Opinion
Interplay between oxidative stress and immunity in the progression of alcohol-mediated liver injury

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Inflammation is recognized increasingly as having an important role in the pathogenesis of alcoholic liver disease (ALD). Nonetheless, the mechanisms by which alcohol maintains hepatic inflammation are still characterized incompletely. Several studies have demonstrated that ethanol-induced oxidative stress promotes immune responses in ALD by stimulating both humoral and cellular reactions against liver proteins adducted to hydroxyethyl free radicals and several lipid peroxidation products. Moreover, ALD patients have autoantibodies targeting cytochrome P4502E1 and oxidized phospholipids. In both chronic alcohol-fed rats and heavy drinkers, the elevation of IgG against lipid peroxidation-derived antigens is associated with tumor necrosis factor-α production and the severity of liver inflammation. On this basis, we propose that allo- and autoimmune reactions associated with oxidative stress might contribute to fueling hepatic inflammation in ALD.

Introduction

Alcohol-related diseases are an important cause of morbidity and mortality in most well developed countries and are a cause of growing concern in developing countries. Alcoholic liver disease (ALD) is a common medical consequence of chronic alcohol abuse. The mortality rate ascribed to ALD in the USA and Western Europe is estimated to be approximately 5–6%, making alcoholic cirrhosis the ninth most frequent cause of death in the general population [1]. ALD itself is a complex nosological entity encompassing steatosis, alcoholic hepatitis and alcoholic fibrosis or cirrhosis. Although almost all heavy drinkers develop fatty liver, alcoholic hepatitis is evident in only 10–35% and only 8–20% progress to cirrhosis [2]. Of those that progress to cirrhosis, 15% will develop hepatocellular carcinoma (HCC) [2]. It is clear that the risk of severe ALD (e.g. alcoholic hepatitis and cirrhosis) increases with time and the amount of ethanol consumed. Nonetheless, gender, genetic, metabolic and nutritional factors also influence disease progression [3]. In spite of more than 50 years of research, our understanding of the pathogenesis of alcohol hepatotoxicity is still limited. In particular, comparatively little is known about the factors that determine why some patients progress to hepatitis and/or cirrhosis and others do not. As a result, there has been little significant progress in developing pathogenesis-directed therapies for established ALD. An important step forward in this field has been the appreciation of the role of inflammatory responses in the pathogenesis of alcohol liver damage 4, 5, 6. However, the mechanisms by which alcohol maintains chronic hepatic inflammation remain an open issue. In this article, we will discuss the role that the modifications of cell constituents caused by ethanol-induced oxidative stress (see Glossary) have in triggering immune reactions as well as the possible implications of immune mechanisms in fueling hepatic inflammation during the progression of ALD.

Section snippets

Oxidative stress and inflammation in the pathogenesis of alcoholic liver injury

Although heavy drinkers have both an increased susceptibility to infections and depressed innate and acquired immunity [7], growing evidence indicates that chronic alcohol intake in rodents mediates the activation of intrahepatic macrophages, also known as Kupffer cells. These then release proinflammatory cytokines and chemokines [tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-8, macrophage chemotactic protein (MCP)-1, RANTES], eicosanoids, reactive oxygen species (ROS) and nitric

Implications of oxidative stress in the stimulation of immune responses in ALD

The immune system is known to have a key role in regulating hepatic inflammation in some chronic liver diseases. Early studies in ALD patients have detected circulating antibodies that target alcohol-altered hepatocytes as well as CD8+ and CD4+ T lymphocytes in the areas of necrosis and intralobular inflammation associated with alcoholic hepatitis [20]. The extension of portal and peri-portal lymphocyte infiltrates evident in approximately 40% of patients with advanced ALD also correlates with

Possible mechanisms in the development of the immune response to oxidative stress-derived antigens

Why oxidative modifications of hepatic constituents activate specific immunological responses is still unclear. The liver is recognized as having unique immunological properties in regulating systemic tolerance to antigens from the portal circulation [35]. Under physiological conditions, Kupffer cells respond to low concentrations of endotoxins by producing TNF-α, IL-10, ROS and prostanoids that downmodulate the antigen presentation by dendritic and endothelial cells and suppress T-cell

Oxidative mechanisms in autoimmune responses associated with ALD

Patients with ALD often show signs of autoimmune reactions involving the presence of non-organ-specific autoantibodies, such as anti-nucleus (ANA) or anti-smooth muscle (SMA) antibodies, as well as liver-specific autoantibodies toward alcohol dehydrogenase or the asialoglycoprotein receptor [53]. In this context, we have observed that approximately 40% of the patients with advanced ALD and 11% of the heavy drinkers with fatty liver only have circulating IgG directed against CYP2E1 [54]. The

Oxidative stress and anti-phospholipid autoreactivity

Anti-phospholipid antibodies (aPL) are an heterogeneous group of autoantibodies characterized by their ability to bind anionic phospholipids alone or in combination with phospholipid-binding proteins, such as β2-glycoprotein 1, prothrombin, protein C and protein S [61]. The presence of aPL characterizes the primary anti-phospholipid syndrome, as well as several autoimmune diseases in which aPL are often responsible for recurrent vascular thrombosis [62]. Nonetheless, aPL are among the

Is there a role for oxidative stress-mediated immune responses in liver inflammation associated with ALD?

The actual contribution of oxidative stress-mediated immune responses to maintain inflammation in ALD has emerged from the observation that the supplementation with N-acetylcysteine reduces both hepatic inflammation and circulating IgG against malonildialdehyde-derived adducts in enteral alcohol-fed rats with low-level circulating endotoxins [43]. Moreover, the IgG reactivity correlates with both the liver TNF-α mRNA expression and the extension of inflammatory infiltrates (M. Ronis, personal

Concluding remarks

The implication of immune mechanisms being involved in the progression of ALD opens a new area of investigation. We propose that the stimulation of CD4+ Th cells by lipid peroxidation-derived antigens promotes the development of both humoral and cellular immune responses against hepatocytes undergoing ethanol-induced oxidative stress. Such processes would possibly contribute to hepatocyte loss. More importantly, in the presence of continuous antigen stimulation, lymphocyte-derived cytokines can

Conflicts of interest

The authors have no conflict of interest.

Acknowledgements

Original research studies of the authors were supported by grants from the Italian Ministry for University and Scientific and Technological Research (PRIN Programs 2002 and 2004), the regional government of Piedmont (Ricerca Sanitaria Finalizzata) (M.V. and E.A.) and the UK Medical Research Council (S.F.S.).

Glossary

Adipokines
a group of cytokines, including adiponectin, leptin, resisistin and visfatin, secreted mainly, but not exclusively, by the adipose tissue that regulates food intake and energy metabolism. Adipokine unbalances are associated with obesity and insulin resistance. However, alterations in adipokine secretion are recognized increasingly as affecting the regulation of inflammatory and immune responses.
Antigen-presenting cells (APCs)
cells presenting peptide fragments derived from self or

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