The role of LPS in alcoholic liver injury has been shown in several studies[12,23,24
]. The importance of gut-derived endotoxin in ALD was suggested by experiments where treating the animals either with antibiotics or with lactobacilli to remove or reduce the gut microflora provided protection from the features of ALD[12,25,26
]. In mice and rats, circulating endotoxin levels were increased after chronic alcohol feeding[27,28
] and plasma endotoxin levels were also increased in patients with ALD compared to normal subjects[29
]. The persistence of endotoxin not only activates the liver immune cells but also affects the function of liver parenchymal cells.
The progression of ALD is a complex phenomenon, as it not only results from the direct effects of alcohol and its metabolites, but other factors also play an important role in its pathogenesis, such as leaky gut, which results in endotoxemia[30
]. Both chronic ethanol- mediated microbial proliferation[31,32
] and acetaldehyde-mediated opening of intestinal tight junctions (TJs)[33
] enhance the passage or release of endotoxins into the intestinal lumen, which are later transported to liver. However, when excess amounts of endotoxin are not cleared efficiently by the liver and accumulate in blood circulation, innate immune cells, including Kupffer cells, are activated, leading to the release of various pro-inflammatory cytokines, chemokines, and other factors[34,35
Kupffer cell activation has been identified as one of the key elements in the pathogenesis of alcoholic steatohepatitis. Studies in mice and rats demonstrated that inactivation of Kupffer cells with gadolinium chloride or clodronate injection can almost fully ameliorate alcohol-induced liver disease[36,37
]. These observations led to the currently accepted model of ALD, where Kupffer cell activation by gut-derived endotoxin, induction of chemokines such as MCP-1, and upregulation of the inflammatory cascade represent a central component of the pathomechanisms of ALD (Figure ).
Figure 1 Mechanisms of alcohol induced liver damage. Alcohol consumption alone, or with its metabolites, disrupts the gut integrity by various mechanisms, including increased reactive oxygen species (ROS), inducible nitric oxide synthase (iNOS), alteration of (more ...)