- 作者: Samuel W. French
- 作者服務機構: Department of Pathology. Harbor-UCLA Medical Center, Torrance, Calif., USA
- 中文摘要: --
- 英文摘要: The intragastric alcohol infusion rat model (IAIRM) ofalcoholic liver disease (ALD) has been utilized in variouslaboratories to study various aspects of ALD pathogene-sis including oxidative stress, cytokine upregulation,hypoxic damage, apoptosis, ubiquitin-proteasome path-way and CYP2E1 induction. The basic value of the modelis that it produces pathologic changes which resembleALD including microvesicular and macrovesicular fat,megamitochondria, apoptosis, central lobular and peri-cellular fibrosis, portal fibrosis, bridging fibrosis, centralnecrosis, and mixed inflammatory infiltrate includingPMNs and lymphocytes. The model is valuable becausethe diet and ethanol intake are totally under the control ofthe investigator. A steady state can be maintained withhigh or low blood alcohol levels for long periods. Thecycling of the blood alcohol levels, when a constant infu-sion rate of alcohol is maintained, simulates binge drink-ing. Using this model the importance of dietary fat, espe-cially the degree of saturation of the fatty acids on theinduction of liver pathology, has been documented. Therole of endotoxin, the Kupffer cell, TNFα, and NADPH oxi-dase have been demonstrated. The importance of 2E1 inoxidative stress induction has been shown using inhibi-tors of the isozyme. The importance of dietary iron in thepathogenesis of cirrhosis has been documented. Acetal-dehyde has been shown to play a role in preventing liverpathology by preventing NFKB activation. Using themodel, to maintain high blood alcohol levels is found tobe necessary to demonstrate proteasomal peptidase in-hibition. Ubiquitin synthesis is also inhibited at highblood alcohol levels in the IAIRM model. Oxidized pro-teins accumulate in the liver at high blood alcohol levels. Neoantigens derived from protein adducts formed withproducts of oxidation induce autoimmune mechanismsof liver injury. Thus, in many ways the model has revolu-tionized our understanding of the pathogenesis of ALD.
- 中文關鍵字: --
- 英文關鍵字: Hypoxia. Cytokine. Oxidative stress. Apoptosis. CYP2E1. Oxidized proteins. Protasome.