TY - JOUR
T1 - Plasminogen activators direct reorganization of the liver lobule after acute injury
AU - Bezerra, Jorge A.
AU - Currier, Angela R.
AU - Melin-Aldana, Hector
AU - Sabla, Gregg
AU - Bugge, Thomas H.
AU - Kombrinck, Keith W.
AU - Degen, Jay L.
N1 - Funding Information:
Supported in part by the Hoffman-LaRoche, Ltd. , Grant ROTRF 477924785 (to J. A. B.) and National Institutes of Health grants DK 55710 (to J. A. B.) and HL 47826 (to J. L. D.).
PY - 2001
Y1 - 2001
N2 - Tissue repair requires an adequate cellular proliferation coordinated with the timely proteolysis of matrix elements. Based on the properties of plasminogen activators in liver cell proliferation and tissue proteolysis, we explored the regulatory role of tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) in liver repair. Using carbon tetrachloride (CCl4) intoxication as a model of acute liver injury, we found that tPA-deficient mice displayed a mild defect in hepatic repair, whereas livers of uPA-deficient mice had a more substantial delay in repair, with injury of centrilobular hepatocytes persisting up to 14 days after CCl4. Notably, functional cooperativity between plasminogen activators was strongly inferred from the profound reparative defect in livers of mice lacking tPA and uPA simultaneously, with persistence of centrilobular injury as far out as 35 days. The defective repair was not because of increased susceptibility 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. These data demonstrate that tPA and uPA play a critical role in hepatic repair via proteolysis of matrix elements and clearance of cellular debris from the field of injury.
AB - Tissue repair requires an adequate cellular proliferation coordinated with the timely proteolysis of matrix elements. Based on the properties of plasminogen activators in liver cell proliferation and tissue proteolysis, we explored the regulatory role of tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) in liver repair. Using carbon tetrachloride (CCl4) intoxication as a model of acute liver injury, we found that tPA-deficient mice displayed a mild defect in hepatic repair, whereas livers of uPA-deficient mice had a more substantial delay in repair, with injury of centrilobular hepatocytes persisting up to 14 days after CCl4. Notably, functional cooperativity between plasminogen activators was strongly inferred from the profound reparative defect in livers of mice lacking tPA and uPA simultaneously, with persistence of centrilobular injury as far out as 35 days. The defective repair was not because of increased susceptibility 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. These data demonstrate that tPA and uPA play a critical role in hepatic repair via proteolysis of matrix elements and clearance of cellular debris from the field of injury.
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U2 - 10.1016/S0002-9440(10)64039-4
DO - 10.1016/S0002-9440(10)64039-4
M3 - Article
C2 - 11238040
AN - SCOPUS:0035101027
SN - 0002-9440
VL - 158
SP - 921
EP - 929
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 3
ER -