Development of an intragastric enteral model in the mouse: studies of alcohol-induced liver disease using knockout technology.
Development of an intragastric enteral model in the mouse: studies of alcohol-induced liver disease using knockout technology.
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DOI：
10.1007/s005340070034
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发表时间：
2000-01-01
期刊：
影响因子：
--
通讯作者：
Thurman, R G
中科院分区：
文献类型：
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作者：
Kono, H;Bradford, B U;Thurman, R G
Tsukamoto和French建立的大鼠连续胃内肠内喂养方案是酒精性肝病研究的一个重大进展。与其他仅产生脂肪的模型不同，使用该模型，现在可以研究炎症，坏死和纤维化。然而，迄今为止所学到的很多东西都涉及抑制剂或营养操纵，这些可能不是特异性的。敲除技术可以避免这些潜在的问题。因此，我们采用大鼠长期灌胃给药方案，使敲除技术可以用于研究酒精性肝损伤的机制。反应性自由基参与了早期酒精性肝损伤的机制;然而，这些物质的关键来源仍不清楚。细胞色素P450（CYP）2 E1主要在肝细胞中由乙醇诱导，可能是导致肝损伤的活性氧的来源之一。另一方面，NADPH氧化酶或黄嘌呤氧化酶也是自由基的有效来源。在使用CYP 2 E1和p47 phox（NADPH氧化酶缺陷）敲除小鼠进行的研究中，据报道，CYP 2 E1的氧化剂在小鼠早期酒精诱导的肝损伤机制中仅起很小的作用。此外，枯否细胞中NADPH氧化酶产生的自由基在早期酒精诱导的肝损伤中起重要作用。因此，这种新的肠内小鼠模型，使用基因敲除技术将提供一个强有力的工具，在酒精的研究。
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.