Pivotal role of PAI-1 in a murine model of hepatic vein thrombosis.
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.
Smith
Layton H
LH
Division of Cardiovascular Medicine, Vanderbilt University Medical Center, 2220 Pierce Ave, Nashville, TN 37232, USA.
Dixon
John D
JD
Stringham
John R
JR
Eren
Mesut
M
Elokdah
Hassan
H
Crandall
Dave L
DL
Washington
Kay
K
Vaughan
Douglas E
DE
D000818:Animals; D006502:Budd-Chiari Syndrome / Q000139:chemically induced / Q000209:etiology* / Q000517:prevention & control; D004195:Disease Models, Animal; D006504:Hepatic Veno-Occlusive Disease / Q000139:chemically induced / Q000209:etiology; D007210:Indoleacetic Acids; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000502:physiology*
D007210:Indoleacetic Acids; D007211:Indoles; D017395:Plasminogen Activator Inhibitor 1; C488103:tiplaxtinin; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester