Urokinase System in Pathogenesis of Pulmonary Fibrosis: A Hidden Threat of COVID-19.
Anna A ShmakovaVladimir S PopovIliya P RomanovNikita R KhabibullinNailya R SabitovaAnna A KarpukhinaYana A KozhevnikovaElla V KurilinaZoya I TsokolaevaPolina S KlimovichKseniya A RubinaYegor S VassetzkyEkaterina V SeminaPublished in: International journal of molecular sciences (2023)
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.
Keyphrases
- pulmonary fibrosis
- coronavirus disease
- sars cov
- single cell
- poor prognosis
- rna seq
- epithelial mesenchymal transition
- high fat diet induced
- induced apoptosis
- weight loss
- gene expression
- cell proliferation
- respiratory syndrome coronavirus
- binding protein
- long non coding rna
- metabolic syndrome
- adipose tissue
- risk assessment
- cell cycle arrest
- physical activity
- high glucose
- endothelial cells
- replacement therapy
- angiotensin ii
- insulin resistance
- oxidative stress
- climate change
- single molecule
- skeletal muscle
- diabetic rats
- drug induced
- low dose
- glycemic control
- anti inflammatory
- gastric bypass