Role of fibroblast growth factor 23 and klotho cross talk in idiopathic pulmonary fibrosis
Role of fibroblast growth factor 23 and klotho cross talk in idiopathic pulmonary fibrosis
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DOI：
10.1152/ajplung.00246.2018
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发表时间：
2019-07-01
影响因子：
4.9
通讯作者：
Krick, Stefanie
中科院分区：
文献类型：
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作者：
Barnes, Jarrod W.;Duncan, Dawn;Krick, Stefanie
特发性肺纤维化（IPF）是一种慢性进行性纤维化间质性肺炎，主要影响老年人。一些报道表明，衰老参与了IPF的潜在致病机制。α - klotho （KL）被认为是一种“年龄抑制”激素，可以防止细胞衰老和氧化应激。在这项研究中，我们评估了人类血浆和特发性肺纤维化（IPF-FB）患者的原代肺成纤维细胞以及暴露于博来霉素的小鼠肺组织中的KL水平，与对照组相比，KL水平明显下调。相反，过表达KL的转基因小鼠对博莱霉素诱导的肺纤维化具有保护作用。重组KL单独处理人肺成纤维细胞不足以抑制转化生长因子- β (tgf - β)诱导的胶原沉积和炎症标志物的表达。有趣的是，成纤维细胞生长因子23 （FGF23）是一种促炎循环蛋白，KL是其辅助受体，在IPF和博来霉素肺中上调。令我们惊讶的是，FGF23和KL共同给药导致IPF-FB的纤维化和炎症显著减少；FGF23单独或与KL联合使用可刺激KL上调。我们得出结论，在IPF中，KL的下调可能有助于纤维化和炎症，FGF23可能通过抑制tgf - β信号传导而作为代偿性抗纤维化和抗炎介质。在KL水平恢复后，FGF23和KL的结合导致炎症和纤维化的消退。总之，这些数据为FGF23/KL轴及其抗纤维化/抗炎特性提供了新的见解，为IPF等衰老相关疾病的潜在治疗开辟了新的途径。
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. alpha-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-beta (TGF-beta)-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 up-egulation. 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-beta 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.