Institute of Emergency and Critical Care Medicine, School of Medicine, National Yang Ming Chiao Tung University, No. 155, Sec. 2, Linong St., Beitou Dist., Taipei, 112, Taiwan.
Department of Respiratory Therapy, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
Part Fibre Toxicol. 2021 Mar 11;18(1):11. doi: 10.1186/s12989-021-00404-3.
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.
空气污染暴露和特发性肺纤维化（IPF）会导致 SARS-CoV-2 感染后的预后不良，但潜在机制尚不清楚。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 可能会增加肺肺泡区域中 ACE2 和 TMPRSS2 的表达。我们测量了对照非 IPF 和 IPF 患者肺组织中的表达水平，并使用鼠动物模型研究了颗粒物（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 的细胞仅限于人肺泡细胞。ACE2 和 TMPRSS2 在 IPF 患者中大量上调，并在人类肺纤维化组织中由成纤维细胞特异性蛋白 1（FSP-1）+肺成纤维细胞共同表达。在动物模型中，PM 暴露增加了博来霉素诱导的肺纤维化的严重程度。ACE2 和 TMPRSS2 也在博来霉素诱导的肺纤维化中的 FSP-1+肺成纤维细胞中表达，并且当与 PM 暴露结合时，它们进一步上调。PM 暴露引起的肺纤维化严重程度和 ACE2 和 TMPRSS2 的表达被 KC（IL-8 的鼠同源物）缺失或 IL-8 受体 CXCR1/2 的抑制剂 reparixin 治疗所阻断。
这些数据表明，空气污染暴露和潜在的 IPF 增加了 SARS-CoV-2 感染的风险和 COVID-19 疾病的严重程度。它可以通过上调肺成纤维细胞中的 ACE2 和 TMPRSS2 来介导，并通过阻断 IL-8/CXCR1/2 途径来预防。
