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

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.

journal_name

Acta Pharmacol Sin

journal_title

Acta pharmacologica Sinica

authors

Liu YY,Shi Y,Liu Y,Pan XH,Zhang KX

doi

10.1038/s41401-018-0007-9

subject

Has Abstract

pub_date

2018-11-01 00:00:00

pages

1735-1745

issue

eissn

1671-4083

issn

1745-7254

pii

10.1038/s41401-018-0007-9

journal_volume

pub_type

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