Ischemia impairs liver regeneration after major tissue loss in rodents: Protective effects of interleukin-6

The effects of ischemia on the regenerative capacity of the liver after maj or tissue loss remain unclear. Interleukin-6 (IL-6) has been shown to confe r protection in models of normothermic ischemia and reperfusion injury and to initiate hepatocyte proliferation after major hepatectomy. Therefore, we investigated the effects of ischemia on the regenerative capacity of the l iver and evaluated the role of IL-6 in reducing reperfusion injury and enha ncing hepatic proliferation in models combining ischemia and major hepatect omy Rats subjected to 70% hepatectomy and 30 minutes of hepatic ischemia sh owed significantly reduced regenerative capacity (mitotic index, proliferat ing cell nuclear antigen, and regenerated liver weight) when compared with animals subjected to hepatectomy alone. Pretreatment of animals subjected t o hepatectomy and ischemia with recombinant interleukin-6 (rIL-6) completel y restored each parameter of regeneration to levels comparable with those o f animals subjected to hepatectomy only. Similar results were obtained in I L-6 deficient (IL-6(-/-)) mice. IL-6(-/-) mice exposed to ischemia and hepa tectomy showed impaired hepatic regeneration when compared with wild-type m ice subjected to the same experimental conditions. The use of rIL-6 complet ely corrected each parameter of regeneration showing the specificity of IL- 6 in this type of injury. The impact of IL-6 on animal survival was studied in a model combining 45 minutes of ischemia and 68% hepatectomy, Five of 7 (71%) animals pretreated with rIL-6 survived permanently, whereas all cont rol animals died within 3 days of surgery (P = .02, Fisher's exact test). I n conclusion, the study shows that ischemia dramatically impairs the regene rative capacity of the liver. IL-6 appears to be a key protective molecule in reducing injury and promoting regeneration following combined ischemia a nd major tissue loss.