elevated in COPD patients. Exposure of airway epithelial cells to cigarette smoke and FGF23 led to a significant increase in IL-1β release via klotho-independent FGFR4-mediated activation of phospholipase Cγ(PLCγ)/nuclear factor of activated T-cells (NFAT) signaling. In addition, klotho knockout mice developed COPD and showed airway inflammation and elevated FGFR4 expression in their lungs, whereas overexpression of klotho led to an attenuation of airway inflammation.In conclusion, cigarette smoke induces airway inflammation by downregulation of klotho and activation of FGFR4 in the airway epithelium in COPD. Inhibition of FGF23 or FGFR4 might serve as a novel anti-inflammatory strategy in COPD.FGF23 and smoke induced FGF receptor 4 signaling lead to the development of airway inflammation and emphysemaFootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Krick has nothing to disclose.Conflict of interest: Dr. Grabner has nothing to disclose.Conflict of interest: Dr. Baumlin has nothing to disclose.Conflict of interest: Dr. Yanucil has nothing to disclose.Conflict of interest: Dr. Helton has nothing to disclose.Conflict of interest: Dr. Grosche has nothing to disclose.Conflict of interest: Dr. Sailland has nothing to disclose.Conflict of interest: Dr. Geraghty has nothing to disclose.Conflict of interest: Dr. Viera has nothing to disclose.Conflict of interest: Dr. Russell has nothing to disclose.Conflict of interest: Dr. Wells has nothing to disclose.Conflict of interest: Dr. Xu has nothing to disclose.Conflict of interest: Dr. Gaggar has nothing to disclose.Conflict of interest: Dr. Barnes has nothing to disclose.Conflict of interest: Dr. King has nothing to disclose.Conflict of interest: Dr. Campos has nothing to disclose.Conflict of interest: Dr. Faul has nothing to disclose.Conflict of interest: Dr. Salathe has nothing to disclose. ER -