Tumor necrosis factor in alcohol enhanced endotoxin liver injury.
Endotoxin administration causes liver injury. Patients with alcoholic liver disease frequently have portal vein and systemic endotoxemia, and some investigators have suggested that endotoxin plays an etiologic role in alcoholic liver injury. Many of the metabolic effects of endotoxin are mediated by the cytokine tumor necrosis factor (TNF). It was the purpose of this study to determine whether TNF plays a role in ethanol-enhanced endotoxin liver injury. Rats were fed either a diet in which 36% of the calories were from ethanol or an isocaloric control diet. After 6 weeks, groups of 10 rats were intravenously injected with either saline, 1 mg/kg endotoxin, or 30 micrograms/kg of a prostaglandin E1 (PGE1) analogue + 1 mg/kg endotoxin 24 hr prior to sacrifice. Ethanol/endotoxin-treated rats had significantly higher liver enzyme levels (ALT: 1064 +/- 355 IU/liter, AST: 2024 +/- 515 IU/liter) compared with isocaloric/endotoxin controls (ALT: 237 +/- 54 IU/liter, AST: 602 +/- 80 IU/liter). Ethanol/endotoxin rats also had significantly higher peak serum TNF concentrations (992 +/- 200 units/ml) compared with isocaloric/endotoxin controls (344 +/- 96 units/ml). Pretreatment of ethanol/endotoxin rats with PGE1 caused significant attenuation of liver injury (ALT: 267 +/- 64 IU/liter, AST: 612 +/- 77 IU/liter) and a diminished serum TNF response. In contrast to chronic ethanol administration, acute gavage with 2 mg/kg ethanol (30% w/v) followed by intravenous injection of 2 mg/kg endotoxin produced significantly lower peak serum TNF concentrations (401 +/- 76 units/ml) than gavage with distilled water (1152 +/- 208 units/ml).(ABSTRACT TRUNCATED AT 250 WORDS)
Honchel
R
R
Graduate School of Toxicology, University of Kentucky Medical Center, Lexington.
Ray
M B
MB
Marsano
L
L
Cohen
D
D
Lee
E
E
Shedlofsky
S
S
McClain
C J
CJ
D000527:Alprostadil / Q000494:pharmacology; D000818:Animals; D004731:Endotoxins / Q000097:blood*; D007274:Injections, Intraperitoneal; D008099:Liver / Q000473:pathology; D008104:Liver Cirrhosis, Alcoholic / Q000473:pathology / Q000503:physiopathology; D008108:Liver Diseases, Alcoholic / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*
D004731:Endotoxins; D014409:Tumor Necrosis Factor-alpha; D000527:Alprostadil