Alcoholic hepatitis: inflammatory cell–mediated hepatocellular injury

doi:10.1016/S0741-8329(02)00205-7

Alcohol

Volume 27, Issue 1, May 2002, Pages 43-46

https://doi.org/10.1016/S0741-8329(02)00205-7 Get rights and content

Abstract

The role that inflammatory cell injury plays in the pathogenesis of alcoholic liver disease is reviewed with emphasis on granulocytes and immunocytes. New insights regarding the mechanism of lymphocytic migration from the portal vein and lymphocytic-mediated hepatocellular injury are also reviewed.

Section snippets

Summary of author's published work

The inflammatory component in alcoholic liver disease (ALD) has been thought to contribute to the progression of the disease. Whether it is a primary source of liver cell injury or it occurs only as a result of liver cell necrosis and only contributes to progression as part of the repair and healing process, which may or may not lead to a residual scar formation, however, is not known.

The role of granulocytes, lymphocytes, and autoimmunity in the pathogenesis of ALD will be summarized.

Summary of other published literature

There have been two recent major breakthroughs, in the understanding of how lymphocytes destroy their target, that are applicable to understanding how ethanol and other pathogens such as viruses cause liver cell injury and progression to cirrhosis. The first major breakthrough was the discovery that lymphocytes, which form an immunologic synapse with antigen-presenting MHC complexes on the surface of the target cells, proceed to nibble the immunologic synapse components by internalizing the

Future directions for research

What now needs to be investigated are the mechanisms of lymphocyte recruitment, retention, and activation as well as down-regulation in the localized microenvironment of the liver in ALD. Once the regulation of the lymphocytic–liver cell interaction is understood, therapeutic interventions can be designed. This approach would include the regulation of the expression of vascular adhesion protein-1 (VAP-1) and vascular cell adhesion molecule-1 (VCAM-1) by liver endothelial cells because these

Acknowledgements

I acknowledge the support of NIH/NIAAA grant 8116. I also thank Adriana Flores for typing the manuscript.

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Cited by (25)

