PLASMINOGEN REGULATES HEPATIC MATRIX REMODELING BY A MECHANISM INDEPENDENT OF FIBRINOLYSIS

Abstract

4 Clearance of necrotic cells and reorganization of extracellular matrix are essential to liver repair after injury. Both processes are severely impaired in livers of plasminogen (Plg)-deficient mice. Plg is a protease with well-defined roles in clotting and repair of extrahepatic tissues by fibrin degradation (fibrinolysis). Therefore, we hypothesized that Plg deficiency leads to defective repair by the accumulation of fibrin in the diseased liver. To address this hypothesis, we administered carbon tetrachloride (CCl4) to mice with the targeted inactivation of genes for Plg (Plgo), fibrinogen (Fibo), or both (Plgo/Fibo), and to nontargeted littermates (controls). Two days after CCl4, livers of all three genotypes and controls had a diffuse diseased appearance. By 7d, control and Fibo livers restored normal appearance, while Plgo livers displayed the same diseased appearance 7-14d after injury. Unexpectedly, Plgo/Fibo livers also appeared diseased at both time points. Microscopically, necrosis in centrilobular hepatocytes was identical in all groups 2d after CCl4, and histology normalized in controls and Fibo livers by 7d. In Plgo and Plgo/Fibo livers, the injury persisted up to 14d, showing no evidence of repair. Liver enzymes peaked at 2d and normalized in all mice by 7d, suggesting no evidence of ongoing liver injury. The hepatic mitogenic index was similar in experimental and control livers, peaking at 2d and returning to baseline levels by 7d. Immunostaining showed fibrin accumulation in diseased areas of Plgo livers, but not in Plgo/Fibo, which stained intensely by trichrome. In conclusion, the genetically superimposed loss of fibrinogen does not rescue the severe defective repair of Plgo livers. These studies establish Plg as an essential component of the proteolytic system directed at reorganization of the hepatic extracellular matrix in a mechanism independent of fibrinolysis.