Excellence Cluster Cardio-Pulmonary Institute, Universities of Giessen and Marburg Lung Center, member of the German Center for Lung Research (DZL), Justus Liebig University Giessen, Giessen, Germany.
Institute for Lung Health (ILH), Justus Liebig University Giessen, Giessen, Germany.
Am J Respir Crit Care Med. 2023 Jun 15;207(12):1576-1590. doi: 10.1164/rccm.202208-1603OC.
Tobacco smoking and air pollution are primary causes of chronic obstructive pulmonary disease (COPD). However, only a minority of smokers develop COPD. The mechanisms underlying the defense against nitrosative/oxidative stress in nonsusceptible smokers to COPD remain largely unresolved. To investigate the defense mechanisms against nitrosative/oxidative stress that possibly prevent COPD development or progression. Four cohorts were investigated: ) sputum samples (healthy, = 4; COPD, = 37), ) lung tissue samples (healthy, = 13; smokers without COPD, = 10; smoker+COPD, = 17), ) pulmonary lobectomy tissue samples (no/mild emphysema, = 6), and ) blood samples (healthy, = 6; COPD, = 18). We screened 3-nitrotyrosine (3-NT) levels, as indication of nitrosative/oxidative stress, in human samples. We established a novel model of a cigarette smoke extract (CSE)-resistant cell line and studied 3-NT formation, antioxidant capacity, and transcriptomic profiles. Results were validated in lung tissue, isolated primary cells, and an model using adeno-associated virus-mediated gene transduction and human precision-cut lung slices. 3-NT levels correlate with COPD severity of patients. In CSE-resistant cells, nitrosative/oxidative stress upon CSE treatment was attenuated, paralleled by profound upregulation of heme oxygenase-1 (HO-1). We identified carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) as a negative regulator of HO-1-mediated nitrosative/oxidative stress defense in human alveolar type 2 epithelial cells (hAEC2s). Consistently, inhibition of HO-1 activity in hAEC2s increased the susceptibility toward CSE-induced damage. Epithelium-specific CEACAM6 overexpression increased nitrosative/oxidative stress and cell death in human precision-cut lung slices on CSE treatment. CEACAM6 expression determines the hAEC2 sensitivity to nitrosative/oxidative stress triggering emphysema development/progression in susceptible smokers.
吸烟和空气污染是慢性阻塞性肺疾病（COPD）的主要原因。然而，只有少数吸烟者会发展为 COPD。对于不易患 COPD 的吸烟者，其抵抗硝化/氧化应激的机制在很大程度上仍未得到解决。本研究旨在探讨可能预防 COPD 发生或进展的抵抗硝化/氧化应激的防御机制。本研究共纳入了四个队列：（1）痰样本（健康者，n=4；COPD 患者，n=37）；（2）肺组织样本（健康者，n=13；不患 COPD 的吸烟者，n=10；患 COPD 的吸烟者，n=17）；（3）肺叶切除术组织样本（无/轻度肺气肿，n=6）；（4）血液样本（健康者，n=6；COPD 患者，n=18）。我们筛选了人类样本中的 3-硝基酪氨酸（3-NT）水平，以作为硝化/氧化应激的标志物。我们建立了一种新型的香烟烟雾提取物（CSE）抗性细胞系，并研究了 3-NT 的形成、抗氧化能力和转录组谱。结果在肺组织、分离的原代细胞和使用腺相关病毒介导的基因转导和人精确切割肺切片的模型中得到了验证。3-NT 水平与患者 COPD 的严重程度相关。在 CSE 抗性细胞中，CSE 处理后硝化/氧化应激减弱，同时血红素加氧酶-1（HO-1）的表达显著上调。我们发现癌胚抗原细胞粘附分子 6（CEACAM6）是人类肺泡 II 型上皮细胞（hAEC2）中 HO-1 介导的硝化/氧化应激防御的负调节因子。一致地，在 hAEC2 中抑制 HO-1 活性会增加其对 CSE 诱导的损伤的易感性。在 CSE 处理时，上皮细胞特异性的 CEACAM6 过表达增加了人精确切割肺切片中的硝化/氧化应激和细胞死亡。CEACAM6 表达决定了 hAEC2 对硝化/氧化应激的敏感性，从而触发易感吸烟者的肺气肿发生/进展。
