Role of fibroblast growth factor 23 and klotho cross talk in idiopathic pulmonary fibrosis

Autor: Samuel B. Hutcheson, Tejaswini Kulkarni, Hai T. Vo, Dominik Kentrup, Joao A. de Andrade, Jarrod W. Barnes, Sadis Matalon, Christian Faul, Naomi J. Logsdon, Carol Farver, Deepali Kurundkar, Jaleesa M. Garth, Stefanie Krick, Morgan L. Locy, Scott Helton, Victor J. Thannickal, R. Denson, Zhihong Yu, Gwendalyn D. King, Dawn Duncan
Rok vydání: 2019
Předmět:
Male
0301 basic medicine
Pulmonary and Respiratory Medicine
Fibroblast growth factor 23
Pathology
medicine.medical_specialty
Physiology
Acute Lung Injury
Primary Cell Culture
Mice
Transgenic
Inflammation
Kidney Function Tests
Bleomycin
Mice
03 medical and health sciences
Idiopathic pulmonary fibrosis
0302 clinical medicine
Transforming Growth Factor beta
Physiology (medical)
medicine
Animals
Humans
Interstitial pneumonia
Klotho Proteins
Lung
Klotho
Aged
Glucuronidase
business.industry
Cell Biology
Fibroblasts
Middle Aged
respiratory system
medicine.disease
Idiopathic Pulmonary Fibrosis
Respiratory Function Tests
respiratory tract diseases
Fibroblast Growth Factors
Fibroblast Growth Factor-23
030104 developmental biology
Gene Expression Regulation
030228 respiratory system
Case-Control Studies
Female
Collagen
medicine.symptom
business
Signal Transduction
Research Article
Zdroj: Am J Physiol Lung Cell Mol Physiol
ISSN: 1522-1504
1040-0605
Popis: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial pneumonia that mainly affects the elderly. Several reports have demonstrated that aging is involved in the underlying pathogenic mechanisms of IPF. α-Klotho (KL) has been well characterized as an “age-suppressing” hormone and can provide protection against cellular senescence and oxidative stress. In this study, KL levels were assessed in human plasma and primary lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF-FB) and in lung tissue from mice exposed to bleomycin, which showed significant downregulation when compared with controls. Conversely, transgenic mice overexpressing KL were protected against bleomycin-induced lung fibrosis. Treatment of human lung fibroblasts with recombinant KL alone was not sufficient to inhibit transforming growth factor-β (TGF-β)-induced collagen deposition and inflammatory marker expression. Interestingly, fibroblast growth factor 23 (FGF23), a proinflammatory circulating protein for which KL is a coreceptor, was upregulated in IPF and bleomycin lungs. To our surprise, FGF23 and KL coadministration led to a significant reduction in fibrosis and inflammation in IPF-FB; FGF23 administration alone or in combination with KL stimulated KL upregulation. We conclude that in IPF downregulation of KL may contribute to fibrosis and inflammation and FGF23 may act as a compensatory antifibrotic and anti-inflammatory mediator via inhibition of TGF-β signaling. Upon restoration of KL levels, the combination of FGF23 and KL leads to resolution of inflammation and fibrosis. Altogether, these data provide novel insight into the FGF23/KL axis and its antifibrotic/anti-inflammatory properties, which opens new avenues for potential therapies in aging-related diseases like IPF.
Databáze: OpenAIRE
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