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端粒酶对肺损伤和端粒缩短诱导的肺纤维化小鼠的治疗作用。

Therapeutic effects of telomerase in mice with pulmonary fibrosis induced by damage to the lungs and short telomeres.

机构信息

Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre, Madrid, Spain.

Bioinformatics Core Unit, Structural Biology and Biocomputing Program, Spanish National Cancer Centre, Madrid, Spain.

出版信息

Elife. 2018 Jan 30;7:e31299. doi: 10.7554/eLife.31299.

DOI:10.7554/eLife.31299
PMID:29378675
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5818250/
Abstract

Pulmonary fibrosis is a fatal lung disease characterized by fibrotic foci and inflammatory infiltrates. Short telomeres can impair tissue regeneration and are found both in hereditary and sporadic cases. We show here that telomerase expression using AAV9 vectors shows therapeutic effects in a mouse model of pulmonary fibrosis owing to a low-dose bleomycin insult and short telomeres. AAV9 preferentially targets regenerative alveolar type II cells (ATII). AAV9--treated mice show improved lung function and lower inflammation and fibrosis at 1-3 weeks after viral treatment, and improvement or disappearance of the fibrosis at 8 weeks after treatment. AAV9- treatment leads to longer telomeres and increased proliferation of ATII cells, as well as lower DNA damage, apoptosis, and senescence. Transcriptome analysis of ATII cells confirms downregulation of fibrosis and inflammation pathways. We provide a proof-of-principle that telomerase activation may represent an effective treatment for pulmonary fibrosis provoked or associated with short telomeres.

摘要

肺纤维化是一种致命的肺部疾病，其特征是纤维性病灶和炎症浸润。短端粒会损害组织再生，在遗传性和散发性病例中都有发现。我们在这里表明，使用 AAV9 载体表达端粒酶在由于低剂量博莱霉素刺激和短端粒引起的肺纤维化小鼠模型中具有治疗效果。AAV9 优先靶向再生的肺泡 II 型细胞（ATII）。在病毒治疗后 1-3 周，接受 AAV9 治疗的小鼠表现出改善的肺功能和更低的炎症和纤维化，并且在治疗 8 周后纤维化得到改善或消失。AAV9 治疗导致更长的端粒和 ATII 细胞的增殖增加，以及更低的 DNA 损伤、细胞凋亡和衰老。ATII 细胞的转录组分析证实纤维化和炎症途径的下调。我们提供了一个原理证明，即端粒酶激活可能代表一种有效的治疗方法，用于治疗由短端粒引起或与之相关的肺纤维化。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f477/5818250/b8cc528284a4/elife-31299-resp-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f477/5818250/6437cc6fbf30/elife-31299-fig1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f477/5818250/b8db92ce641d/elife-31299-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f477/5818250/d5a1f6008dab/elife-31299-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f477/5818250/267ff2c9ef23/elife-31299-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f477/5818250/adacb1262e48/elife-31299-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f477/5818250/1108dcfbdf83/elife-31299-fig4-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f477/5818250/e67491ea7539/elife-31299-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f477/5818250/cb0ef555e8ba/elife-31299-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f477/5818250/b8cc528284a4/elife-31299-resp-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f477/5818250/6437cc6fbf30/elife-31299-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f477/5818250/45fef32811ce/elife-31299-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f477/5818250/b8db92ce641d/elife-31299-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f477/5818250/d5a1f6008dab/elife-31299-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f477/5818250/267ff2c9ef23/elife-31299-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f477/5818250/adacb1262e48/elife-31299-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f477/5818250/1108dcfbdf83/elife-31299-fig4-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f477/5818250/e67491ea7539/elife-31299-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f477/5818250/cb0ef555e8ba/elife-31299-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f477/5818250/b8cc528284a4/elife-31299-resp-fig1.jpg

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