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Am J Physiol Gastrointest Liver Physiol (November 13, 2002). doi:10.1152/ajpgi.00336.2002
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Articles in PresS, published online ahead of print November 13, 2002
Am J Physiol Gastrointest Liver Physiol, 10.1152/ajpgi.00336.2002
Submitted on August 9, 2002
Accepted on November 8, 2002

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

Angela R. Currier1, Gregg E. Sabla1, Stephanie Locaputo1, Hector Melin-Aldana2, Jay L. Degen3, and Jorge A. Bezerra1*

1 Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital Research Foundation and Department of Pediatrics, Cincinnati, OH, USA
2 Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital Research Foundation and Department of Pediatrics, Cincinnati, OH, USA; Division of Pathology, Children's Hospital Research Foundation and Department of Pediatrics, Cincinnati, OH, USA
3 Division of Developmental Biology, Children's Hospital Research Foundation and Department of Pediatrics, Cincinnati, OH, USA

* To whom correspondence should be addressed. E-mail: jorge.bezerra{at}chmcc.org.

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 following an acute injury. Notably, high levels of circulating uPA in uPAT-Plg° mice did not prevent the long-term extra-hepatic abnormalities previously associated with plasminogen deficiency. These data demonstrate that plasminogen directs the hepatocyte injury induced by the uPA transgene and mediates the reparative properties of uPA in the liver.




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