Urokinase System in Pathogenesis of Pulmonary Fibrosis: A Hidden Threat of COVID-19
Pulmonary fibrosis is a common and threatening post-COVID-19 complication with poorly resolved molecular mechanisms and no established treatment. The plasminogen activator system, including urokinase (uPA) and urokinase receptor (uPAR), is involved in the pathogenesis of COVID-19 and contributes to...
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| Format: | Article |
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MDPI AG
2023-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/2/1382 |
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| author | Anna A. Shmakova Vladimir S. Popov Iliya P. Romanov Nikita R. Khabibullin Nailya R. Sabitova Anna A. Karpukhina Yana A. Kozhevnikova Ella V. Kurilina Zoya I. Tsokolaeva Polina S. Klimovich Kseniya A. Rubina Yegor S. Vassetzky Ekaterina V. Semina |
| author_facet | Anna A. Shmakova Vladimir S. Popov Iliya P. Romanov Nikita R. Khabibullin Nailya R. Sabitova Anna A. Karpukhina Yana A. Kozhevnikova Ella V. Kurilina Zoya I. Tsokolaeva Polina S. Klimovich Kseniya A. Rubina Yegor S. Vassetzky Ekaterina V. Semina |
| author_sort | Anna A. Shmakova |
| collection | DOAJ |
| description | Pulmonary fibrosis is a common and threatening post-COVID-19 complication with poorly resolved molecular mechanisms and no established treatment. The plasminogen activator system, including urokinase (uPA) and urokinase receptor (uPAR), is involved in the pathogenesis of COVID-19 and contributes to the development of lung injury and post-COVID-19 pulmonary fibrosis, although their cellular and molecular underpinnings still remain obscure. The aim of the current study was to assess the role of uPA and uPAR in the pathogenesis of pulmonary fibrosis. We analyzed uPA and uPAR expression in human lung tissues from COVID-19 patients with pulmonary fibrosis using single-cell RNA-seq and immunohistochemistry. We modeled lung fibrosis in <i>Plau</i>-/- and <i>Plaur</i>-/- mice upon bleomycin instillation and explored the effect of uPAR downregulation in A549 and BEAS-2B lung epithelial cells. We found that uPAR expression drastically decreased in the epithelial airway basal cells and monocyte/macrophage cells, whereas uPA accumulation significantly increased in tissue samples of COVID-19 patients. Lung injury and fibrosis in <i>Plaur</i>-/- vs. WT mice upon bleomycin instillation revealed that uPAR deficiency resulted in pro-fibrogenic uPA accumulation, IL-6 and ACE2 upregulation in lung tissues and was associated with severe fibrosis, weight loss and poor survival. uPAR downregulation in A549 and BEAS-2B was linked to an increased N-cadherin expression, indicating the onset of epithelial–mesenchymal transition and potentially contributing to pulmonary fibrosis. Here for the first time, we demonstrate that plasminogen treatment reversed lung fibrosis in <i>Plaur</i>-/- mice: the intravenous injection of 1 mg of plasminogen on the 21st day of bleomycin-induced fibrosis resulted in a more than a two-fold decrease in the area of lung fibrosis as compared to non-treated mice as evaluated by the 42nd day. The expression and function of the plasminogen activator system are dysregulated upon COVID-19 infection, leading to excessive pulmonary fibrosis and worsening the prognosis. The potential of plasminogen as a life-saving treatment for non-resolving post-COVID-19 pulmonary fibrosis warrants further investigation. |
| first_indexed | 2024-03-09T12:22:17Z |
| format | Article |
| id | doaj.art-e729196c7ccb48d79f8f3e151cd50f0a |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T12:22:17Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-e729196c7ccb48d79f8f3e151cd50f0a2023-11-30T22:39:34ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-01-01242138210.3390/ijms24021382Urokinase System in Pathogenesis of Pulmonary Fibrosis: A Hidden Threat of COVID-19Anna A. Shmakova0Vladimir S. Popov1Iliya P. Romanov2Nikita R. Khabibullin3Nailya R. Sabitova4Anna A. Karpukhina5Yana A. Kozhevnikova6Ella V. Kurilina7Zoya I. Tsokolaeva8Polina S. Klimovich9Kseniya A. Rubina10Yegor S. Vassetzky11Ekaterina V. Semina12Institute of Experimental Cardiology, National Medical Research Centre of Cardiology Named after Academician E.I. Chazov, 121552 Moscow, RussiaFaculty of Medicine, Lomonosov Moscow State University, 119192 Moscow, RussiaFaculty of Medicine, Lomonosov Moscow State University, 119192 Moscow, RussiaFaculty of Medicine, Lomonosov Moscow State University, 119192 Moscow, RussiaFaculty of Medicine, Lomonosov