Upregulation of ACE2 and TMPRSS2 by particulate matter and idiopathic pulmonary fibrosis: A potential role in severe COVID-19
Abstract Background: Air pollution and idiopathic pulmonary fibrosis (IPF) cause a poor prognosis after COVID-19 infection, but the underlying mechanisms are not well exploited. Angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) are the keys to the entry of SARS-CoV-2. 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.Results: 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-inuced 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.Conclusions: These data suggest that poor prognosis after COVID-19 infection caused by air pollution and IPF is mediated through upregulation of ACE2 and TMPRSS2 in pulmonary fibroblasts, which can be prevented by blocking the IL-8/CXCR1/2 pathway.