Hsin-Hsien Li1,2, Chen-Chi Liu1,3,4, Tien-Wei Hsu1,5, Jiun-Han Lin1,5, Jyuan-Wei Hsu3,4, Anna Fen-Yau Li4,6, Yi-Chen Yeh4,6, Shih-Chieh Hung7,8,9, Han-Shui Hsu10,11. 1. 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. 2. Department of Respiratory Therapy, College of Medicine, Chang Gung University, Taoyuan, Taiwan. 3. Division of Traumatology, Emergency Department, Taipei Veteran General Hospital, Taipei, Taiwan. 4. Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan. 5. Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan. 6. Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan. 7. Institute of New Drug Development, Biomedical Sciences, China Medical University, 7F, No. 6, Xueshi Rd., North Dist., Taichung, 404, Taiwan. hung3340@gmail.com. 8. Integrative Stem Cell Center, Department of Orthopedics, China Medical University Hospital, Taichung, Taiwan. hung3340@gmail.com. 9. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan. hung3340@gmail.com. 10. 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. hsuhs@vghtpe.gov.tw. 11. Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan. hsuhs@vghtpe.gov.tw.
Abstract
BACKGROUND: 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. 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-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. CONCLUSIONS: 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.
BACKGROUND: 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. 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-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. CONCLUSIONS: 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.
Entities:
Keywords:
ACE2; Air pollution; COVID-19; Idiopathic pulmonary fibrosis; TMPRSS2
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