Plasminogen deficiency leads to impaired lobular reorganization and matrix accumulation after chronic liver injury.
To determine the regulatory role of plasminogen in hepatic repair following a chronic liver injury, we injected carbon tetrachloride (CCl(4)) biweekly into mice lacking plasminogen (Plg(0)) and plasminogen-sufficient littermates (Plg(+)). On gross examination, we found that Plg(0) livers became enlarged and pale with foci of red nodules as early as 4 weeks after CCl(4) injection, while Plg(+) livers appeared minimally affected by 6 weeks. Microscopically, Plg(0) 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 Plg(0) 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 Plg(0) livers. Taken together, these data suggest that the progressive accumulation of fibrin-unrelated matrix substrates in Plg(0) livers after a chronic injury results from the combined effects of impaired proteolysis and increased matrix production.
Pohl
J F
JF
Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital Research Foundation and Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA.
Melin-Aldana
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Sabla
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Degen
J L
JL
Bezerra
J A
JA
D000347:Afibrinogenemia / Q000235:genetics; D000818:Animals; D002251:Carbon Tetrachloride / Q000008:administration & dosage; D056486:Chemical and Drug Induced Liver Injury; D002908:Chronic Disease; D005109:Extracellular Matrix / Q000378:metabolism*; D005337:Fibrin / Q000172:deficiency; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D010958:Plasminogen / Q000172:deficiency* / Q000235:genetics; D013997:Time Factors
D005337:Fibrin; D010958:Plasminogen; D002251:Carbon Tetrachloride; D020780:Matrix Metalloproteinase 9