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Thrombin inhibits migration of human hepatic myofibroblasts

Jennifer Gillibert-Duplantier1, Véronique Neaud, Jean-Frédéric Blanc

  • 1INSERM U889, Université Victor Segalen Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France. jean.rosenbaum@gref.u-bordeaux2.fr

American Journal of Physiology. Gastrointestinal and Liver Physiology
|March 24, 2007
PubMed

Insights

Thrombin, a key enzyme in liver fibrogenesis, inhibits human liver myofibroblast migration through two distinct pathways. This action, mediated by protease-activated receptor-1 (PAR-1), may regulate liver scarring.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Hepatology

Background:

  • Emerging data suggest thrombin's involvement in liver fibrogenesis.
  • The precise mechanism by which thrombin influences liver fibrosis remains unclear.
  • Understanding thrombin's role in myofibroblast behavior is crucial for deciphering fibrogenesis.

Purpose of the Study:

  • To investigate the effect of thrombin on human liver myofibroblast migration.
  • To elucidate the molecular mechanisms underlying thrombin's action on myofibroblasts.

Main Methods:

  • Assessed myofibroblast migration in response to thrombin.
  • Utilized thrombin antagonists, PAR-1 mimetic peptides, and antibodies to probe receptor involvement.
  • Investigated the roles of cyclooxygenase-2 (COX-2), prostaglandin E(2), and EP(2) receptors.
  • Examined signaling pathways including Akt-1 phosphorylation and PDGF-beta receptor activation.

Main Results:

  • Thrombin significantly inhibited both basal and PDGF-BB-induced myofibroblast migration.
  • The inhibitory effect on basal migration was dependent on thrombin's catalytic activity, PAR-1 activation, COX-2, prostaglandin E(2), and EP(2) receptor signaling.
  • Thrombin's inhibition of PDGF-BB-induced migration involved the suppression of PDGF-induced Akt-1 phosphorylation via dephosphorylation of the PDGF-beta receptor, independent of COX-2.

Conclusions:

  • Thrombin exerts dual inhibitory effects on human liver myofibroblast migration.
  • These mechanisms, involving PAR-1, COX-2/prostaglandin pathways, and PDGF receptor signaling, suggest thrombin's regulatory role in liver fibrogenesis.
  • Modulation of myofibroblast migration by thrombin may be a key factor in controlling liver scarring progression.

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