Plasminogen activators direct reorganization of the liver lobule after acute injury

Tissue repair requires an adequate cellular proliferation coordinated with the timely proteolysis of matrix elements, Based on the properties of plasm inogen activators in liver cell proliferation and tissue proteolysis, we ex plored the regulatory role of tissue-type plasminogen activator (tPA) and u rokinase-type plasminogen activator (uPA) in liver repair. Using carbon tet rachloride (CCl4) intoxication as a model of acute liver injury, we found t hat tPA-deficient mice displayed a mild defect in hepatic repair, whereas l ivers of uPA-deficient mice had a more substantial delay in repair, with in jury of centrilobular hepatocytes persisting up to 14 days after CCl4. Nota bly, functional cooperativity between plasminogen activators was strongly i nferred from the profound reparative defect in livers of mice lacking tPA a nd uPA simultaneously, with persistence of centrilobular injury as far out as 35 days. The defective repair was not because of increased susceptibilit y of experimental mice to the toxin or to inadequate cellular proliferation . Instead, lack of plasminogen activators led to the accumulation of fibrin and fibronectin within injured areas and poor removal of necrotic cells. T hese data demonstrate that tPA and uPA play a critical role in hepatic repa ir via proteolysis of matrix elements and clearance of cellular debris from the field of injury.