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Antitumor Necrosis Factor Antibodies Reduce Hepatic Steatosis During Total Parenteral Nutrition and Bowel Rest in the Rat

Department of Surgery, Hebrew University -Hadassah Medical School, Jerusalem, Israel

Herve Bercovier, DVM

Department of Clinical Microbiology, Hebrew University -Hadassah Medical School, Jerusalem, Israel

Elliot Berry, MD

Department of Nutrition, Hebrew University -Hadassah Medical School, Jerusalem, Israel

Ruth Gallilly, MSc, PHD

Lautenberg Center for General and Tumor Immunology, Hebrew University -Hadassah Medical School, Jerusalem, Israel

Elad Feigin, MD

Department of Surgery, Hebrew University -Hadassah Medical School, Jerusalem, Israel

Herbert R. Freund, MD

Department of Surgery, Hebrew University -Hadassah Medical School, Jerusalem, Israel

Background: In previous studies, we demonstrated the overgrowth of gram-negative bacteria in the gut and an enhanced release of tumor necrosis factor (TNF) by peritoneal macrophages, suggesting that endotoxin, TNF, or both, may act as hepatotoxins to produce hepatic steatosis during total parenteral nutrition (TPN) and bowel rest. The present study attempts to better define the role of each of these two mediators. The first part examines the LD₅₀ for various doses of endotoxin in TPN-treated rats compared with free-feeding and free-feeding saline-infused rats. In the second part we repeatedly administered anti-TNF monoclonal antibodies to rats subjected to TPN and bowel rest. Methods: In the first set of experiments, 87 male Sabra rats were randomized into three groups: free-feeding, nfused with normal saline, and infused with TPN. On day 7 of ,he experiment, all rats received an IV injection of endotoxin at various doses (1.5, 2.5, 5.0, 7.5, and 10 mg/kg). The LD₅₀ in the three groups and at the various doses of lipopolysaccharide ested was determined at 24 hours postinjection. In the second set of experiments, 38 male Sabra rats were randomized into three groups: infused with normal saline and fed rat food ad libitum, infused with TPN, and infused with TPN but also receiving monoclonal antibodies against TNF. Results: Lower endotoxin doses were required to achieve LD₅₀ in the two IV-infused groups (2.5 to 5.0 mg/kg) compared with the free-feeding group (7.5 mg/kg) (p < .03). These findings suggest a moderate increase in susceptibility to the lethal effect of endotoxin in IV-treated rats. The total hepatic fat and triglyceride levels, which were markedly increased in TPN rats, were significantly reduced by using anti-TNF antibodies. Enhanced TNF production by peritoneal macrophages during TPN was completely eliminated by anti-TNF antibodies, probably the result of suppressed TNF production. Conclusions: The continuous translocation of endotoxin from gram-negative bacterial overgrowth in the gut during TPN and bowel rest results in enhanced release of TNF by macrophages. TNF causes hepatic dysfunction, portrayed in the present experimental model as hepatic steatosis. TPN-induced hepatic steatosis was significantly reduced by the administration of monoclonal antibodies against TNF-. (Journal of Parenteral and Enteral Nutrition 19:80-82, 1995)

Journal of Parenteral and Enteral Nutrition, Vol. 19, No. 1, 80-82 (1995)
DOI: 10.1177/014860719501900180


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