Moscow State University, 119192 Moscow, RussiaKoltzov Institute of Developmental Biology, 117334 Moscow, RussiaFaculty of Medicine, Lomonosov Moscow State University, 119192 Moscow, RussiaInstitute of Experimental Cardiology, National Medical Research Centre of Cardiology Named after Academician E.I. Chazov, 121552 Moscow, RussiaInstitute of Experimental Cardiology, National Medical Research Centre of Cardiology Named after Academician E.I. Chazov, 121552 Moscow, RussiaInstitute of Experimental Cardiology, National Medical Research Centre of Cardiology Named after Academician E.I. Chazov, 121552 Moscow, RussiaFaculty of Medicine, Lomonosov Moscow State University, 119192 Moscow, RussiaKoltzov Institute of Developmental Biology, 117334 Moscow, RussiaInstitute of Experimental Cardiology, National Medical Research Centre of Cardiology Named after Academician E.I. Chazov, 121552 Moscow, RussiaPulmonary fibrosis is a common and threatening post-COVID-19 complication with poorly resolved molecular mechanisms and no established treatment. The plasminogen activator system, including urokinase (uPA) and urokinase receptor (uPAR), is involved in the pathogenesis of COVID-19 and contributes to the development of lung injury and post-COVID-19 pulmonary fibrosis, although their cellular and molecular underpinnings still remain obscure. The aim of the current study was to assess the role of uPA and uPAR in the pathogenesis of pulmonary fibrosis. We analyzed uPA and uPAR expression in human lung tissues from COVID-19 patients with pulmonary fibrosis using single-cell RNA-seq and immunohistochemistry. We modeled lung fibrosis in <i>Plau</i>-/- and <i>Plaur</i>-/- mice upon bleomycin instillation and explored the effect of uPAR downregulation in A549 and BEAS-2B lung epithelial cells. We found that uPAR expression drastically decreased in the epithelial airway basal cells and monocyte/macrophage cells, whereas uPA accumulation significantly increased in tissue samples of COVID-19 patients. Lung injury and fibrosis in <i>Plaur</i>-/- vs. WT mice upon bleomycin instillation revealed that uPAR deficiency resulted in pro-fibrogenic uPA accumulation, IL-6 and ACE2 upregulation in lung tissues and was associated with severe fibrosis, weight loss and poor survival. uPAR downregulation in A549 and BEAS-2B was linked to an increased N-cadherin expression, indicating the onset of epithelial–mesenchymal transition and potentially contributing to pulmonary fibrosis. Here for the first time, we demonstrate that plasminogen treatment reversed lung fibrosis in <i>Plaur</i>-/- mice: the intravenous injection of 1 mg of plasminogen on the 21st day of bleomycin-induced fibrosis resulted in a more than a two-fold decrease in the area of lung fibrosis as compared to non-treated mice as evaluated by the 42nd day. The expression and function of the plasminogen activator system are dysregulated upon COVID-19 infection, leading to excessive pulmonary fibrosis and worsening the prognosis. The potential of plasminogen as a life-saving treatment for non-resolving post-COVID-19 pulmonary fibrosis warrants further investigation.https://www.mdpi.com/1422-0067/24/2/1382COVID-19pulmonary fibrosisurokinase uPAurokinase receptor uPARplasminogenscRNA-seq |
| spellingShingle | Anna A. Shmakova Vladimir S. Popov Iliya P. Romanov Nikita R. Khabibullin Nailya R. Sabitova Anna A. Karpukhina Yana A. Kozhevnikova Ella V. Kurilina Zoya I. Tsokolaeva Polina S. Klimovich Kseniya A. Rubina Yegor S. Vassetzky Ekaterina V. Semina Urokinase System in Pathogenesis of Pulmonary Fibrosis: A Hidden Threat of COVID-19 International Journal of Molecular Sciences COVID-19 pulmonary fibrosis urokinase uPA urokinase receptor uPAR plasminogen scRNA-seq |
| title | Urokinase System in Pathogenesis of Pulmonary Fibrosis: A Hidden Threat of COVID-19 |
| title_full | Urokinase System in Pathogenesis of Pulmonary Fibrosis: A Hidden Threat of COVID-19 |
| title_fullStr | Urokinase System in Pathogenesis of Pulmonary Fibrosis: A Hidden Threat of COVID-19 |
| title_full_unstemmed | Urokinase System in Pathogenesis of Pulmonary Fibrosis: A Hidden Threat of COVID-19 |
| title_short | Urokinase System in Pathogenesis of Pulmonary Fibrosis: A Hidden Threat of COVID-19 |
| title_sort | urokinase system in pathogenesis of pulmonary fibrosis a hidden threat of covid 19 |
| topic | COVID-19 pulmonary fibrosis urokinase uPA urokinase receptor uPAR plasminogen scRNA-seq |
| url | https://www.mdpi.com/1422-0067/24/2/1382 |
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