Fibroblast growth factor 23 and Klotho contribute to airway inflammation.
Fibroblast growth factor 23 and Klotho contribute to airway inflammation.
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DOI：
10.1183/13993003.00236-2018
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发表时间：
2018-07
期刊：
影响因子：
--
通讯作者：
Salathe M
中科院分区：
文献类型：
--
作者：
Krick S;Grabner A;Baumlin N;Yanucil C;Helton S;Grosche A;Sailland J;Geraghty P;Viera L;Russell DW;Wells JM;Xu X;Gaggar A;Barnes J;King GD;Campos M;Faul C;Salathe M
成纤维细胞生长因子（FGF）23的循环水平与慢性肾脏疾病的全身炎症和死亡率增加有关。α-klotho是FGF 23的共受体，在慢性阻塞性肺疾病（COPD）中下调。然而，FGF 23和klotho介导的FGFR激活是否描绘了COPD的病理生理机制仍不清楚。我们假设FGF 23可以通过klotho非依赖性FGFR 4激活来增强气道炎症。使用来自COPD和对照患者的血浆和经支气管活检组织和分离自COPD患者的原代人支气管上皮细胞以及鼠COPD模型研究FGF 23及其作用。COPD患者血浆FGF 23水平显著升高。气道上皮细胞暴露于香烟烟雾和FGF 23导致IL-1β释放显著增加，这是通过非klotho依赖性FGFR 4介导的磷脂酶Cγ（PLCγ）/活化T细胞核因子（NFAT）信号转导激活实现的。此外，klotho基因敲除小鼠发展为COPD，并显示出气道炎症和肺中FGFR 4表达升高，而klotho的过表达导致气道炎症减弱。总之，香烟烟雾通过下调klotho和激活COPD气道上皮中的FGFR 4诱导气道炎症。抑制FGF 23或FGFR 4可能作为COPD的一种新型抗炎策略。
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.
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影响因子：
9.6
作者：
Fu, Juan-juan;McDonald, Vanessa M.;Gibson, Peter G.
通讯作者：
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影响因子：
3.3
作者：
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DOI：
10.1056/nejmoa0706130
发表时间：
2008-08-07
期刊：
The New England journal of medicine
影响因子：
--
作者：
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DOI：
10.1152/ajplung.00073.2016
发表时间：
2016-07-01
影响因子：
4.9
作者：
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通讯作者：
Geraghty, Patrick
影响因子：
2.5
作者：
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