Pivotal role of PAI-1 in a murine model of hepatic vein thrombosis

Blood. 2006 Jan 1;107(1):132-4. doi: 10.1182/blood-2005-07-2681. Epub 2005 Sep 13.

Abstract

Hepatic veno-occlusive disease (VOD) is a common complication of high-dose chemotherapy associated with bone marrow transplantation. While the pathogenesis of VOD is uncertain, plasminogen activator inhibitor-1 (PAI-1) has emerged as a diagnostic marker and predictor of VOD in humans. In this study, we investigated the role of PAI-1 in a murine model of VOD produced by long-term nitric oxide synthase inhibition using L-NAME. After 6 weeks, wild-type (WT) mice developed extensive fibrinoid hepatic venous thrombi and biochemical evidence of hepatic injury and dysfunction. In contrast, PAI-1-deficient mice were largely protected from the development of hepatic vein thrombosis. Furthermore, WT mice that received tiplaxtinin, an antagonist of PAI-1, were effectively protected from L-NAME-induced thrombosis. Taken together, these data indicate that NO and PAI-1 play pivotal and antagonistic roles in hepatic vein thrombosis and that PAI-1 is a potential target in the prevention and treatment of VOD in humans.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Budd-Chiari Syndrome / chemically induced
  • Budd-Chiari Syndrome / etiology*
  • Budd-Chiari Syndrome / prevention & control
  • Disease Models, Animal
  • Hepatic Veno-Occlusive Disease / chemically induced
  • Hepatic Veno-Occlusive Disease / etiology
  • Indoleacetic Acids
  • Indoles / pharmacology
  • Mice
  • Mice, Knockout
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Nitric Oxide / pharmacology
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Plasminogen Activator Inhibitor 1 / genetics
  • Plasminogen Activator Inhibitor 1 / physiology*

Substances

  • Indoleacetic Acids
  • Indoles
  • Plasminogen Activator Inhibitor 1
  • tiplaxtinin
  • Nitric Oxide
  • Nitric Oxide Synthase
  • NG-Nitroarginine Methyl Ester