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 Plau-/- and Plaur-/-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 Plaur-/- 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 Plaur-/- 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.
The coronavirus disease 2019 (COVID-19) pandemic requires not only the creation of vaccines to prevent the spread of the disease, but also the development of novel drugs aimed at reducing viral load, suppressing an excessive immune response and preventing the severe complications such as lung fibrosis and acute respiratory distress syndrome. One of the promising targets for studying the development of pneumonia, systemic inflammation and disseminated intravascular coagulation in COVID-19 is the plasminogen activator system. In patients with a severe disease course, impaired activity or expression of plasminogen activators significantly increases the blood level of D-dimer and fibrinogen, as well as correlates with intravascular coagulation and thrombus formation. The second promising target for studying the pathogenesis of COVID-19 is the adiponectin/T-cadherin system: adiponectin is able to reduce the content of pro-inflammatory cytokines, the increase of which is characteristic of COVID-19, and stimulate the production of an anti-inflammatory cytokine interleukin-10. The review describes the role of plasminogen and T-cadherin activators in their possible participation in the development of pulmonary fibrosis in COVID-19 and hemostasis regulation, as well as cardio- and vasculoprotective function of adiponectin and its receptor, T-cadherin.
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