Attenuation of neutrophil-mediated liver injury in mice by drug-free E-selectin binding polymer
2020, Journal of Controlled Release
Citation Excerpt :
Yet, despite the extensive research efforts, little progress has been made on the development of novel treatments for ARLD [7]. Pathological evaluations of liver tissue from human alcoholics have consistently demonstrated the presence of neutrophils in the liver parenchyma that contribute to pathologic findings noted in alcoholic liver injury [11–13]. Similar pathologic changes are noted in rodent models [14,15].
Inflammation with neutrophils infiltration is a prominent feature of alcohol-related liver disease (ARLD) and contributes to the severity of liver injury. Although an array of potential treatments has been studied, the standard treatment regimen is controversial and can induce severe side effects and infection-related complications. E-selectin, a cytokine inducible cell adhesion molecule, mediates the initial interaction of leucocytes with endothelial cells, and facilitates their further adhesion and extravasation into inflamed tissues. Given the important role of E-selectin in leukocytes trafficking, we hypothesized that a synthetic polymer presenting multiple copies of E-selectin binding peptide in a polyvalent manner (P-Esbp) may block the “roads” that facilitate neutrophil infiltration, inhibit the recruitment of neutrophils to the inflamed sites and reduce the extent of liver injury. We now demonstrate in vitro that P-Esbp reduced the recruitment of neutrophils (collected from blood of donors) on activated human umbilical vein endothelial cells (HUVEC) under flow conditions. Pre-treatment of mice with P-Esbp prior to alcohol binge attenuated alcohol-induced serum transaminase (ALT, AST) elevation, reduced pro-inflammatory cytokines (TNFα and IL-1ẞ) and chemokines (MIP-2/CXCL2 and MCP-1/CCL2) in National Institute on Alcohol Abuse and Alcoholism (NIAAA) model. Also, the up-regulation of neutrophil marker Ly6G and the number of MPO positive cells in the injured tissue was significantly reduced by the treatment, indicating diminished neutrophil infiltration. Moreover, as a result of P-Esbp treatment, E-selectin expression in the liver (mRNA and protein level) was downregulated, suggesting a potential to decrease ongoing local inflammatory response. Overall, our findings highlight the anti-inflammatory properties of the “drug-free” P-Esbp and its therapeutic potential to attenuate an excessive inflammation where infiltrating neutrophils can damage tissues and organs.
Liver proteomics in progressive alcoholic steatosis
2013, Toxicology and Applied Pharmacology
Citation Excerpt :
Alcoholic steatohepatitis is a limiting step in ALD as ~ 50% of individuals develop cirrhosis and fibrosis (Lucey et al., 2009; Miranda-Mendez et al., 2010; Newton et al., 2009). Once alcoholic steatohepatitis develops, abstinence from drinking reverses this condition in only 10% of the individuals (French, 2002; Newton et al., 2009). Hence early detection of the various stages of progressive ethanol-induced liver injury is important in managing its reversal and/or therapeutic management.
Fatty liver is an early stage of alcoholic and nonalcoholic liver disease (ALD and NALD) that progresses to steatohepatitis and other irreversible conditions. In this study, we identified proteins that were differentially expressed in the livers of rats fed 5% ethanol in a Lieber–DeCarli diet daily for 1 and 3 months by discovery proteomics (two-dimensional gel electrophoresis and mass spectrometry) and non-parametric modeling (Multivariate Adaptive Regression Splines). Hepatic fatty infiltration was significantly higher in ethanol-fed animals as compared to controls, and more pronounced at 3 months of ethanol feeding. Discovery proteomics identified changes in the expression of proteins involved in alcohol, lipid, and amino acid metabolism after ethanol feeding. At 1 and 3 months, 12 and 15 different proteins were differentially expressed. Of the identified proteins, down regulation of alcohol dehydrogenase (− 1.6) at 1 month and up regulation of aldehyde dehydrogenase (2.1) at 3 months could be a protective/adaptive mechanism against ethanol toxicity. In addition, betaine-homocysteine S-methyltransferase 2 a protein responsible for methionine metabolism and previously implicated in fatty liver development was significantly up regulated (1.4) at ethanol-induced fatty liver stage (1 month) while peroxiredoxin-1 was down regulated (− 1.5) at late fatty liver stage (3 months). Nonparametric analysis of the protein spots yielded fewer proteins and narrowed the list of possible markers and identified d-dopachrome tautomerase (− 1.7, at 3 months) as a possible marker for ethanol-induced early steatohepatitis. The observed differential regulation of proteins have potential to serve as biomarker signature for the detection of steatosis and its progression to steatohepatitis once validated in plasma/serum.
Effect of diethylcarbamazine on chronic hepatic inflammation induced by alcohol in C57BL/6 mice
2012, European Journal of Pharmacology
Citation Excerpt :
Alcoholic liver disease (ALD) is a collective term for the pathophysiological changes caused by chronic alcohol consumption, which include oxidative stress generation, liver steatosis, inflammatory response, fibrosis and cirrhosis. Progression of the disease involves various proinflammatory molecules such as interleukins, cytokines, adhesion molecules and nuclear factor-κB (NF-κB) (Nanji et al., 1999; French, 2002; Achur et al., 2010; Ballas et al., 2012). The activated NF-κB, if being translocated into the nucleus, will facilitate transcription of many downstream genes, including inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2); both are key mediators in recruitment of inflammatory cells (Bhaskaran et al., 2010; Arias-Salvatierra et al., 2011).
