IPF lung fibroblasts have a senescent phenotype

被引:235
作者
Alvarez, Diana [1 ,2 ]
Cardenes, Nayra [1 ,2 ]
Sellares, Jacobo [1 ,2 ]
Bueno, Marta [3 ]
Corey, Catherine [3 ]
Hanumanthu, Vidya Sagar [4 ]
Peng, Yating [1 ,2 ]
D'Cunha, Hannah [1 ,2 ]
Sembrat, John [1 ,2 ]
Nouraie, Mehdi [2 ,3 ]
Shanker, Swaroop [1 ,2 ]
Caufield, Chandler [1 ,2 ]
Shiva, Sruti [3 ]
Armanios, Mary [5 ]
Mora, Ana L. [2 ,3 ]
Rojas, Mauricio [1 ,2 ,3 ,4 ]
机构
[1] Dorothy P & Richard P Simmons Ctr Interstitial Lu, Pittsburgh, PA USA
[2] Univ Pittsburgh, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA USA
[3] Univ Pittsburgh, Vasc Med Inst, Pittsburgh, PA USA
[4] Univ Pittsburgh, McGowan Inst Regenerat Med, Pittsburgh, PA USA
[5] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA
关键词
idiopathic pulmonary fibrosis; fibroblasts; senescence; aging; telomeres; mitochondria; TGF-beta; collagen; IDIOPATHIC PULMONARY-FIBROSIS; ENDOPLASMIC-RETICULUM STRESS; CELLULAR SENESCENCE; TELOMERE SYNDROMES; DISEASE; LENGTH; DIFFERENTIATION; IDENTIFICATION; PROLIFERATION; PARADIGMS;
D O I
10.1152/ajplung.00220.2017
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
The mechanisms of aging that are involved in the development of idiopathic pulmonary fibrosis (IPF) are still unclear. Although it has been hypothesized that the proliferation and activation of human lung fibroblasts (hLFs) are essential in IPF, no studies have assessed how this process works in an aging lung. Our goal was to elucidate if there were age-related changes on primary hLFs isolated from IPF lungs compared with age-matched controls. We investigated several hallmarks of aging in hLFs from IPF patients and age-matched controls. IPF hLFs have increased cellular senescence with higher expression of beta-galactosidase, p21, p16, p53, and cytokines related to the senescence-associated secretory phenotype (SASP) as well as decreased proliferation/apoptosis compared with age-matched controls. Additionally, we observed shorter telomeres, mitochondrial dysfunction, and upon transforming growth factor-beta stimulation, increased markers of endoplasmic reticulum stress. Our data suggest that IPF hLFs develop senescence resulting in a decreased apoptosis and that the development of SASP may be an important contributor to the fibrotic process observed in IPF. These results might change the existing paradigm, which describes fibroblasts as aberrantly activated cells, to a cell with a senescence phenotype.
引用
收藏
页码:L1164 / L1173
页数:10
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