Interleukin-6 inhibits oxidative injury and necrosis after extreme liver resection.
Extreme hepatectomy or resection of more than 80% of liver mass often leads to liver failure and death and is a major limitation to therapeutic liver resection for patients with liver tumors. We sought to define the mechanisms leading to liver failure and to determine the utility of interleukin-6 (IL-6) administration to improve outcomes. Mice were injected with Chinese hamster ovary cells expressing human IL-6 or no recombinant protein, or were administered recombinant IL-6 or carrier by osmotic mini-pump. Mice were then subjected to 70% or 87% hepatectomy. Light and electron microscopy of liver sections after 87% hepatectomy showed ballooning hepatocytes, vacuolar changes, and mitochondrial abruption, with absence of anoikic nuclei. No significant activation of executor caspases or DNA laddering was observed, although a dramatic decrease in cellular adenosine triphosphate (ATP) stores was measured, suggesting cell death was by a necrotic pathway involving mitochondrial dysfunction. A large increase in protein oxidation was observed, indicative of significant oxidative stress. IL-6 treatment before 87% hepatectomy resulted in less biochemical and histological evidence of liver injury as well as earlier proliferating chain nuclear antigen (PCNA) expression and accelerated recovery of liver mass. IL-6 pretreatment induced the antioxidative injury proteins, ref-1 and GPX1, decreased protein oxidation, vacuolar changes and leakage of mitochondrial products, improved ATP stores, and maintained cellular ultrastructure after 87% hepatectomy.


CONCLUSIONS
Massive oxidative injury and mitochondrial dysfunction occurs in the liver after extreme hepatectomy. IL-6 improves recovery and survival from extreme liver resection by enhancing pro-growth pathways, reducing oxidative stress, and maintaining mitochondrial function.
Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
Xiaoling
X
Jin
Zongxiu
Z
Zhang
Donna
D
Beer-Stolz
Teresa A
TA
Zimmers
Leonidas G
LG
Koniaris
D000255:Adenosine Triphosphate / Q000172:deficiency; D000818:Animals; D053938:DNA Fragmentation; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D006498:Hepatectomy; D015850:Interleukin-6 / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D008099:Liver / Q000293:injuries / Q000473:pathology / Q000601:surgery*; D017114:Liver Failure, Acute / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000378:metabolism; D009336:Necrosis / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000094765:Glutathione Peroxidase GPX1
D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D000255:Adenosine Triphosphate; D005979:Glutathione Peroxidase; C486216:Apex1 protein, mouse; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse