Plasminogen deficiency leads to impaired lobular reorganization and matrixaccumulation after chronic liver injury

To determine the regulatory role of plasminogen in hepatic repair following a chronic liver injury, we injected carbon tetrachloride (CCl4) biweekly i nto mice lacking plasminogen (Plg(0)) and plasminogen-sufficient littermate s; (Plg(+)). On gross examination, we found that Plg(0) livers became enlar ged and pale with foci of red nodules as early as 4 weeks after CCl4 inject ion, while Plg(+) livers appeared minimally affected by 6 weeks. Microscopi cally, Plg(0) livers had a pronounced pericentral linking, with accumulatio n of centrilobular eosinophilic material in injured areas, which resulted i n a significant increase in liver mass and total protein. Immunohistochemis try revealed that fibrin accumulated progressively in injured regions. Howe ver, the combined genetic loss of plasminogen and fibrinogen did not correc t the abnormal phenotype. Mason's trichrome staining revealed intense signa l in centrilobular regions and electron microscopy showed a marked increase in fibrillary material demonstrating an excessive accumulation of extracel lular matrix in Plg(0) mice. The zone-specific increase in matrix component s was associated with an increase in the number of activated hepatic stella te cells within injured sites of Plg(0) livers. Taken together, these data suggest that the progressive accumulation of fibrin-unrelated matrix substr ates in Plg(0) livers after a chronic injury results from the combined effe cts of impaired proteolysis and increased matrix production.