Plasminogen deficiency leads to impaired remodeling after a toxic injury to the liver

Cellular proliferation and tissue remodeling are central to the regenerativ e response after a toxic injury to the liver. To explore the role of plasmi nogen in hepatic tissue remodeling and regeneration, we used carbon tetrach loride to induce an acute liver injury in plasminogen-deficient (Plg degree s) mice and nontransgenic littermates (Plg(+)). On day 2 after CCl4, livers of Plg(+) and Plg degrees mice had a similar diseased pale/lacy appearance , followed by restoration of normal appearance in Plg(+) livers by day 7. I n contrast, Plg degrees 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 o f impaired proliferative response in Plg degrees mice. Notably, fibrin depo sition was a prominent feature in diseased centrilobular areas in Plg degre es livers for at least 30 days after injury. Nonetheless, the genetically s uperimposed loss of the A alpha fibrinogen chain (Plg degrees/Fib degrees m ice) did not correct the abnormal phenotype, These data show that plasminog en deficiency impedes the clearance of necrotic: tissue from a diseased hep atic microenvironment and the subsequent reconstitution of normal liver arc hitecture in a fashion that is unrelated to circulating fibrinogen.