LIVER-REGENERATION AND THE EFFECT OF EXOGENOUS PUTRESCINE ON REGENERATIVE ACTIVITY AFTER PARTIAL-HEPATECTOMY IN CIRRHOTIC RATS

There are conflicting data regarding the ability of the liver to regenerate after partial hepatectomy in animals and humans with cirrhosis. The purpose of this study was to document liver regeneration after partial hepatectomy in a carbon tetrachloride rat model of cirrhosis and to determine whether exogenous putrescine, a polyamine that has been reported to stimulate liver regeneration in animal models of acute liver failure, enhances regenerative activity in cirrhosis. Liver fibrosis and cirrhosis were produced by weekly intragastric gavage with carbon tetrachloride in 130 adult male rats. Vehicle-gavaged rats (n = 12) served as healthy controls. At surgery and at 4 and 8 hr after 70% hepatectomy, rats received normal saline solution or 1 or 10 mg/kg putrescine by intraperitoneal injection. Another group (n = 32) of carbon tetrachloride-treated rats was given putrescine (100 mg/kg) or normal saline solution twice daily for 10 days before partial hepatectomy and at 0, 4 and 8 hr after partial hepatectomy. Liver regeneration was documented 24 and 48 hr after partial hepatectomy on the basis of restitution of liver mass, ornithine decarboxylase activity and [H-3]thymidine incorporation into liver DNA. Automated image analysis of the resected liver specimens separated carbon tetrachloride-treated rats into two subgroups: those with bridging fibrosis (fibrotic group) and those with micronodular cirrhosis (cirrhotic group). Restitution of liver mass and ornithine decarboxylase activity at 24 and 48 hr after partial hepatectomy were similar to carbon tetrachloride-treated rats (both fibrotic and cirrhotic) and vehicle-treated healthy controls. Hepatic DNA synthesis, however, was significantly impaired at 48 hr in fibrotic rats (42.1 +/- 20.6 dpm/ng DNA; p < 0.05) and at 24 and 48 hr in cirrhotic rats (22.9 +/- 9.6 and 27.0 +/- 11.3 dpm/ng DNA, respectively; p < 0.005 and p < 0.001) compared with vehicle-treated healthy controls (52.6 +/- 9.2 and 78.3 +/- 6.9 dpm/ng DNA at 24 and 48 hr, respectively). Putrescine therapy after or before and after partial hepatectomy did not alter restored liver mass, ornithine decarboxylase activity or DNA synthesis at 24 or 48 hr after partial hepatectomy in fibrotic or cirrhotic rats compared with their respective saline solution-treated controls. The results of this study indicate that hepatic DNA synthesis is impaired in rats with fibrosis and cirrhosis after partial hepatectomy and that exogenous putrescine does not enhance fiver regeneration in this model of chronic liver disease.