Reduced expression of BMP3 contributes to the development of pulmonary fibrosis and predicts the unfavorable prognosis in IIP patients.
Reduced expression of BMP3 contributes to the development of pulmonary fibrosis and predicts the unfavorable prognosis in IIP patients.
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BMP3表达减少有助于肺纤维化的发展并预测IIP患者的不良预后
DOI：
10.18632/oncotarget.20083
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发表时间：
2017-10-06
期刊：
影响因子：
--
通讯作者：
Yi X
中科院分区：
文献类型：
--
作者：
Yu X;Gu P;Huang Z;Fang X;Jiang Y;Luo Q;Li X;Zhu X;Zhan M;Wang J;Fan L;Chen R;Yu J;Gu Y;Liang A;Yi X
特发性肺纤维化（IPF）和特发性非特异性间质性肺炎（INSIP）是两种相关的疾病，涉及不同程度的肺纤维化，目前尚无有效的治疗方法。骨形态发生蛋白3（BMP 3）是转化生长因子β（TGF-β）超家族的成员之一，在肺纤维化的发病机制中未见报道。本研究旨在探讨BMP 3在肺纤维化中从临床诊断到分子信号调节的潜在作用。进行RNA测序以探索IIP患者的潜在生物标志物。采用免疫组化法检测83例IPF和INSIP中BMP 3的表达。在成纤维细胞和博来霉素诱导的小鼠肺纤维化模型中研究BMP 3的功能。对83例有5年以上随访资料的47例IIP患者进行BMP 3表达的临床相关性分析。RNA测序和免疫组化染色均显示，IPF和INSIP患者肺组织中BMP 3显著下调。BMP 3在博莱霉素诱导的小鼠肺纤维化组织中表达降低。BMP 3的上调可能通过抑制成纤维细胞的增殖和TGF-β1信号转导而阻止肺纤维化的发生。最后，IPF患者中BMP 3相对较高的表达与较低/较差的死亡率相关。静脉注射重组BMP 3。因此，BMP 3的低表达可能提示IPF患者预后不良，以BMP 3为靶点可能是治疗肺纤维化的一种新的潜在方法。
Idiopathic pulmonary fibrosis (IPF) and idiopathic nonspecific interstitial pneumonia (INSIP) are two related diseases involving varying degrees of pulmonary fibrosis with no effective cure. Bone morphogenetic protein 3 (BMP3) is a member of the transforming growth factor-β (TGF-β) super-family, which has not been implicated in pulmonary fibrosis previously. In this study, we aimed to investigate the potential role of BMP3 playing in pulmonary fibrosis from clinical diagnosis to molecular signaling regulation. RNA sequencing was performed to explore the potential biomarker of IIP patients. The expression of BMP3 was evaluated in 83 cases of IPF and INSIP by immunohistochemistry. The function of BMP3 was investigated in both fibroblast cells and a bleomycin-induced murine pulmonary fibrosis model. The clinical relevance of BMP3 expression were analyzed in 47 IIP patients, which were included in 83 cases and possess more than five-year follow-up data. Both RNA-sequencing and immunohistochemistry staining revealed that BMP3 was significantly down-regulated in lung tissues of patients with IPF and INSIP. Consistently, lower expression of BMP3 also was found in pulmonary fibrotic tissues of bleomycin-induced mice model. Up-regulation of BMP3 prevented pulmonary fibrosis processing through inhibiting cellular proliferation of fibroblasts as well as TGF-β1 signal transduction. Finally, the relatively higher expression of BMP3 in IPF patients was associated with less/worse mortality. Intravenous injection of recombinant BMP3. Taken together, our results suggested that the low expression level of BMP3 may indicate the unfavorable prognosis of IPF patients, targeting BMP3 may represent a novel potential therapeutic method for pulmonary fibrosis management.
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