Department of Thoracic Medicine and Surgery, Temple University, Philadelphia, PA, 19140, USA.
Center for Inflammation, Translational and Clinical Lung Research, Temple University, Philadelphia, PA, 19140, USA.
Sci Rep. 2019 Jan 29;9(1):920. doi: 10.1038/s41598-018-37000-z.
Emphysema is characterized by alveolar wall destruction induced mainly by cigarette smoke. Oxidative damage of DNA may contribute to the pathophysiology of this disease. We studied the impairment of the non-homologous end joining (NHEJ) repair pathway and DNA damage in alveolar type II (ATII) cells and emphysema development. We isolated primary ATII cells from control smokers, nonsmokers, and patients with emphysema to determine DNA damage and repair. We found higher reactive oxygen species generation and DNA damage in ATII cells obtained from individuals with this disease in comparison with controls. We also observed low phosphorylation of H2AX, which activates DSBs repair signaling, in emphysema. Our results indicate the impairement of NHEJ, as detected by low XLF expression. We also analyzed the role of DJ-1, which has a cytoprotective activity. We detected DJ-1 and XLF interaction in ATII cells in emphysema, which suggests the impairment of their function. Moreover, we found that DJ-1 KO mice are more susceptible to DNA damage induced by cigarette smoke. Our results suggest that oxidative DNA damage and ineffective the DSBs repair via the impaired NHEJ may contribute to ATII cell death in emphysema.
肺气肿的特征是肺泡壁破坏，主要由香烟烟雾引起。DNA 的氧化损伤可能有助于该疾病的病理生理学。我们研究了非同源末端连接 (NHEJ) 修复途径和肺泡 II 型 (ATII) 细胞中的 DNA 损伤以及肺气肿的发展。我们从对照组吸烟者、非吸烟者和肺气肿患者中分离出原代 ATII 细胞，以确定 DNA 损伤和修复情况。与对照组相比，我们在患有这种疾病的个体中获得的 ATII 细胞中发现了更高的活性氧生成和 DNA 损伤。我们还观察到 H2AX 的磷酸化水平较低，这激活了 DSBs 修复信号。我们的结果表明，NHEJ 受损，这可以通过 XLF 表达降低来检测到。我们还分析了 DJ-1 的作用，DJ-1 具有细胞保护活性。我们在肺气肿的 ATII 细胞中检测到 DJ-1 和 XLF 的相互作用，这表明它们的功能受损。此外，我们发现 DJ-1 KO 小鼠对香烟烟雾引起的 DNA 损伤更敏感。我们的结果表明，氧化 DNA 损伤和通过受损的 NHEJ 导致 DSBs 修复无效可能导致肺气肿中 ATII 细胞死亡。
