Telomere shortening activates TGF-β/Smads signaling in lungs and enhances both lipopolysaccharide and bleomycin-induced pulmonary fibrosis

• 来源期刊: 中国药理学报（英文版）
• 关键词: telomerase telomere shortening TGF-β/Smads pulmonary fibrosis lipopolysaccharide bleomycin
• 年，卷（期）: 2018,（11）
• 页码范围: 1735-1745
• 页数: 11页
• 语种: 英文

摘要

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.