Telomere dysfunction in alveolar epithelial cells causes lung remodeling and fibrosis
Telomere dysfunction in alveolar epithelial cells causes lung remodeling and fibrosis
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DOI：
10.1172/jci.insight.86704
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发表时间：
2016-09-08
期刊：
影响因子：
8
通讯作者：
Wolters, Paul J.
中科院分区：
文献类型：
--
作者：
Naikawadi, Ram P.;Disayabutr, Supparerk;Wolters, Paul J.
特发性肺纤维化（IPF）患者II型肺泡上皮细胞（AEC）的端粒较短。功能失调的端粒是否直接导致肺纤维化的发展仍不清楚。本研究的目的是研究II型AEC中的端粒功能障碍是否会导致小鼠（SPC-Cre TRF 1（fl/fl）小鼠）肺纤维化，该功能障碍由端粒掩蔽蛋白TRF 1缺失介导。在II型AEC中缺失TRF 1 2周增加γ H2 AX DNA损伤灶，但不增加肺的组织病理学变化。在II型AEC中缺失TRF 1长达9个月导致短端粒和肺重塑，其特征在于II型AEC、α-平滑肌肌动蛋白（+）间充质细胞、胶原沉积和衰老相关β-半乳糖苷酶（+）肺上皮细胞数量增加。胶原表达细胞中TRF 1的缺失导致肺水肿，但不导致纤维化。这些结果表明，在II型AEC中延长的端粒功能障碍，而不是胶原表达细胞，导致年龄依赖性肺重塑和纤维化。我们的结论是II型AEC中的端粒功能障碍足以引起肺纤维化，并且可能是导致IPF的主要分子缺陷。SPC-Cre TRF 1（fl/fl）小鼠将用于评估由端粒功能障碍介导的肺纤维化的细胞和分子机制。
Telomeres are short in type II alveolar epithelial cells (AECs) of patients with idiopathic pulmonary fibrosis (IPF). Whether dysfunctional telomeres contribute directly to development of lung fibrosis remains unknown. The objective of this study was to investigate whether telomere dysfunction in type II AECs, mediated by deletion of the telomere shelterin protein TRF1, leads to pulmonary fibrosis in mice (SPC-Cre TRF1(fl/fl) mice). Deletion of TRF1 in type II AECs for 2 weeks increased gamma H2AX DNA damage foci, but not histopathologic changes in the lung. Deletion of TRF1 in type II AECs for up to 9 months resulted in short telomeres and lung remodeling characterized by increased numbers of type II AECs, alpha-smooth muscle actin(+) mesenchymal cells, collagen deposition, and accumulation of senescence-associated beta-galactosidase(+) lung epithelial cells. Deletion of TRF1 in collagen-expressing cells caused pulmonary edema, but not fibrosis. These results demonstrate that prolonged telomere dysfunction in type II AECs, but not collagen-expressing cells, leads to age-dependent lung remodeling and fibrosis. We conclude that telomere dysfunction in type II AECs is sufficient to cause lung fibrosis, and may be a dominant molecular defect causing IPF. SPC-Cre TRF1(fl/fl) mice will be useful for assessing cellular and molecular mechanisms of lung fibrosis mediated by telomere dysfunction.