Chronic alcohol intoxication induces hepatic injury through enhanced macrophage inflammatory protein-2 production and intercellular adhesion molecule-1 expression in the liver

✍ Scribed by A P Bautista

• Publisher: John Wiley and Sons
• Year: 1997
• Tongue: English
• Weight: 464 KB
• Volume: 25
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.510250214

✦ Synopsis

culosis, hepatitis, and the human immunodeficiency virus/ This study tested the hypothesis that prolonged conacquired immune deficiency syndrome. Paradoxically, sumption of alcohol directly or indirectly, through endochronic alcohol intoxication may activate some aspects of nontoxin influx in the circulation, stimulates the Kupffer specific immune defense mechanisms that could initiate hecells to produce macrophage inflammatory protein-2 patic injury and liver diseases in susceptible individuals. For (MIP 2 ) and up-regulates the expression of adhesion molexample, production of proinflammatory cytokines and cheecules, i.e., CD18 on PMNs and its counter-receptor, inmokine is enhanced following alcohol consumption and in tercellular adhesion molecule-1 (ICAM-1), on hepatic individuals with alcoholic liver disease. [1][2][3] It has also been cells. As a result, enhanced sequestration and cell-cell widely accepted that leukocyte infiltration of the liver is a interaction among these cell types may occur in the common feature of both alcoholic hepatitis and alcoholic cirliver, which in turn could result in altered hepatic function and hepatotoxicity. This hypothesis was tested in rhosis. These are major hepatic disorders associated with alcohol-fed, specific pathogen-free, male Sprague-Dawexcessive alcohol consumption. 4 Enhanced infiltration of inley rats. After 16 weeks of feeding, endotoxin (0.2 { 0.043 flammatory polymorphonuclear neutrophils (PMNs) into the EU/mL) and MIP 2 (625 { 100 pg/mL) were detected in liver during chronic alcohol intoxication is expected to conthe sera of alcoholic rats but not in the pair-fed rats. tribute to this phenomenon. The mechanism by which alcohol Concomitantly, serum aspartate transaminase (AST) acenhances the migration of PMNs into the liver may be associtivity was significantly increased. Small lipid deposition ated with ethanol-mediated alteration in the expression of and inflammatory-like changes in the liver were also obleukocyte cell surface receptors that promote migration of served. Isolated Kupffer cells from alcohol-fed rats re-PMNs to the sites of inflammation. [4][5][6] It has been shown that leased large amount of MIP 2 (ú600 pg/10 6 Kupffer cells/ b 2 -integrin (CD18) expression on PMNs of chronic alcoholic 24 hr) in vitro compared with Kupffer cells from pairrats is increased after 16 weeks of ethanol feeding. 6 It has fed rats (õ150 pg/10 6 Kupffer cells/24 hr). At the same also been demonstrated that there is increased hepatic setime, the expression of CD18 and ICAM-1 on polymorquestration of PMNs in chronically alcoholic rats. 7 This is phonuclear neutrophils (PMNs) and hepatic cells was accompanied by low-level endotoxemia and priming of heincreased more than twofold. Monoclonal antibody 1F12, patic phagocytes for enhanced f-met-leu-phe-mediated suan anti-CD18 antibody, attenuated hepatic injury in peroxide release. 7 In endotoxemia, it has been demonstrated vivo, and in PMN-hepatocyte coculture in vitro in the that intercellular adhesion molecule-1 (ICAM-1) expression alcohol-fed group. Another factor that could contribute is up-regulated, and that anti-ICAM-1 antibodies and soluto hepatic injury was MIP 2 , which was cytotoxic to alcoble ICAM-1 are protective against hepatic injury following holic hepatocytes in vitro. This was reversed by cyclolipopolysaccharide (LPS) treatment. 8 These observations heximide, thus suggesting the indirect hepatotoxic efsupport the notion that adhesion molecules play an imfect of MIP 2 . In addition, isolated PMNs and Kupffer portant role in the induction of hepatic injury during endotoxcells from alcohol-fed rats released large amounts of suemia, presumably by enhancing the interaction between peroxide, which may also play a role in hepatic injury. CD18 adhesion molecule on inflammatory leukocytes and These results demonstrate that MIP 2 and adhesion mole-ICAM-1 on target cells, e.g., hepatocytes.

cules may contribute, at least in part, in the initiation of

The migration of inflammatory PMNs to the site of inflamhepatic injury during alcohol intoxication. (HEPATOLOGY mation is not solely regulated by adhesion molecules, but also 1997;25:335-342.)

by cytokines and chemotactic lipids and proteins produced by hepatocytes and Kupffer cells after exposure to alcohol. Prolonged consumption of alcohol has been shown to be associated with modulation of specific and nonspecific im-In the rat model, it has been shown that alcohol exposure mune defense mechanisms. As a result, chronic alcoholics can lead to enhanced production of an interleukin (IL)-8-like become susceptible to infections, such as pneumonia, tuberchemokine by Kupffer cells 6 and hepatocytes. 9,10 Proinflammatory cytokines, tumor necrosis factor, and IL-1 are not directly chemotactic, but are known to enhance the expres-Abbreviations: PMN, polymorphonuclear neutrophil; ICAM-1, intercellular adhesion sion of adhesion molecules, and promote the production of molecule-1; LPS, lipopolysaccharide; IL, interleukin; MIP, macrophage inflammatory proother chemokines, such as IL-8. 11 Increased serum levels of tein; ROI, reactive oxygen intermediate; AST, aspartate transaminase; IgG, immunoglobulin G.