Some pharmacological studies showed that diethylcarbamazine (DEC) interferes with the arachidonic acid metabolism, acting as an anti-inflammatory drug. The chronic alcohol consumption activates the hepatic inflammatory response associated to T-cell activation and overproduction of pro-inflammatory cytokines. The present work analyzed the anti-inflammatory effect of DEC on hepatic cells of alcoholic mice. Thirty-two male C57BL/6 mice were equally divided in the following groups: (a) control group (C), which received only water, (b) DEC-treated group, which received 50 mg/kg for 12 day (DEC50), (c) the alcoholic group (EtOH), submitted to only alcohol and (d) the alcohol-DEC treated group (EtOH50), submitted to alcohol plus DEC treatment after the induction of chronic alcoholism for 5 weeks. Biochemical analyses were performed and liver fragments were processed for light microscopy, transmission electron microscopy, immunohistochemical and western blot. The level of AST increased significantly in alcoholic group whereas a significant reduction of serum AST was detected in the EtOH50 group. Histological and ultrastructural analysis of alcoholic group showed evident hepatocellular damage, which was strikingly reduced in the alcoholic DEC-treated group. Immunohistochemistry results revealed highly expression of inflammatory markers as MDA, NF-κB, TNF-α, IL-6, VCAM and ICAM by the hepatic cells of the EtOH group; however no immunoreactivity for any of these cytokines was detected after DEC treatment. Western blot analyses showed increased MCP-1 and iNOS expression in EtOH group, which was significantly inhibited by DEC treatment. According to the present results, DEC can be a potential drug for the treatment of chronic inflammation induced by chronic alcoholism.
Interaction of osteopontin with neutrophil α<inf>4</inf>β<inf>1</inf> and α<inf>9</inf>β<inf>1</inf> integrins in a rodent model of alcoholic liver disease
2008, Toxicology and Applied Pharmacology
Previous studies from our laboratory have reported that osteopontin (OPN) mediated higher hepatic neutrophil infiltration makes female rats more susceptible to alcoholic steatohepatitis (ASH) than their male counterparts. The objective of the current work was to investigate the patho-mechanism by which OPN attracts the hepatic neutrophils in ASH. We hypothesized that OPN-mediated hepatic neutrophil infiltration is a result of signaling by N-terminal integrin binding motif (SLAYGLR) of OPN through its receptor α₉β₁ (VLA9) and α₄β₁ (VLA4) integrins on neutrophils. Compared to the males, females in the ASH group exhibited higher expression of α₄β₁ and α₉β₁ protein and mRNA and a significant decrease in the expression of these integrins was observed in rats treated with neutralizing OPN antibody. Immunoprecipitation experiments suggested the binding of OPN to α₄β₁ and α₉β₁ integrins. OPN-mediated neutrophil infiltration was also confirmed using Boyden chamber assays, and antibodies directed against α₄ and β₁ integrins was found to significantly inhibit neutrophilic migration in vitro. In conclusion, these data suggest that SLAYGLR-mediated α₄β₁ and α₉β₁ integrin signaling may be responsible for higher hepatic neutrophil infiltration and higher liver injury in the rat ASH model.
Role of osteopontin in hepatic neutrophil infiltration during alcoholic steatohepatitis
2005, Toxicology and Applied Pharmacology
Alcoholic liver disease (ALD) is a major complication of heavy alcohol (EtOH) drinking and is characterized by three progressive stages of pathology: steatosis, steatohepatitis, and fibrosis/cirrhosis. Alcoholic steatosis (AS) is the initial stage of ALD and consists of fat accumulation in the liver accompanied by minimal liver injury. AS is known to render the hepatocytes increasingly sensitive to toxicants such as bacterial endotoxin (LPS). Alcoholic steatohepatitis (ASH), the second and rate-limiting step in the progression of ALD, is characterized by hepatic fat accumulation, neutrophil infiltration, and neutrophil-mediated parenchymal injury. However, the pathogenesis of ASH is poorly defined. It has been theorized that the pathogenesis of ASH involves interaction of increased circulating levels of LPS with hepatocytes being rendered highly sensitive to LPS due to heavy EtOH consumption. We hypothesize that osteopontin (OPN), a matricellular protein (MCP), plays an important role in the hepatic neutrophil recruitment due to its enhanced expression during the early phase of ALD (AS and ASH). To study the role of OPN in the pathogenesis of ASH, we induced AS in male Sprague–Dawley rats by feeding EtOH-containing Lieber–DeCarli liquid diet for 6 weeks. AS rats experienced extensive fat accumulation and minimal liver injury. Moderate induction in OPN was observed in AS group. ASH was induced by feeding male Sprague–Dawley rats EtOH-containing Lieber–DeCarli liquid diet for 6 weeks followed by LPS injection. The ASH rats had substantial neutrophil infiltration, coagulative oncotic necrosis, and developed higher liver injury. Significant increases in the hepatic and circulating levels of OPN was observed in the ASH rats. Higher levels of the active, thrombin-cleaved form of OPN in the liver in ASH group correlated remarkably with hepatic neutrophil infiltration. Finally, correlative studies between OPN and hepatic neutrophil infiltration was corroborated in a simple rat peritoneal model where enhanced peritoneal fluid neutrophil infiltration was noted in rats injected OPN intraperitoneally. Taken together these data indicate that OPN expression induced during ASH may play a significant role in the pathogenesis of ASH by stimulating neutrophil transmigration.
The Role of T Lymphocytes in the Pathogenesis of Alcoholic Liver Disease
2005, Comprehensive Handbook of Alcohol Related Pathology

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Review articleAlcoholic hepatitis: inflammatory cell–mediated hepatocellular injury☆

Abstract

Section snippets

Summary of author's published work

Summary of other published literature

Future directions for research

Acknowledgements

Hepatology

Gastroenterology

Exp Mol Pathol

Leucocyte adhesion molecules and alcoholic liver disease

Alcohol Alcohol

Hydroxyethyl radicals in ethanol hepatotoxicity

Front Biosci

Expression of the β1 chain (CD29) of integrins and CD45 in alcoholic liver disease

Am J Gastroenterol

Alcohol modulation of human normal T-cell activation, maturation, and migration

Alcohol Clin Exp Res

Costimulationbuilding an immunological synapse

Science

Mechanisms of alcoholic liver injury

Can J Gastroenterol

Review article
Alcoholic hepatitis: inflammatory cell–mediated hepatocellular injury☆