Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou, 311121, China.
Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
Acta Pharmacol Sin. 2018 Nov;39(11):1735-1745. doi: 10.1038/s41401-018-0007-9. Epub 2018 Jun 20.
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.
端粒缩短与特发性肺纤维化（IPF）有关，IPF 是一种病因不明的高发病率和高死亡率的肺部疾病。然而，其潜在机制在很大程度上仍不清楚。在这项研究中，我们使用具有正常端粒的野生型（WT）小鼠和端粒较短的第 3 代（G3）或 G2 端粒酶 RNA 成分（TERC）敲除 Terc 小鼠，通过气管内注射用或不用脂多糖（LPS）或博来霉素进行处理。我们发现，在 LPS 诱导下，G3 Terc 小鼠表现出更严重的肺纤维化，这表现为α-SMA、I 型胶原和羟脯氨酸含量显著增加。有趣的是，与 WT 小鼠相比，G3 Terc 小鼠肺部 TGF-β/Smads 信号明显激活，表现为磷酸化 Smad3 和 TGF-β1 水平显著升高。与 LPS 处理的 WT 或未处理的 G3 Terc 小鼠相比，LPS 处理的 G3 Terc 小鼠肺部 TGF-β/Smads 信号的激活显著增加。在博来霉素诱导的模型中也证实了类似的 TGF-β/Smads 信号激活模式以及端粒缩短在肺纤维化中的增强作用。此外，与 WT 小鼠相比，LPS 刺激在 G3 Terc 小鼠肺部产生更多的细胞衰老、凋亡和固有免疫细胞（包括巨噬细胞和中性粒细胞）浸润。据我们所知，这是首次报道端粒缩短在肺部激活 TGF-β/Smads 信号。我们的数据表明，端粒缩短与环境诱导的肺损伤协同作用加速了肺纤维化的发展，并且端粒缩短通过激活 TGF-β/Smads 信号赋予 IPF 发生的固有增强因素。
