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Telomere shortening activates TGF-β/Smads signaling in lungs and enhances both lipopolysaccharide and bleomycin-induced pulmonary fibrosis.
Acta Pharmacologica Sinica ( IF 8.2 ) Pub Date : 2018-Nov-01 , DOI: 10.1038/s41401-018-0007-9
Ying-ying Liu , Yao Shi , Ya Liu , Xing-hua Pan , Ke-xiong Zhang

Telomere shortening is associated with idiopathic pulmonary fibrosis (IPF), a high-morbidity and high-mortality lung disease of unknown etiology. However, the underlying mechanisms remain largely unclear. In this study, wild-type (WT) mice with normal telomeres and generation 3 (G3) or G2 telomerase RNA component (TERC) knockout Terc-/- mice with short telomeres were treated with and without lipopolysaccharide (LPS) or bleomycin by intratracheal injection. We show that under LPS induction, G3 Terc-/- mice develop aggravated pulmonary fibrosis as indicated by significantly increased α-SMA, collagen I and hydroxyproline content. Interestingly, TGF-β/Smads signaling is markedly activated in the lungs of G3 Terc-/- mice, as indicated by markedly elevated levels of phosphorylated Smad3 and TGF-β1, compared with those of WT mice. This TGF-β/Smads signaling activation is significantly increased in the lungs of LPS-treated G3 Terc-/- mice compared with those of LPS-treated WT or untreated G3 Terc-/- mice. A similar pattern of TGF-β/Smads signaling activation and the enhancing role of telomere shortening in pulmonary fibrosis are also confirmed in bleomycin-induced model. Moreover, LPS challenge produced more present cellular senescence, apoptosis and infiltration of innate immune cells, including macrophages and neutrophils in the lungs of G3 Terc-/- mice, compared with WT mice. To our knowledge, this is the first time to report telomere shortening activated TGF-β/Smads signaling in lungs. Our data suggest that telomere shortening cooperated with environment-induced lung injury accelerates the development of pulmonary fibrosis, and telomere shortening confers an inherent enhancing factor to the genesis of IPF through activation of TGF-β/Smads signaling.

中文翻译:

端粒缩短可激活肺中的TGF-β/ Smads信号传导,并增强脂多糖和博来霉素诱导的肺纤维化。

端粒缩短与特发性肺纤维化(IPF)有关,后者是病因不明的高发病率和高死亡率肺病。但是,基本机制仍不清楚。在这项研究中,对具有正常端粒和第3代(G3)或G2端粒酶RNA成分(TERC)的野生型(WT)小鼠的端粒较短的Terc - /-小鼠进行气管内治疗,无论是否使用脂多糖(LPS)或博来霉素注射。我们显示,在LPS诱导下,G3 Terc - /-小鼠发展为严重的肺纤维化,如明显增加的α-SMA,胶原蛋白I和羟脯氨酸含量所表明的。有趣的是,TGF-β/ Smads信号在G3 Terc的肺中被明显激活- /-与野生型小鼠相比,磷酸化的Smad3和TGF-β1的水平显着升高,这说明了小鼠。这种TGF-β/ Smad蛋白信号传导激活是在LPS处理的G3 TERC的肺显著增加- / -小鼠与LPS处理的WT或未经处理的G3 TERC的比较- / -小鼠。在博来霉素诱导的模型中也证实了TGF-β/ Smads信号转导激活和端粒缩短在肺纤维化中的增强作用的相似模式。此外,LPS激发产生了更多的细胞衰老,凋亡和先天免疫细胞(包括G3 Terc肺中的巨噬细胞和中性粒细胞)的浸润- /-与野生型小鼠相比。据我们所知,这是首次报道端粒缩短了肺中活化的TGF-β/ Smads信号转导。我们的数据表明端粒缩短与环境引起的肺损伤协同作用加速了肺纤维化的发展,端粒缩短通过激活TGF-β/ Smads信号传导为IPF的产生赋予了固有的增强因子。
更新日期:2018-06-20
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