Künzi Lisa, Holt Gregory E
1Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, University of Miami, Miami, FL USA.
2Division of Pulmonology, Department of Medicine, Miami VA Medical Center, Miami, FL USA.
Cell Death Discov. 2019 Aug 5;5:127. doi: 10.1038/s41420-019-0205-3. eCollection 2019.
Tobacco smoke negatively affects human bronchial epithelial (HBE) cells and is directly implicated in the etiology of smoking related respiratory diseases. Smoke exposure causes double-stranded DNA breaks and DNA damage activates PARP-1, the key mediator of the parthanatos pathway of cell death. We hypothesize that smoke exposure activates the parthanatos pathway in HBE cells and represents a cell death mechanism that contributes to smoking related lung diseases. We exposed fully differentiated, primary HBE cells grown at the air liquid interface to cigarette smoke and evaluated them for parthanatos pathway activation. Smoke exposure induced mitochondrial to nuclear translocation of Apoptosis-Inducing Factor (AIF) and Endonuclease G (EndoG) within the first three hours characteristic of the parthanatos pathway. Exposing cells to an increasing number of cigarettes revealed that significant activation of the parthanatos pathway occurs after exposure to higher levels of smoke. Use of the specific PARP-1 inhibitor, BMN673, abrogated the effect of smoke induced activation of the parthanatos pathway. Smoke-mediated activation of the parthanatos pathway is increased in HBE cells originating from habitual smokers compared to non-smokers. This suggests that chronic smoke exposure leads to an increase in smoke-mediated activation of the parthanatos pathway and implicates its contribution in the pathogenesis of smoke-related lung diseases.
烟草烟雾对人支气管上皮（HBE）细胞产生负面影响，并且直接与吸烟相关呼吸系统疾病的病因有关。烟雾暴露会导致双链DNA断裂，而DNA损伤会激活PARP-1，PARP-1是细胞死亡的parthanatos途径的关键介质。我们假设烟雾暴露会激活HBE细胞中的parthanatos途径，并且代表一种导致吸烟相关肺部疾病的细胞死亡机制。我们将在气液界面生长的完全分化的原代HBE细胞暴露于香烟烟雾中，并评估它们的parthanatos途径激活情况。烟雾暴露在parthanatos途径特有的前三小时内诱导了凋亡诱导因子（AIF）和核酸内切酶G（EndoG）从线粒体向细胞核的转位。将细胞暴露于越来越多的香烟中发现，在暴露于更高水平的烟雾后，parthanatos途径会发生显著激活。使用特异性PARP-1抑制剂BMN673可消除烟雾诱导的parthanatos途径激活的作用。与非吸烟者相比，来自习惯性吸烟者的HBE细胞中，烟雾介导的parthanatos途径激活增加。这表明慢性烟雾暴露会导致烟雾介导的parthanatos途径激活增加，并暗示其在烟雾相关肺部疾病发病机制中的作用。
