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端粒功能障碍对成纤维细胞、Club 细胞和基底细胞的影响与肺纤维化的发展。

Consequences of telomere dysfunction in fibroblasts, club and basal cells for lung fibrosis development.

机构信息

Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Melchor Fernández Almagro 3, Madrid, E-28029, Spain.

Animal Surgery and Medicine Department, Faculty of Veterinary Science, Complutense University of Madrid, Madrid, Spain.

出版信息

Nat Commun. 2022 Oct 6;13(1):5656. doi: 10.1038/s41467-022-32771-6.

DOI:10.1038/s41467-022-32771-6
PMID:36202783
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9537293/
Abstract

TRF1 is an essential component of the telomeric protective complex or shelterin. We previously showed that dysfunctional telomeres in alveolar type II (ATII) cells lead to interstitial lung fibrosis. Here, we study the lung pathologies upon telomere dysfunction in fibroblasts, club and basal cells. TRF1 deficiency in lung fibroblasts, club and basal cells induced telomeric damage, proliferative defects, cell cycle arrest and apoptosis. While Trf1 deletion in fibroblasts does not spontaneously lead to lung pathologies, upon bleomycin challenge exacerbates lung fibrosis. Unlike in females, Trf1 deletion in club and basal cells from male mice resulted in lung inflammation and airway remodeling. Here, we show that depletion of TRF1 in fibroblasts, Club and basal cells does not lead to interstitial lung fibrosis, underscoring ATII cells as the relevant cell type for the origin of interstitial fibrosis. Our findings contribute to a better understanding of proper telomere protection in lung tissue homeostasis.

摘要

TRF1 是端粒保护复合物或庇护体的必需组成部分。我们之前的研究表明，肺泡 II 型 (ATII) 细胞中的功能失调端粒会导致间质性肺纤维化。在这里，我们研究了端粒功能障碍在成纤维细胞、club 细胞和基底细胞中引起的肺病理变化。肺成纤维细胞、club 细胞和基底细胞中的 TRF1 缺乏会导致端粒损伤、增殖缺陷、细胞周期停滞和细胞凋亡。虽然成纤维细胞中 Trf1 的缺失不会自发导致肺部疾病，但博来霉素刺激会加重肺纤维化。与女性不同，雄性小鼠的 club 细胞和基底细胞中 Trf1 的缺失会导致肺部炎症和气道重塑。在这里，我们表明，成纤维细胞、club 细胞和基底细胞中 TRF1 的耗竭不会导致间质性肺纤维化，这突显了 ATII 细胞是间质纤维化起源的相关细胞类型。我们的研究结果有助于更好地理解肺组织稳态中适当的端粒保护。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe52/9537293/25417c4607ea/41467_2022_32771_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe52/9537293/ac61939779c2/41467_2022_32771_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe52/9537293/12ed2337240d/41467_2022_32771_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe52/9537293/83ad4be2f03c/41467_2022_32771_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe52/9537293/4fc19c612740/41467_2022_32771_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe52/9537293/602261ff00ac/41467_2022_32771_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe52/9537293/e9ca93b33ed4/41467_2022_32771_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe52/9537293/507a9e00c4b4/41467_2022_32771_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe52/9537293/422d961370a5/41467_2022_32771_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe52/9537293/15df40965fdc/41467_2022_32771_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe52/9537293/25417c4607ea/41467_2022_32771_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe52/9537293/ac61939779c2/41467_2022_32771_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe52/9537293/12ed2337240d/41467_2022_32771_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe52/9537293/83ad4be2f03c/41467_2022_32771_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe52/9537293/4fc19c612740/41467_2022_32771_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe52/9537293/602261ff00ac/41467_2022_32771_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe52/9537293/e9ca93b33ed4/41467_2022_32771_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe52/9537293/507a9e00c4b4/41467_2022_32771_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe52/9537293/422d961370a5/41467_2022_32771_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe52/9537293/15df40965fdc/41467_2022_32771_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe52/9537293/25417c4607ea/41467_2022_32771_Fig10_HTML.jpg

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本文引用的文献

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IGF1R acts as a cancer-promoting factor in the tumor microenvironment facilitating lung metastasis implantation and progression.

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