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Coagulation cascade proteases and tissue fibrosis.

R C Chambers1, G J Laurent

  • 1Centre for Cardiopulmonary Biochemistry and Respiratory Medicine, University College London, Rayne Institute, 5 University Street, London WC1E 6JJ, U.K. r.chambers@ucl.ac.uk

Biochemical Society Transactions
|May 25, 2002
PubMed
Summary

Coagulation proteases, like thrombin, promote fibrosis by activating protease-activated receptor-1 (PAR-1). Inhibiting PAR-1 may offer a new strategy for treating fibrotic disorders.

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Area of Science:

  • Biochemistry
  • Cell Biology
  • Pathology

Background:

  • Fibrotic disorders involve excessive extracellular matrix deposition and coagulation activity.
  • Coagulation proteases (thrombin, Factor Xa, VIIa) influence cellular responses in inflammation and tissue repair.
  • Protease-activated receptors (PARs) mediate cellular effects of these proteases.

Purpose of the Study:

  • To investigate the role of coagulation proteases and PAR-1 in fibrotic disorders.
  • To explore the mechanisms by which thrombin and Factor Xa contribute to fibrosis.
  • To evaluate the potential of PAR-1 antagonists as antifibrotic agents.

Main Methods:

  • In vitro studies on protease-activated receptor (PAR) activation.
  • In vivo studies using proteolytic inhibitors, PAR-1 antagonists, and PAR-1-deficient mice.

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  • Analysis of fibrogenic mediator induction (e.g., PDGF, CTGF).

    • Main Results:

    • Thrombin predominantly mediates profibrotic effects via PAR-1.
    • Factor Xa's mitogenic effects on fibroblasts are also mediated via PAR-1.
    • Coagulation proteases induce fibrogenic mediators like platelet-derived growth factor and connective tissue growth factor.
    • In vivo studies confirm the role of coagulation proteases in inflammation and vascular pathologies.

    Conclusions:

    • Coagulation proteases play a significant role in the pathogenesis of fibrosis.
    • PAR-1 is a key mediator of the profibrotic effects of coagulation proteases.
    • PAR-1 antagonists show potential as therapeutic agents for fibrotic diseases.