Clinics and Research in Hepatology and Gastroenterology
SeminarMechanisms of the inflammatory reaction implicated in alcoholic hepatitis: 2011 update
Introduction
Excessive alcohol consumption is one of the leading causes of chronic liver disease and a major public health issue worldwide, with an estimated 3.8% of all global death [1]. Alcoholic liver disease includes a combination of steatosis, inflammation, hepatocyte necrosis, and fibrosis [2]. However, the underlying pathophysiological mechanisms involved in their development are still largely unknown.
Alcoholic hepatitis is characterized by hepatocellular necrosis and neutrophil infiltration surrounding damaged hepatocytes [3]. The neutrophil infiltration of the liver is often associated with Kupffer cell (the hepatic macrophage) hyperplasia and lymphocyte infiltration [4], [5]. The inflammatory cascade that results from the activation and cooperation of these immune cells leads to hepatocellular injury and subsequent acute hepatic failure. The goal of this article is to review the pathophysiological mechanism involved in the generation and progression of the inflammatory process during alcoholic hepatitis, based on the recent advances from experimental and clinical studies of alcoholic liver disease. We will focus on the immune and non-immune cell populations that contribute to alcohol-induced liver inflammation. The main activation factors and consequences of activation of different hepatic cell populations will also be reviewed.
Section snippets
Kupffer cells activation
The activation of Kupffer cells (KC) seems to play a central role in the initiation of alcohol-induced hepatic inflammation. KC inactivation with gadolinium chloride significantly reduced alcohol-induced liver damage in rats [6]. Thus, the contributions of different factors, such as alcohol and its metabolites, endotoxin, reactive oxygen species, hepatic iron, to the activation of KC will be discussed further below.
Release of inflammatory mediators
The main consequence of KC activation is the release of pro-inflammatory cytokines (particularly TNF-alpha and IL-1β) and ROS. TNF-alpha is a powerful pro-inflammatory cytokine that was intensively studied in ALD. It operates by binding to two structurally related cell surface receptors: TNF-R1 and TNF-R2. However, TNF-R1 seems to be responsible for mediating the majority of TNF-alpha function. TNF-R1 knockout mice were almost completely protected of liver injury induced by continuous enteral
Conclusion
The progression of alcohol-induced liver damage involves complex interactions of several immune cells and hepatocytes through the release of pro-inflammatory and anti-inflammatory cytokines and chemokines (Fig. 2).
These recent advances in our understanding of pathogenesis of alcoholic hepatitis are needed to develop new approaches to its treatment. For instance therapeutic applications from these new insights could be the probiotics to prevent alcoholic liver intestinal barrier disruption and
Disclosure of interest
The authors declare that they have no conflicts of interest concerning this article.
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