Serial review: alcohol, oxidative stress and cell injuryThe role of kupffer cell oxidant production in early ethanol-induced liver disease1, 2
Introduction
Mechanisms responsible for hepatotoxicity of ethanol have not been fully characterized despite years of research. It is known that chronic ethanol ingestion stimulates hepatic oxygen consumption and causes fatty liver, hepatomegaly, inflammation, fibrosis, and cirrhosis. Moreover, ethanol consumption has long been associated with hepatic oxidative stress, yet the primary source of oxidants remains unknown. Now exciting evidence has recently emerged implicating hepatic macrophages (i.e., Kupffer cells) in several aspects of this pathophysiology. Importantly, multiple approaches to understanding the role of Kupffer cells in oxidant production has lead to the hypothesis that indeed, Kupffer cell-derived oxidants are involved in mechanisms of early ethanol-induced liver injury.
Section snippets
The role of kupffer cells in early ethanol-induced liver injury
While hepatocytes have historically been the central focus of most studies investigating the effects of ethanol on liver function, recent data have demonstrated that Kupffer cells produce key mediators that stimulate ethanol metabolism [1] and initiate early ethanol-induced liver injury [2]. Specifically, Kupffer cells are stimulated following ethanol consumption to produce free radicals and cytokines such as tumor necrosis factor alpha (TNFα) [3].
The evidence for a role of Kupffer cells in
Role of free radicals in the mechanism of ethanol-induced liver injury
Free radical production by ethanol has been implicated as a factor in its hepatotoxicity and most likely participates in the progression in alcoholic liver disease [10], [11], [12], [13]. Although evidence of lipid radical formation due to ethanol treatment in vivo has been reported, only recently have free radicals from ethanol alone been detected in living animals using the spin trapping technique with electron spin resonance (ESR) spectroscopy [14], [15]. In rats exposed to ethanol via the
The use of pharmacological radical scavengers in alcohol-induced liver injury
To address the critical role of oxidants in the pathogenesis due to chronic ethanol, rats fed ethanol intragastrically for 4 weeks were treated with one of several pharmacological “antioxidants” or inhibitors. These experiments followed the recommendation of Dr. Arthur Cederbaum, who suggested that the efficacy of exogenous antioxidants against ethanol-induced oxidative stress be tested. Indeed, rats given diphenylene iodonium chloride (DPI), an inhibitor of NADPH oxidase, and fed ethanol had
Knockout technology: studies with ethanol
The use of knockout technology has been applied to nearly all fields of biology and allows evaluation of a single gene or gene product independent of nonspecific drugs or inhibitors. The challenge, however, in using knockout technology for alcoholic liver research was to adapt the intragastric feeding model to mice, the species where most gene knockouts exist. This challenge was recently overcome in studies using mice deficient in the TNFα receptor 1 (TNFR1) [24]. Wild-type and TNFR1 knockout
Antioxidant gene transfer
The above studies using knockout mice have clearly demonstrated a role for oxidants in alcohol-induced liver injury and have provided strong evidence for Kupffer cells as a predominant source of these oxidants. Experiments using recombinant adenovirus containing the transgenes for various superoxide dismutase isoforms have demonstrated that SOD gene delivery is protective against oxidative stress, lending further support to the importance of oxidants. The rationale for gene transfer is based on
Adenovirus transduces kupffer cells: role of oxidants
Since overexpression of Cu/Zn SOD blunted pathology as well as production of TNFα, which is largely from Kupffer cells, these observations led us to hypothesize that the delivery of Cu/Zn-SOD by adenovirus blunted ethanol-induced liver injury at the level of Kupffer cells. Indeed, it was shown for the first time that adenovirus transduced Kupffer cells and was able to inactivate them by the delivery of either superoxide dismutase or dominant-negative IκBα [42]. Specifically, it was also shown
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Guest Editor: Arthur Cederbaum
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This article is part of a series of reviews on “Alcohol, Oxidative Stress and Cell Injury.” The full list of papers may be found on the homepage of the journal.
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Dr. Michael Wheeler received his doctorate in pharmacology from the University of North Carolina in 2000 under Dr. Ronald Thurman, focusing on the role of oxidative stress in alcoholic liver disease. Since then, he has worked as a postdoctoral fellow at the University of North Carolina with Dr. R. Jude Samulski. This work has focused on the development of viral vectors for liver-specific gene delivery. Dr. Ronald Thurman has been a significant contributor to alcohol research for many years. He earned his Ph.D. in Pharmacology at the University of Illinois Medical College in 1968. Dr. Thurman was a distinguished professor of Pharmacology at the University of North Carolina and director of the Laboratory of Hepatobiology of Toxicology. His major contributions to alcohol research include Swift Increase in Alcohol Metabolism (SIAM), the role of Kupffer cells in early alcohol-induced liver disease, and the adaptation of the enteral feeding model to transgenic and knockout mice. Other authors are established researchers with expertise in alcohol metabolism, oxidative stress, signal transduction, transgenic animals, and viral gene therapy.