Telomere shortening activates TGF-β/Smads signaling in lungs and enhances both lipopolysaccharide and bleomycin-induced pulmonary fibrosis. (November 2018)

• Record Type: Journal Article
• Authors: Liu, Ying-ying; Shi, Yao; Liu, Ya; Pan, Xing-hua; Zhang, Ke-xiong
• Is Part Of: Acta pharmacologica Sinica. Volume 39:Number 11(2018)
• Page Start: 1735
• Page End: 1745
• Publication Date: 2018-11
• Subjects: telomerase -- telomere shortening -- TGF-β/Smads -- pulmonary fibrosis -- lipopolysaccharide -- bleomycin; Pharmacology -- Periodicals; 615.105
• DOI: 10.1038/s41401-018-0007-9
• Languages: English
• ISSNs: 1671-4083

Abstract

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) knockoutTerc − /− mice with short telomeres were treated with and without lipopolysaccharide (LPS) or bleomycin by intratracheal injection. We show that under LPS induction, G3Terc − /− 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 G3Terc − /− 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 G3Terc − /− mice compared with those of LPS-treated WT or untreated G3Terc − /− 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 G3Terc − /− 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.