Department of Geriatrics, Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, PR China.
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, PR China.
J Pathol. 2021 Jan;253(1):17-30. doi: 10.1002/path.5555. Epub 2020 Oct 27.
Angiotensin-converting enzyme 2 (ACE2) has been identified as the functional receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and a target for disease prevention. However, the relationship between ACE2 expression and its clinical implications in SARS-CoV-2 pathogenesis remains unknown. Here, we explored the location and expression of ACE2, and its correlation with gender, age, and cigarette smoke (CS), in a CS-exposed mouse model and 224 non-malignant lung tissues (125 non-smokers, 81 current smokers, and 18 ex-smokers) by immunohistochemistry. Moreover, the correlations of ACE2 with CS-induced oxidative stress-related markers, hypoxia-inducible factor-1α (HIF-1α), inducible nitric oxide synthase (iNOS), and 4-hydroxynonenal (4-HNE) were investigated. Chromatin immunoprecipitation and luciferase reporter assays identified the cause of ACE2 overexpression in human primary lung epithelial cells. We demonstrated that ACE2 was predominantly overexpressed on the apical surface of bronchial epithelium, while reduced in alveolar epithelium, owing to the dramatically decreased abundance of alveolar type II pneumocytes in CS-exposed mouse lungs. Consistent with this, ACE2 was primarily significantly overexpressed in human bronchial and alveolar epithelial cells in smokers regardless of age or gender. Decreased ACE2 expression was observed in bronchial epithelial cells from ex-smokers compared with current smokers, especially in those who had ceased smoking for more than 10 years. Moreover, ACE2 expression was positively correlated with the levels of HIF-1α, iNOS, and 4-HNE in both mouse and human bronchioles. The results were further validated using a publicly available dataset from The Cancer Genome Atlas (TCGA) and our previous integrated data from Affymetrix U133 Plus 2.0 microarray (AE-meta). Finally, our results showed that HIF-1α transcriptionally upregulates ACE2 expression. Our results indicate that smoking-induced ACE2 overexpression in the apical surface of bronchial epithelial cells provides a route by which SARS-CoV-2 enters host cells, which supports clinical relevance in attenuating the potential transmission risk of COVID-19 in smoking populations by smoking cessation. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
血管紧张素转换酶 2（ACE2）已被确定为严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）的功能受体，也是疾病预防的靶点。然而，ACE2 表达与其在 SARS-CoV-2 发病机制中的临床意义之间的关系尚不清楚。在这里，我们通过免疫组织化学方法研究了 ACE2 的位置和表达及其与性别、年龄和香烟烟雾（CS）的关系，该研究在 CS 暴露的小鼠模型和 224 个非恶性肺组织（125 个不吸烟者、81 个当前吸烟者和 18 个戒烟者）中进行。此外，还研究了 ACE2 与 CS 诱导的氧化应激相关标志物、缺氧诱导因子-1α（HIF-1α）、诱导型一氧化氮合酶（iNOS）和 4-羟基壬烯醛（4-HNE）的相关性。染色质免疫沉淀和荧光素酶报告基因测定鉴定了人原代肺上皮细胞中 ACE2 过表达的原因。我们证明，由于 CS 暴露的小鼠肺中肺泡 II 型上皮细胞的数量急剧减少，ACE2 主要在上皮细胞的顶端表面过表达，而在肺泡上皮细胞中则减少。与此一致的是，无论年龄或性别如何，吸烟的人支气管和肺泡上皮细胞中的 ACE2 主要显著过表达。与当前吸烟者相比，戒烟者的支气管上皮细胞中的 ACE2 表达减少，尤其是戒烟 10 年以上的戒烟者。此外，ACE2 表达与小鼠和人细支气管中的 HIF-1α、iNOS 和 4-HNE 水平呈正相关。使用来自癌症基因组图谱（TCGA）的公开数据集和我们之前来自 Affymetrix U133 Plus 2.0 微阵列（AE-meta）的综合数据对结果进行了进一步验证。最后，我们的结果表明，HIF-1α 转录上调 ACE2 的表达。我们的结果表明，吸烟诱导的支气管上皮细胞顶端表面的 ACE2 过表达为 SARS-CoV-2 进入宿主细胞提供了一种途径，这支持了通过戒烟来减轻吸烟人群中 COVID-19 潜在传播风险的临床相关性。2020 年英国和爱尔兰病理学学会。约翰威立父子公司出版。
