The expression of regenerative growth factors in chronic liver injury and repair.

Acute hepatic injury initiates known cellular and molecular events for regeneration. In contrast, the molecular mechanisms of repair following chronic liver injuries have not been defined. Transforming growth factor alpha (TGF alpha) and hepatocyte growth factor (HGF) are hepatocyte mitogens whose in vivo expression in liver is central to the regulation of regeneration. To study the role of TGF alpha and HGF in liver injury and repair, we used a model of reversible biliary obstruction without a bilioenteric anastomosis. In rats, the common bile duct was obstructed either by a vessel loop suspended from the abdominal wall (LOOP) or by ligation and division (DLD). After 7 days of obstruction, animals were autopsied or were decompressed by subcutaneous release of the loop and then autopsied at 1, 2, 4, 7, or 10 days of postdecompression. Serum bilirubin (mg/dl) increased to 14.8 +/- 2.9 (DLD) and 10.3 +/- 3.0 (LOOP) (+/- SEM, NS, ANOVA) at 7 days of obstruction. Liver sections demonstrated equal ductal hyperplasia and collagen deposition after LOOP and DLD. Biliary decompression reversed bile duct proliferation and normalized bilirubin. Analysis of injured and repairing liver mRNA by ribonuclease protection assay showed that TGF alpha mRNA levels were not significantly altered by injury or during repair. HGF mRNA was elevated following obstruction and showed increased expression 1 day after decompression, peaking at 2 days of repair. This evidence of modulation of HGF during liver repair following chronic cholestatic injury suggests that HGF may have a role in cellular proliferation during repair or act as a compensatory growth factor during injury.