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

被引:22
作者
Pineiro-Hermida, Sergio [1 ]
Martinez, Paula [1 ]
Bosso, Giuseppe [1 ]
Flores, Juana Maria [2 ]
Saraswati, Sarita [1 ]
Connor, Jane [3 ]
Lemaire, Raphael [3 ]
Blasco, Maria A. [1 ]
机构
[1] Spanish Natl Canc Ctr CNIO, Telomeres & Telomerase Grp, Mol Oncol Program, Melchor Fernandez Almagro 3, E-28029 Madrid, Spain
[2] Univ Complutense Madrid, Anim Surg & Med Dept, Fac Vet Sci, Madrid, Spain
[3] AstraZeneca, BioPharmaceut R&D, Res & Early Dev Resp Inflammat & Autoimmune RIA, Gaithersburg, MD 20878 USA
基金
欧洲研究理事会;
关键词
IDIOPATHIC PULMONARY-FIBROSIS; STEM-CELL; AIRWAY; TRF1; MUTATIONS; SHELTERIN; ASSOCIATION; MECHANISMS; ALVEOLAR; COMPLEX;
D O I
10.1038/s41467-022-32771-6
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Telomere dysfunction induced by TRF1 depletion in fibroblasts, club and basal cells did not lead to interstitial lung fibrosis, underscoring alveolar type II cells as the relevant cell type in pulmonary fibrosis. 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.
引用
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页数:18
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