Abstract:
:Cellular senescence has been implicated in diverse pathologies. However, there is conflicting evidence regarding the role of this process in tissue fibrosis. Although dysregulation of microRNAs is a key mechanism in the pathogenesis of lung fibrosis, it is unclear whether microRNAs function by regulating cellular senescence in the disease. In this study, we found that miR-34a demonstrated greater expression in the lungs of patients with idiopathic pulmonary fibrosis and in mice with experimental pulmonary fibrosis, with its primary localization in lung fibroblasts. More importantly, miR-34a was up-regulated significantly in both human and mouse lung myofibroblasts. We found that mice with miR-34a ablation developed more severe pulmonary fibrosis than did wild-type animals after fibrotic lung injury. Mechanistically, we found that miR-34a induced a senescent phenotype in lung fibroblasts because this microRNA increased senescence-associated β-galactosidase activity, enhanced expression of senescence markers, and decreased cell proliferative capacities. Consistently, we found that primary lung fibroblasts from fibrotic lungs of miR-34a-deficient mice had a diminished senescent phenotype and enhanced resistance to apoptosis as compared with those from wild-type animals. We also identified multiple miR-34a targets that likely mediated its activities in inducing senescence in lung fibroblasts. In conclusion, our data suggest that miR-34a functions through a negative feedback mechanism to restrain fibrotic response in the lungs by promoting senescence of pulmonary fibroblasts.
journal_name
Am J Respir Cell Mol Biolauthors
Cui H,Ge J,Xie N,Banerjee S,Zhou Y,Antony VB,Thannickal VJ,Liu Gdoi
10.1165/rcmb.2016-0163OCsubject
Has Abstractpub_date
2017-02-01 00:00:00pages
168-178issue
2eissn
1044-1549issn
1535-4989journal_volume
56pub_type
杂志文章abstract::Endothelin-1 is a potent bronchoconstrictor peptide with pro-inflammatory and growth-promoting properties. After exposure of sensitized Brown-Norway rats to six repeated ovalbumin exposures, there was an increase in pro-endothelin (ET)-1 messenger RNA compared with saline-exposed control rats 24 h after the final expo...
journal_title:American journal of respiratory cell and molecular biology
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journal_title:American journal of respiratory cell and molecular biology
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journal_title:American journal of respiratory cell and molecular biology
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journal_title:American journal of respiratory cell and molecular biology
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journal_title:American journal of respiratory cell and molecular biology
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journal_title:American journal of respiratory cell and molecular biology
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doi:10.1165/rcmb.2013-0187OC
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journal_title:American journal of respiratory cell and molecular biology
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journal_title:American journal of respiratory cell and molecular biology
pub_type: 杂志文章
doi:10.1165/rcmb.2014-0231OC
更新日期:2015-09-01 00:00:00
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journal_title:American journal of respiratory cell and molecular biology
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