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Am J Physiol Gastrointest Liver Physiol 284: G508-G515, 2003. First published November 13, 2002; doi:10.1152/ajpgi.00336.2002
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Vol. 284, Issue 3, G508-G515, March 2003

Plasminogen directs the pleiotropic effects of uPA in liver injury and repair

Angela R. Currier1, Gregg Sabla1, Stephanie Locaputo1, Hector Melin-Aldana1,2, Jay L. Degen3, and Jorge A. Bezerra1

Divisions of 1 Gastroenterology, Hepatology, and Nutrition, 2 Pathology, and 3 Developmental Biology, Children's Hospital Research Foundation and Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio 45229-3039

The urokinase-type plasminogen activator (uPA) plays a central role in liver repair. Nevertheless, the hepatic overexpression of uPA results in panlobular injury and neonatal mortality. Here, we define the molecular mechanisms of liver injury and explore whether uPA can regulate liver repair independently of plasminogen. To address the hypothesis that the liver injury in transgenic mice results from the intracellular activation of plasminogen by transgene-derived uPA (uPAT), we generated mice that overexpress uPAT and lack functional plasminogen (uPAT-Plg-). In these mice, loss of plasminogen abolished the hepatocyte-specific injury and prevented the formation of regenerative nodules displayed by uPAT littermates. Despite the increased expression of hepatic uPA, livers of uPAT-Plg- mice were unable to clear necrotic cells and restore normal lobular organization after an acute injury. Notably, high levels of circulating uPA in uPAT-Plg- mice did not prevent the long-term extrahepatic abnormalities previously associated with plasminogen deficiency. These data demonstrate that plasminogen directs the hepatocyte injury induced by uPAT and mediates the reparative properties of uPA in the liver.

regeneration; urokinase; proliferation; hepatocyte; tissue remodeling


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