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

Autor:	Cheng Ying Hsieh, Joen Rong Sheu, Wei Lin Chen, Chih Hao Yang, Jie Heng Tsai, Chi Li Chung
Jazyk:	angličtina
Rok vydání:	2019
Předmět:	0301 basic medicine Male Mesoderm lcsh:Chemistry chemistry.chemical_compound Mice Phosphatidylinositol 3-Kinases 0302 clinical medicine lcsh:QH301-705.5 Spectroscopy Aged 80 and over mesothelial–mesenchymal transition biology General Medicine Exudates and Transudates Middle Aged respiratory system thrombin Computer Science Applications Effusion Plasminogen activator inhibitor-1 Pleura plasminogen activator inhibitor-1 Female pleural fibrosis residual pleura thickening medicine.drug Signal Transduction Adult tuberculous pleural fibrosis Catalysis Article Inorganic Chemistry 03 medical and health sciences Tissue factor Young Adult Thrombin In vivo Plasminogen Activator Inhibitor 1 medicine Animals Humans Tuberculosis Receptor PAR-1 Physical and Theoretical Chemistry tuberculous pleural effusion Molecular Biology Aged business.industry Organic Chemistry Mycobacterium tuberculosis Fibrosis In vitro respiratory tract diseases Fibronectin Mice Inbred C57BL Pleural Effusion Disease Models Animal pleural mesothelial cell 030104 developmental biology 030228 respiratory system chemistry lcsh:Biology (General) lcsh:QD1-999 biology.protein Cancer research business Plasminogen activator Follow-Up Studies
Zdroj:	International Journal of Molecular Sciences, Vol 20, Iss 20, p 5076 (2019) International Journal of Molecular Sciences Volume 20 Issue 20
ISSN:	1422-0067
Popis:	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&ndash 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 &alpha smooth muscle actin (&alpha SMA) and fibronectin, and attenuated pleural fibrosis. In pleural mesothelial cells (PMCs), thrombin concentration-dependently increased PAI-1, &alpha 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&minus 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.
Databáze:	OpenAIRE
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