Antitumor necrosis factor antibodies reduce hepatic steatosis during total parenteral nutrition and bowel rest in the rat.
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, infused with normal saline, and infused with TPN. On day 7 of the 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 tested 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-alpha.
Pappo
I
I
Department of Surgery, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Bercovier
H
H
Berry
E
E
Gallilly
R
R
Feigin
E
E
Freund
H R
HR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D002784:Cholesterol / Q000378:metabolism; D005234:Fatty Liver / Q000209:etiology / Q000517:prevention & control*; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D010289:Parenteral Nutrition, Total / Q000009:adverse effects*; D051381:Rats; D014280:Triglycerides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000502:physiology
D000911:Antibodies, Monoclonal; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D002784:Cholesterol