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Eur Respir J. 2018 Jul 4;52(1). pii: 1800236. doi: 10.1183/13993003.00236-2018. Print 2018 Jul.

Fibroblast growth factor 23 and Klotho contribute to airway inflammation.

Author information

1
Division of Pulmonary, Allergy and Critical Care Medicine, Dept of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA.
2
Division of Nephrology, Dept of Medicine, Duke University Medical Center, Duke University, Durham, NC, USA.
3
Division of Pulmonary, Critical Care and Sleep Medicine, Dept of Medicine, University of Miami Leonard M. Miller School of Medicine, Miami, FL, USA.
4
Division of Nephrology, Dept of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA.
5
Division of Pulmonary and Critical Care Medicine, Dept of Medicine, State University of New York Downstate Medical Center, Brooklyn, NY, USA.
6
UAB Lung Health Center, Birmingham, AL, USA.
7
Dept of Neurobiology, The University of Alabama at Birmingham, Birmingham, AL, USA.
8
Both senior authors contributed equally to this work.

Abstract

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 FGF receptor (FGFR) activation delineates a pathophysiological mechanism in COPD remains unclear. We hypothesised 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 interleukin-1β release via Klotho-independent FGFR4-mediated activation of phospholipase Cγ/nuclear factor of activated T-cells signalling. 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.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.

PMID:
29748308
PMCID:
PMC6044452
DOI:
10.1183/13993003.00236-2018
[Indexed for MEDLINE]
Free PMC Article

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