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 (β-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 β-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.

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 (CLAD)——肺移植后长期生存的主要限制因素。尽管较短的供体端粒长度与 CLAD 风险增加有关，但尚不清楚短端粒是 CLAD 病理的原因还是结果。我们的目标是测试端粒功能障碍是否会导致 CLAD 中观察到的病理变化。人类 CLAD 肺的组织病理学和分子分析表明，通过 teloFISH 量化的肺上皮细胞端粒缩短，表面活性蛋白 C 免疫反应性 II 型肺泡上皮细胞数量增加，以及衰老标志物（β-半乳糖苷酶、p16、p53 和 p21）的表达增加在肺上皮细胞中。TRF1^F/F（端粒重复结合因子 1 flox/flox）小鼠与他莫昔芬诱导的 SCGB1a1-cre 小鼠杂交产生SCGB1a1-creTRF1 ^F/F老鼠。在他莫昔芬诱导俱乐部细胞中 TRF1 缺失 9 个月后，小鼠出现了混合的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四倍，细支气管和相邻肺实质周围的胶原蛋白沉积， II 型肺泡上皮细胞数量增加，上皮细胞中衰老相关 β-半乳糖苷酶的表达，以及气道上皮细胞中 SCGB1a1 的表达降低。这些发现表明，气道上皮细胞的端粒功能障碍导致以气道为中心的肺重塑和纤维化，类似于在 CLAD 患者中观察到的情况，并表明肺上皮细胞端粒功能障碍可能是 CLAD 的分子驱动因素。