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(American Journal of Pathology. 2001;159:2179-2186.)
© 2001 American Society for Investigative Pathology

Regular Article

Plasminogen Deficiency Leads to Impaired Lobular Reorganization and Matrix Accumulation after Chronic Liver Injury

John F. Pohl^*, Hector Melin-Aldana, Gregg Sabla^*, Jay L. Degen and Jorge A. Bezerra^*

From the Divisions of Pediatric Gastroenterology, Hepatology, and Nutrition,^*
Pathology,
and Developmental Biology,
Children’s Hospital Research Foundation and Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio

To determine the regulatory role of plasminogen in hepatic repair following a chronic liver injury, we injected carbon tetrachloride (CCl₄) biweekly into mice lacking plasminogen (Plg0) and plasminogen-sufficient littermates (Plg⁺). On gross examination, we found that Plg0 livers became enlarged and pale with foci of red nodules as early as 4 weeks after CCl₄ injection, while Plg⁺ livers appeared minimally affected by 6 weeks. Microscopically, Plg0 livers had a pronounced pericentral linking, with accumulation of centrilobular eosinophilic material in injured areas, which resulted in a significant increase in liver mass and total protein. Immunohistochemistry revealed that fibrin accumulated progressively in injured regions. However, the combined genetic loss of plasminogen and fibrinogen did not correct the abnormal phenotype. Mason’s trichrome staining revealed intense signal in centrilobular regions and electron microscopy showed a marked increase in fibrillary material demonstrating an excessive accumulation of extracellular matrix in Plg0 mice. The zone-specific increase in matrix components was associated with an increase in the number of activated hepatic stellate cells within injured sites of Plg0 livers. Taken together, these data suggest that the progressive accumulation of fibrin-unrelated matrix substrates in Plg0 livers after a chronic injury results from the combined effects of impaired proteolysis and increased matrix production.

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