Endothelial thrombomodulin downregulation caused by hypoxia contributes to severe infiltration and coagulopathy in COVID-19 patient lungs
| Autor: | Taejoon Won, Megan K. Wood, David M. Hughes, Monica V. Talor, Zexu Ma, Jowaly Schneider, John T. Skinner, Beejan Asady, Erin Goerlich, Marc K. Halushka, Allison G. Hays, Deok-Ho Kim, Chirag R. Parikh, Avi Z. Rosenberg, Isabelle Coppens, Roger A. Johns, Nisha A. Gilotra, Jody E. Hooper, Andrew Pekosz, Daniela Čiháková |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Aged
80 and over Male Medicine (General) SARS-CoV-2 Thrombomodulin immunothrombosis COVID-19 Down-Regulation Endothelial Cells General Medicine Blood Coagulation Disorders Middle Aged General Biochemistry Genetics and Molecular Biology Article endothelial cell dysfunction R5-920 Medicine Humans Female Endothelium Vascular Hypoxia Lung Aged |
| Zdroj: | EBioMedicine EBioMedicine, Vol 75, Iss, Pp 103812-(2022) |
| ISSN: | 2352-3964 |
| Popis: | Summary: Background: Thromboembolism is a life-threatening manifestation of coronavirus disease 2019 (COVID-19). We investigated a dysfunctional phenotype of vascular endothelial cells in the lungs during COVID-19. Methods: We obtained the lung specimens from the patients who died of COVID-19. The phenotype of endothelial cells and immune cells was examined by flow cytometry and immunohistochemistry (IHC) analysis. We tested the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the endothelium using IHC and electron microscopy. Findings: The autopsy lungs of COVID-19 patients exhibited severe coagulation abnormalities, immune cell infiltration, and platelet activation. Pulmonary endothelial cells of COVID-19 patients showed increased expression of procoagulant von Willebrand factor (VWF) and decreased expression of anticoagulants thrombomodulin and endothelial protein C receptor (EPCR). In the autopsy lungs of COVID-19 patients, the number of macrophages, monocytes, and T cells was increased, showing an activated phenotype. Despite increased immune cells, adhesion molecules such as ICAM-1, VCAM-1, E-selectin, and P-selectin were downregulated in pulmonary endothelial cells of COVID-19 patients. Notably, decreased thrombomodulin expression in endothelial cells was associated with increased immune cell infiltration in the COVID-19 patient lungs. There were no SARS-CoV-2 particles detected in the lung endothelium of COVID-19 patients despite their dysfunctional phenotype. Meanwhile, the autopsy lungs of COVID-19 patients showed SARS-CoV-2 virions in damaged alveolar epithelium and evidence of hypoxic injury. Interpretation: Pulmonary endothelial cells become dysfunctional during COVID-19, showing a loss of thrombomodulin expression related to severe thrombosis and infiltration, and endothelial cell dysfunction might be caused by a pathologic condition in COVID-19 patient lungs rather than a direct infection with SARS-CoV-2. Funding: This work was supported by the Johns Hopkins University, the American Heart Association, and the National Institutes of Health. |
| Databáze: | OpenAIRE |
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