Thrombin Upregulates PAI-1 and Mesothelial-Mesenchymal Transition Through PAR-1 and Contributes to Tuberculous Pleural Fibrosis

Int J Mol Sci. 2019 Oct 13;20(20):5076. doi: 10.3390/ijms20205076.


Thrombin is an essential procoagulant and profibrotic mediator. However, its implication in tuberculous pleural effusion (TBPE) remains unknown. The effusion thrombin and plasminogen activator inhibitor-1 (PAI-1) levels were measured among transudative pleural effusion (TPE, n = 22) and TBPE (n = 24) patients. Pleural fibrosis, identified as radiological residual pleural thickening (RPT) and shadowing, was measured at 12-month follow-up. Moreover, in vivo and in vitro effects of thrombin on PAI-1 expression and mesothelial-mesenchymal transition (MMT) were assessed. We demonstrated the effusion thrombin levels were significantly higher in TBPE than TPE, especially greater in TBPE patients with RPT > 10mm than those without, and correlated positively with PAI-1 and pleural fibrosis area. In carbon black/bleomycin-treated mice, knockdown of protease-activated receptor-1 (PAR-1) markedly downregulated α-smooth muscle actin (α-SMA) and fibronectin, and attenuated pleural fibrosis. In pleural mesothelial cells (PMCs), thrombin concentration-dependently increased PAI-1, α-SMA, and collagen I expression. Specifically, Mycobacterium tuberculosis H37Ra (MTBRa) induced thrombin production by PMCs via upregulating tissue factor and prothrombin, and PAR-1 silencing considerably abrogated MTBRa-stimulated PAI-1 expression and MMT. Consistently, prothrombin/PAR-1 expression was evident in the pleural mesothelium of TBPE patients. Conclusively, thrombin upregulates PAI-1 and MMT and may contribute to tuberculous pleural fibrosis. Thrombin/PAR-1 inhibition may confer potential therapy for pleural fibrosis.

Keywords: mesothelial–mesenchymal transition; plasminogen activator inhibitor-1; pleural fibrosis; pleural mesothelial cell; residual pleura thickening; thrombin; tuberculous pleural effusion; tuberculous pleural fibrosis.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Disease Models, Animal
  • Exudates and Transudates / metabolism
  • Female
  • Fibrosis
  • Follow-Up Studies
  • Humans
  • Male
  • Mesoderm / drug effects
  • Mesoderm / growth & development
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Mycobacterium tuberculosis / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Plasminogen Activator Inhibitor 1 / metabolism*
  • Pleura / pathology*
  • Pleural Effusion / metabolism
  • Pleural Effusion / pathology
  • Receptor, PAR-1 / metabolism*
  • Signal Transduction
  • Thrombin / metabolism*
  • Tuberculosis / metabolism*
  • Tuberculosis / pathology
  • Young Adult


  • Plasminogen Activator Inhibitor 1
  • Receptor, PAR-1
  • Thrombin