Development of an intragastric enteral model in the mouse: studies of alcohol-induced liver disease using knockout technology.
The establishment of a continuous intragastric enteral feeding protocol in the rat by Tsukamoto and French was a major development in research of alcohol-induced liver disease. Unlike other models which only produce fat, with this model, inflammation, necrosis, and fibrosis can now be studied. However, much of what has been learned to date involves inhibitors or nutritional manipulation which may not be specific. Knockout technology could avoid these potential problems. Therefore, we have adapted a rat long-term intragastric protocol to the mouse so that the knockout technology can be used to study the mechanism of alcohol-induced liver injury. Reactive free radicals are involved in the mechanisms of early alcohol-induced liver injury; however, the key source of these species remains unclear. Cytochrome P450 (CYP) 2E1 is induced predominantly in hepatocytes by ethanol and could be one source of reactive oxygen species leading to liver injury. On the other hand, NADPH oxidase or xanthine oxidase is also a potent source of free radicals. In studies using CYP2E1 and p47phox (NADPH oxidase-deficient) knockout mice with this enteral model, it was reported that oxidants from CYP2E1 play only a small role in the mechanisms of early alcohol-induced liver injury in the mouse. Further, free radicals from NADPH oxidase in Kupffer cells play an important role in early alcohol-induced liver injury. Thus, this new enteral mouse model using knockout technology will provide a powerful tool in alcohol research.
Kono
H
H
Laboratory of Hepatobiology and Toxicology, Department of Pharmacology, University of North Carolina, Chapel Hill, NC, USA.
Bradford
B U
BU
Rusyn
I
I
Fujii
H
H
Matsumoto
Y
Y
Yin
M
M
Thurman
R G
RG
D000818:Animals; D019392:Cytochrome P-450 CYP2E1 / Q000502:physiology; D004731:Endotoxins / Q000502:physiology; D004750:Enteral Nutrition / Q000379:methods*; D007728:Kupffer Cells / Q000502:physiology; D008108:Liver Diseases, Alcoholic / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D004731:Endotoxins; D014409:Tumor Necrosis Factor-alpha; D019392:Cytochrome P-450 CYP2E1