Plasminogen deficiency leads to impaired remodeling after a toxic injury to the liver.
Cellular proliferation and tissue remodeling are central to the regenerative response after a toxic injury to the liver. To explore the role of plasminogen in hepatic tissue remodeling and regeneration, we used carbon tetrachloride to induce an acute liver injury in plasminogen-deficient (Plg(o)) mice and nontransgenic littermates (Plg(+)). On day 2 after CCl(4), livers of Plg(+) and Plg(o) mice had a similar diseased pale/lacy appearance, followed by restoration of normal appearance in Plg(+) livers by day 7. In contrast, Plg(o) livers remained diseased for as long as 2.5 months, with a diffuse pale/lacy appearance and persistent damage to centrilobular hepatocytes. The persistent centrilobular lesions were not a consequence of impaired proliferative response in Plg(o) mice. Notably, fibrin deposition was a prominent feature in diseased centrilobular areas in Plg(o) livers for at least 30 days after injury. Nonetheless, the genetically superimposed loss of the Aalpha fibrinogen chain (Plg(o)/Fib(o) mice) did not correct the abnormal phenotype. These data show that plasminogen deficiency impedes the clearance of necrotic tissue from a diseased hepatic microenvironment and the subsequent reconstitution of normal liver architecture in a fashion that is unrelated to circulating fibrinogen.
Bezerra
J A
JA
Children's Hospital Research Foundation, Department of Pediatrics, University of Cincinnati, OH 45229-3039, USA. jorge.bezerra@chmcc.org
Bugge
T H
TH
Melin-Aldana
H
H
Sabla
G
G
Kombrinck
K W
KW
Witte
D P
DP
Degen
J L
JL
D000347:Afibrinogenemia / Q000235:genetics; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002725:Chloroform / Q000633:toxicity; D005337:Fibrin / Q000096:biosynthesis; D005340:Fibrinogen / Q000235:genetics; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D008115:Liver Regeneration / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D010958:Plasminogen / Q000172:deficiency* / Q000235:genetics
D002725:Chloroform; D005337:Fibrin; D005340:Fibrinogen; D010958:Plasminogen