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Upregulation of ACE2 and TMPRSS2 by particulate matter and idiopathic pulmonary fibrosis: a potential role in severe COVID-19
Particle and Fibre Toxicology ( IF 10 ) Pub Date : 2021-03-11 , DOI: 10.1186/s12989-021-00404-3
Hsin-Hsien Li , Chen-Chi Liu , Tien-Wei Hsu , Jiun-Han Lin , Jyuan-Wei Hsu , Anna Fen-Yau Li , Yi-Chen Yeh , Shih-Chieh Hung , Han-Shui Hsu

Air pollution exposure and idiopathic pulmonary fibrosis (IPF) cause a poor prognosis after SARS-CoV-2 infection, but the underlying mechanisms are not well explored. Angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) are the keys to the entry of SARS-CoV-2. We therefore hypothesized that air pollution exposure and IPF may increase the expression of ACE2 and TMPRSS2 in the lung alveolar region. We measured their expression levels in lung tissues of control non-IPF and IPF patients, and used murine animal models to study the deterioration of IPF caused by particulate matter (PM) and the molecular pathways involved in the expression of ACE2 and TMPRSS2. In non-IPF patients, cells expressing ACE2 and TMPRSS2 were limited to human alveolar cells. ACE2 and TMPRSS2 were largely upregulated in IPF patients, and were co-expressed by fibroblast specific protein 1 (FSP-1) + lung fibroblasts in human pulmonary fibrotic tissue. In animal models, PM exposure increased the severity of bleomycin-induced pulmonary fibrosis. ACE2 and TMPRSS2 were also expressed in FSP-1+ lung fibroblasts in bleomycin-induced pulmonary fibrosis, and when combined with PM exposure, they were further upregulated. The severity of pulmonary fibrosis and the expression of ACE2 and TMPRSS2 caused by PM exposure were blocked by deletion of KC, a murine homologue of IL-8, or treatment with reparixin, an inhibitor of IL-8 receptors CXCR1/2. These data suggested that risk of SARS-CoV-2 infection and COVID-19 disease severity increased by air pollution exposure and underlying IPF. It can be mediated through upregulating ACE2 and TMPRSS2 in pulmonary fibroblasts, and prevented by blocking the IL-8/CXCR1/2 pathway.

中文翻译:

颗粒物和特发性肺纤维化上调ACE2和TMPRSS2:在严重COVID-19中的潜在作用

暴露于空气污染和特发性肺纤维化(IPF)导致SARS-CoV-2感染后预后较差,但尚未深入探讨其潜在机制。血管紧张素转换酶2(ACE2)和跨膜丝氨酸蛋白酶2(TMPRSS2)是SARS-CoV-2进入的关键。因此,我们假设空气污染暴露和IPF可能会增加肺泡区域中ACE2和TMPRSS2的表达。我们测量了它们在对照非IPF和IPF患者的肺组织中的表达水平,并使用鼠类动物模型研究了由颗粒物(PM)引起的IPF恶化以及涉及ACE2和TMPRSS2表达的分子途径。在非IPF患者中,表达ACE2和TMPRSS2的细胞仅限于人类肺泡细胞。IPF患者中的ACE2和TMPRSS2在很大程度上被上调,并且在人肺纤维化组织中由成纤维细胞特异性蛋白1(FSP-1)+肺成纤维细胞共表达。在动物模型中,PM暴露会增加博来霉素诱导的肺纤维化的严重程度。ACE2和TMPRSS2在博来霉素诱导的肺纤维化中也表达于FSP-1 +肺成纤维细胞中,当与PM暴露结合使用时,它们会进一步上调。PM暴露引起的肺纤维化的严重程度以及ACE2和TMPRSS2的表达被KC缺失,鼠类IL-8同源物或用reparixin(IL-8受体CXCR1 / 2的抑制剂)治疗所阻断。这些数据表明,空气污染暴露和潜在的IPF会增加SARS-CoV-2感染的风险和COVID-19疾病的严重性。它可以通过上调肺成纤维细胞中的ACE2和TMPRSS2来介导,
更新日期:2021-03-11
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