Role of Kupffer cell-derived reactive oxygen intermediates in alcoholic liver disease in rats in vivo.
The pathophysiology of alcoholic liver disease (ALD) remains largely unknown. In this work, we have developed an experimental rat model to elucidate the mechanism of liver injury, including ALD, in which Kupffer cell-derived reactive oxygen intermediates (ROIs) might be involved. Groups of male Wistar rats were pair-fed on a liquid high-fat diet containing ethanol (36% of total calories) or isocaloric carbohydrate with or without dietary carbonyl iron (0.5% w/v) for 3 weeks. In this rat model, we investigated Kupffer cell-derived ROI generation, which affected hepatocellular injury and hepatic fibrosis in ALD. The production of ROIs in Kupffer cells isolated from the iron-fed, the ethanol-fed, and the ethanol plus iron-fed rats were significantly increased, compared with that in Kupffer cells isolated from control rats (iron > ethanol+iron > ethanol > > control). However, hepatic vitamin E content in the ethanol plus iron-fed rats was decreased rather than that in the iron-fed rats. Then, lipid peroxidation of isolated microsomes was assessed as malondialdehyde equivalents determined by thiobarbituric acid assay. Compared with controls, the malondialdehyde equivalents were elevated in experimental groups (ethanol+iron > ethanol > iron > control). Serum ALT levels were greatly elevated in rats fed a diet containing both ethanol and iron (ethanol+iron > iron > ethanol > control). Hepatic content of hydroxyproline was significantly increased in ethanol plus iron-fed rats, compared with rats other than the ethanol plus iron-fed group (ethanol+iron > iron > ethanol > control). These results suggested that the enhanced Kupffer cell-derived ROI generation could itself contribute to the increased susceptibility to lipid peroxidation, which might cause hepatocellular injury and lead to hepatic fibrosis in ALD.
Takeyama
Y
Y
First Department of Internal Medicine, School of Medicine, Fukuoka University, Japan.
Kamimura
S
S
Kuroiwa
A
A
Sohda
T
T
Irie
M
M
Shijo
H
H
Okumura
M
M
D000818:Animals; D007501:Iron / Q000378:metabolism; D007728:Kupffer Cells / Q000473:pathology / Q000502:physiology*; D015227:Lipid Peroxidation / Q000502:physiology; D008104:Liver Cirrhosis, Alcoholic / Q000473:pathology / Q000503:physiopathology; D008108:Liver Diseases, Alcoholic / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008862:Microsomes, Liver / Q000473:pathology / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*
D017382:Reactive Oxygen Species; D008315:Malondialdehyde; D007501:Iron