Bone Morphogenetic Protein-Inducer Tilorone Identified by High-Throughput Screening Is Antifibrotic In Vivo
Bone Morphogenetic Protein-Inducer Tilorone Identified by High-Throughput Screening Is Antifibrotic In Vivo
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DOI：
10.1165/rcmb.2012-0201oc
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发表时间：
2013-04-01
影响因子：
6.4
通讯作者：
Myllarniemi, Marjukka
中科院分区：
文献类型：
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作者：
Lepparanta, Outi;Tikkanen, Jussi M.;Myllarniemi, Marjukka
特发性肺纤维化（IPF）是一种进行性肺部疾病，预后不良，治疗选择很少。在分子水平上，IPF患者肺部骨形态发生蛋白（BMP）抑制剂gremlin的含量增加，导致BMP信号传导减少，转化生长因子β信号传导增加。基于这些发现，我们假设，受损的BMP信号传导的恢复将提供一种新的策略，用于预防纤维化进展或用于治疗肺纤维化。我们使用报告细胞系和化合物库的高通量筛选作为寻找增加肺上皮细胞中BMP信号传导而不增加转化生长因子β信号传导的分子的方法。通过研究其对BMP靶基因表达、Smad蛋白磷酸化和二氧化硅诱导的肺纤维化小鼠模型的影响，进一步分析了最有前途的候选药物。最有前途的候选药物替洛龙在报告细胞中诱导BMP信号传导，并增加肺上皮A549细胞中BMP-7和BMP靶基因Id 3的表达。在小鼠肺纤维化模型中，替洛龙降低肺羟脯氨酸含量和胶原基因Col 1A 1和Col 3A 1的表达。与未处理的小鼠相比，用替洛龙处理的小鼠显示出显著减少的组织学变化。这些发现表明，替洛龙具有生物学显著的抗纤维化特性。
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with a poor prognosis and very few therapeutic options. On the molecular level, patients with IPF have increased amounts of the bone morphogenetic protein (BMP) inhibitor gremlin in their lungs, which results in decreased BMP signaling, and an increase in transforming growth factor-beta signaling. Based on these findings, we hypothesized that restoration of the impaired BMP signaling would offer a novel strategy for the prevention of fibrosis progression or for the treatment of pulmonary fibrosis. We used reporter cell lines and high-throughput screening of a chemical compound library as an approach to finding molecules that increase BMP signaling in lung epithelial cells, without increasing transforming growth factor-beta signaling. The most promising candidate drug was analyzed further by studying its effects on BMP target gene expression, Smad protein phosphorylation, and a mouse model of silica-induced pulmonary fibrosis. The most promising drug candidate, tilorone, induced BMP signaling in the reporter cells and increased the expression of BMP-7 and a BMP target gene, Id3, in lung epithelial A549 cells. In a mouse model of pulmonary fibrosis, tilorone decreased lung hydroxyproline content and the expression of collagen genes Col1A1 and Col3A1. Mice treated with tilorone showed markedly decreased histological changes, compared with untreated mice. These findings indicate that tilorone has biologically significant antifibrotic properties.