Transforming growth factor-α (TGF-α) improves hepatic DNA synthesis after hepatectomy in cirrhotic rats

Impaired liver regeneration in cirrhosis complicates the surgical treatment of liver tumors which arise in this setting. We developed a rat model to investigate the regenerative response of cirrhotic liver after hepatectomy and studied the effect of exogenous transforming growth factor-α (TGF-α), a potent liver mitogen. Micronodular cirrhosis was established by the simultaneous administration of CCl₄ and phenobarbital. Hepatic DNA synthesis ([³H]thymidine incorporation into DNA) 24 hr after partial hepatectomy in cirrhotic rats was 15.6 ± 3.4 cpm/μg DNA (means ± SEM), which was significantly lower than in normal rats (37.3 ± 3.4 cpm/μg DNA, P < 0.05). Exogenous TGF-α (30 nmole/kg, sc every 12 hr) significantly improved [³H]thymidine incorporation (35.6 ± 8.2 cpm/μg DNA, P < 0.05). An autoradiographic nuclear labeling index also confirmed increased DNA synthesis (6.7% vs 13.4%). TGF-α had no effect on normal regenerating liver (42.5 ± 8.8 cpm/μg DNA, NS). Although the significance of TGF-α-enhanced liver regeneration in cirrhosis has yet to be assessed, this model may be useful for the study of mechanisms which control hepatic proliferation.