Urokinase System in Pathogenesis of Pulmonary Fibrosis: A Hidden Threat of COVID-19

Abstract

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.

Chronic HIV‐1 Tat action induces HLA‐DR downregulation in B cells: A mechanism for lymphoma immune escape in people living with HIV

“…For the NF‐κB‐mCherry reporter plasmid, five NF‐κB response element repeats and a minimal promoter (Table ) were incorporated in the mCherry2‐C1 plasmid. Small hairpin RNA (shRNA) targeting the human CIITA gene and a scrambled shRNA sequence (Table ) were cloned into the pLKO.1 plasmid as previously described 13 …”

“…Small hairpin RNA (shRNA) targeting the human CIITA gene and a scrambled shRNA sequence (Table S2) were cloned into the pLKO.1 plasmid as previously described. 13…”

Molecular mechanisms of COVID-19-induced pulmonary fibrosis and epithelial-mesenchymal transition

“…The relationship between plasminogen activation system and acute lung injury has been vigorously discussed. At the same time, its role in COVID-19-induced PF is also being widely studied (Shmakova et al, 2023). Studies have shown that urokinase plasminogen activator (uPA) and urokinase-type plasminogen activator receptor (uPAR) are involved in the pathogenesis of COVID-19 and contribute to the development of PF through single-cell RNA-seq and immunohistochemical analysis.…”

“…At the end of 2019, an unprecedented outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) broke out in Wuhan, Hubei Province, China, and then spread rapidly throughout China and the world (Shmakova et al, 2023). The unprecedented spread of COVID-19 has brought great challenges and harms to global public health, and attracted the attention and response of the world.…”

“…Approximately 30 percent of patients present with SARS-CoV-2-associated pulmonary fibrosis (PF), and this proportion increased with disease severity and duration. Established fibrosis worsened already impaired lung function in COVID-19 survivors (Francone et al, 2020;Fu et al, 2020;Vasarmidi et al, 2020;Bocchino et al, 2022;Saifi et al, 2022;Shmakova et al, 2023). Even after recovery from COVID-19, up to 17% of patients will develop PF (Pan et al, 2020).…”