Neutrophil-mediated tissue injury in alcoholic hepatitis

doi:10.1016/S0741-8329(02)00200-8

Alcohol

Volume 27, Issue 1, May 2002, Pages 23-27

https://doi.org/10.1016/S0741-8329(02)00200-8 Get rights and content

Abstract

The presence of polymorphonuclear leukocytes (neutrophils) in liver parenchyma is a prominent feature of alcoholic hepatitis. However, the pathophysiological importance of these phagocytes and potential injury mechanisms in alcoholic hepatitis remain unclear. This review summarizes the current knowledge on basic mechanisms of neutrophil-induced liver injury as it emerged from studying a number of different experimental models. This general concept of neutrophil-mediated liver cell injury agrees with many observations made by examining liver sections obtained from patients with alcoholic hepatitis. These include the presence of extravasated neutrophils in the liver, evidence for degranulation of neutrophils in the parenchyma, and excessive formation of neutrophil chemoattractants such as CXC chemokines in liver cells. Colocalization and a strong quantitative correlation between apoptotic hepatocytes and neutrophils could indicate apoptosis-induced transmigration of neutrophils during alcoholic hepatitis, similar to events previously demonstrated in experimental models. Furthermore, circulating neutrophils are primed for reactive oxygen species and inflammatory mediator formation. However, clear evidence for a neutrophil-induced injury in alcoholic hepatitis is missing. Unfortunately, most experimental models of alcoholic liver disease do not have a prominent neutrophilic infiltrate. Therefore, a high priority of future research has to be to develop an experimental model that realistically mimics the neutrophil component of alcoholic hepatitis in human beings. This would allow investigators to test the concept that neutrophils are important for cell injury during alcoholic hepatitis and to identify potential therapeutic intervention strategies.

Introduction

Alcoholic hepatitis is a serious complication of chronic alcohol abuse in human beings. Pathological evaluations of liver tissues have demonstrated the presence of polymorphonuclear leukocytes (neutrophils) in the parenchyma Hall 1985, Takahashi et al. 1987. Most investigators agree that neutrophils may contribute greatly to the pathological findings. However, direct proof for the involvement of neutrophils in the tissue injury during alcoholic hepatitis and insight into the mechanism of cell damage are currently not available. Nevertheless, during the past decade, substantial progress has been made in the general understanding of neutrophil-induced injury mechanisms in the liver Jaeschke 1997, Jaeschke & Smith 1997. The aim of this review is to summarize the current knowledge on neutrophil cytotoxicity and relate this information to pathological findings of alcoholic hepatitis.

Section snippets

Mechanisms of neutrophil-induced liver injury

In a number of experimental models, there is clear evidence that neutrophils contribute greatly to liver dysfunction and cell injury. These models include hepatic ischemia-reper- fusion (Jaeschke et al., 1990), endotoxemia (Jaeschke et al., 1991b), sepsis (Molnar et al., 1997), hemorrhagic shock and resuscitation (Bauer et al., 1995), remote organ trauma (Hill et al., 1992), and certain drug toxicities (Dahm et al., 1991). For neutrophils to cause injury to hepatocytes, they have to go through

Pathological features of alcoholic hepatitis in human beings

Examination of liver biopsy specimens obtained from patients with acute alcoholic hepatitis has revealed prominent neutrophil infiltration Hall 1985, Takahashi et al. 1987. These neutrophils are generally extravasated and located close to hepatocytes, which demonstrate various degrees of degeneration and cell necrosis. Furthermore, many neutrophils have their primary and secondary granules released (Takahashi et al., 1987). These findings are consistent with a neutrophil attack on hepatocytes

Future directions

On the basis of this discussion, a high priority in future research has to be to develop a relevant animal model of alcoholic hepatitis. The experience with different animal models of neutrophil-induced liver injury shows that activation and recruitment of neutrophils into the liver vasculature and their transmigration and attack on parenchymal cells are highly complex processes, which require an initiating event. At present, only a limited number of scenarios are known to trigger such a severe

Acknowledgements

Studies from my laboratory were supported in part by National Institutes of Health grants GM-42957, ES-06091, and AA-12916.

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Review articleNeutrophil-mediated tissue injury in alcoholic hepatitis☆

Abstract

Introduction

Section snippets

Mechanisms of neutrophil-induced liver injury

Pathological features of alcoholic hepatitis in human beings

Future directions

Acknowledgements

Distinct patterns of chemokine expression are associated with leukocyte recruitment of alcoholic hepatitis and alcoholic cirrhosis

J Pathol

A natural glycoprotein inhibitor (NIF) of CD11b/CD18 reduces leukocyte adhesion in the liver after hemorrhagic shock

Shock

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

Hepatology

Neutrophilic infiltration in alcoholic hepatitis

Alcohol

Endotoxin induced hepatic necrosis in rats on an alcohol diet

J Pathol

Listeria monocytogenes infection increases neutrophil adhesion and damage to a murine hepatocyte cell line in vitro

Immunol Lett

Neutrophil margination and extravasation in sinusoids and venules of liver during endotoxin-induced injury

Am J Physiol

The role of cytokine networks in the local liver injury following hepatic ischemia/reperfusion in the rat

Hepatology

Chemotactic activity of the lipid peroxidation product 4-hydroxynonenal and homologous hydroxyalkenals

Biol Chem Hoppe Seyler

An antibody to neutrophils attenuates alpha-naphthylisothiocyanate-induced liver injury

J Pharmacol Exp Ther

Transcriptional activation of vascular cell adhesion molecule-1 gene in vivo and its role in the pathophysiology of neutrophil-induced liver injury in murine endotoxin shock

J Immunol

Cytokine-induced upregulation of hepatic intercellular adhesion molecule-1 messenger RNA expression and its role in the pathophysiology of murine endotoxin shock and acute liver failure

Hepatology

Inhibition of NF-κB activation by dimethyl sulfoxide correlates with suppression of TNF-α formation, reduced ICAM-1 gene transcription and protection against endotoxin-induced liver injury

Shock

Increased P-selectin gene expression in the liver vasculature and its role in the pathophysiology of neutrophil-induced liver injury in murine endotoxin shock

J Leukoc Biol

Differential induction of mRNA for ICAM-1 and selectins in hepatocytes, Kupffer cells and endothelial cells during endotoxemia

Biochem Biophys Res Commun

Endotoxin-induced activation of the nuclear transcription factor κB and expression of E-selectin messenger RNA in hepatocytes, Kupffer cells, and endothelial cells in vivo

J Immunol

Intercellular adhesion molecule-1 (ICAM-1) expression and its role in neutrophil-induced ischemia-reperfusion injury in the liver

J Leukoc Biol

Pathology and pathogenesis of alcoholic liver disease

A Mac-1 antibody reduces liver and lung injury but not neutrophil sequestration after intestinal ischemia-reperfusion

Surgery

Reactive oxygen and ischemia/reperfusion injury of the liver

Chem Biol Interact

Cellular adhesion moleculesregulation and functional significance in the pathogenesis of liver diseases

Am J Physiol

Reactive oxygen and mechanisms of inflammatory liver injury

J Gastroenterol Hepatol

Superoxide generation by Kupffer cells and priming of neutrophils during reperfusion after hepatic ischemia

Free Radic Res Commun

Superoxide generation by neutrophils and Kupffer cells during in vivo reperfusion after hepatic ischemia in rats

J Leukoc Biol

Review article
Neutrophil-mediated tissue injury in alcoholic hepatitis☆