Airway Epithelial Telomere Dysfunction Drives Remodeling Similar to Chronic Lung Allograft Dysfunction
Airway Epithelial Telomere Dysfunction Drives Remodeling Similar to Chronic Lung Allograft Dysfunction
复制标题
气道上皮端粒功能障碍驱动重塑，类似于慢性肺同种异体移植功能障碍
DOI：
10.1165/rcmb.2019-0374oc
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发表时间：
2020-10-01
影响因子：
6.4
通讯作者：
Wolters, Paul J.
中科院分区：
文献类型：
--
作者：
Naikawadi, Ram P.;Green, Gary;Wolters, Paul J.
端粒功能障碍与多种肺纤维化过程有关，包括慢性肺同种异体移植功能障碍（chronic lung allograft dysfunction， CLAD），这是肺移植术后长期生存的主要限制。虽然较短的供体端粒长度与增加的覆层风险有关，但尚不清楚短端粒是覆层病理的原因还是结果。我们的目的是测试端粒功能障碍是否有助于在CLAD中观察到的病理改变。组织病理学和分子分析显示，通过teloFISH定量的肺上皮细胞端粒缩短，表面活性剂蛋白C免疫反应型肺泡上皮细胞数量增加，肺上皮细胞中衰老标志物（β -半乳糖苷酶，p16， p53和p21）表达增加。将TRF1（端粒重复结合因子1 flox/flox）小鼠与他莫昔芬诱导的SCGB1a1-cre小鼠杂交，生成SCGB1a1-creTRF1（F/F）小鼠。他莫昔芬诱导俱乐部细胞中TRF1缺失9个月后，小鼠出现混合性阻塞性和限制性肺生理，微计算机断层扫描显示小气道闭塞，气道上皮细胞端粒长度减少4倍，细支气管和邻近肺实质周围胶原沉积，II型肺泡上皮细胞数量增加，上皮细胞中衰老相关β -半乳糖苷酶表达增加。降低SCGB1a1在气道上皮细胞中的表达。这些发现表明，分离到气道上皮细胞的端粒功能障碍导致气道中心肺重构和纤维化，类似于在CLAD患者中观察到的情况，并提示肺上皮细胞端粒功能障碍可能是CLAD的分子驱动因素。
Telomere dysfunction is associated with multiple fibrotic lung processes, including chronic lung allograft dysfunction (CLAD)-the major limitation to long-term survival following lung transplantation. Although shorter donor telomere lengths are associated with an increased risk of CLAD, it is unknown whether short telomeres are a cause or consequence of CLAD pathology. Our objective was to test whether telomere dysfunction contributes to the pathologic changes observed in CLAD. Histopathologic and molecular analysis of human CLAD lungs demonstrated shortened telomeres in lung epithelial cells quantified by teloFISH, increased numbers of surfactant protein C immunoreactive type II alveolar epithelial cells, and increased expression of senescence markers (beta-galactosidase, p16, p53, and p21) in lung epithelial cells. TRF1(F/F) (telomere repeat binding factor 1 flox/flox) mice were crossed with tamoxifen-inducible SCGB1a1-cre mice to generate SCGB1a1-creTRF1(F/F) mice. Following 9 months of tamoxifen-induced deletion of TRF1 in club cells, mice developed mixed obstructive and restrictive lung physiology, small airway obliteration on microcomputed tomography, a fourfold decrease in telomere length in airway epithelial cells, collagen deposition around bronchioles and adjacent lung parenchyma, increased type II aveolar epithelial cell numbers, expression of senescence-associated beta-galactosidase in epithelial cells, and decreased SCGB1a1 expression in airway epithelial cells. These findings demonstrate that telomere dysfunction isolated to airway epithelial cells leads to airway-centric lung remodeling and fibrosis similar to that observed in patients with CLAD and suggest that lung epithelial cell telomere dysfunction may be a molecular driver of CLAD.