@article{APS9872,
author = {Ying-ying Liu and Yao Shi and Ya Liu and Xing-hua Pan and Ke-xiong Zhang},
title = {Telomere shortening activates TGF-β/Smads signaling in lungs and enhances both lipopolysaccharide and bleomycin-induced pulmonary fibrosis},
journal = {Acta Pharmacologica Sinica},
volume = {39},
number = {11},
year = {2018},
keywords = {},
abstract = {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.},
issn = {1745-7254}, url = {http://www.chinaphar.com/article/view/9872}
}