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Immunology

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Description

Kupffer cells or Browicz-Kupffer cells are specialized macrophages located in the liver that form part of the reticuloendothelial system. The cells were first observed by Karl Wilhelm von Kupffer in 1876. The scientist called them "sternzellen" (star cells or stellate cells) but thought falsely that they were an integral part of the endothelium of the liver blood vessels and that they originated from it. In 1898, after several years of research, Tadeusz Browicz identified them correctly as macrophages.

Their development begins in the bone marrow with the genesis of promonocytes and monoblasts into monocytes and then on to peripheral blood monocytes completing their differentiation into Kupffer cells.

Helmy et al. identified a receptor present in Kupffer cells, the complement receptor of the immunoglobulin family (CRIg). Mice without CRIg could not clear complement system-coated pathogens. CRIg is conserved in mice and humans and is a critical component of the innate immune system.

As a result of steady state population dynamics or inflammation it is suggested that M-CSF (Monocyte-colony stimulation factor) is the cytokine responsible for its differentiation.

http://www.dadamo.com/wiki/kupffer.jpg

Model of the association between endotoxin release, Kupffer cell activation, and liver injury. Following chronic alcohol ingestion, endotoxin released from certain intestinal bacteria moves from the gut into the bloodstream and into the liver. There the endotoxin activates Kupffer cells—a type of immune cell (i.e., macrophages) residing in the liver—by interacting with a molecule called CD14 located on the surface of those cells. This interaction causes the production of the regulatory nuclear factor kappa B (NFκB), which in turn leads to the generation of significant amounts of cytotoxic factors, namely superoxide radicals (O2) and various signaling molecules (i.e., cytokines), most prominently TNF–α. TNF–α has been shown to be an essential factor in the injury to primary liver cells (i.e., hepatocytes) associated with alcoholic liver disease.

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Links with endotoxin

One substance that can effectively activate Kupffer cells is bacterial endotoxin. This molecule, also known as lipopolysaccharide, is a component of the cell walls of some of the bacteria that normally inhabit the intestine. When the bacteria die, the endotoxin is released into the intestine, from which some of it can cross the intestinal wall and enter the bloodstream. Higher–than–normal amounts of endotoxin entering the bloodstream or tissues can cause fever, chills, shock, and various other symptoms and can often lead to more severe conditions, such as endotoxemia or adult respiratory distress syndrome (ARDS).

Several lines of research have shown that gut–derived endotoxin plays a critical role in alcoholic liver disease. For example, studies have found that patients with alcoholic liver disease have elevated levels of endotoxin circulating in the blood. Furthermore, in experiments with rodents, researchers have found that eliminating all bacteria and, consequently, all the endotoxin from the intestine (e.g., by using antibiotics) completely prevented alcohol–induced liver injury. Similarly, by lowering the number of intestinal bacteria through other means (e.g., administration of lactobacillus bacteria, which are present in yogurt), investigators could curb the rise in endotoxin levels in alcohol–treated animals.

As endotoxin crosses the intestinal barrier and enters the bloodstream, it interacts with the Kupffer cells in the liver, thereby activating them. Thus, it was hypothesized that Kupffer cell activation by endotoxin derived from intestinal bacteria causes those cells to generate superoxide and TNF–α, both of which can lead to tissue damage in the liver. Experiments on isolated cells grown in culture (i.e., in vitro experiments) as well as other experimental approaches have confirmed this hypothesis. For example, endotoxin did not induce the production of superoxide or TNF–α in isolated Kupffer cells that contained excess amounts of an antioxidant capable of eliminating superoxide (i.e., the enzyme superoxide dismutase). This finding supports the connection between endotoxin, Kupffer cells, and superoxide production.

Changes in gut permeability lead to increased endotoxin levels in the blood

Several mechanisms may underlie the significant increase in endotoxin levels in the bloodstream following chronic alcohol use. According to one hypothesis, chronic alcohol use leads to higher endotoxin levels in the blood because it prevents Kupffer cells from effectively clearing these molecules from the circulation. In addition, increased absorption of endotoxin from the intestine may play a role in alcohol–induced liver disease . Researchers found that, in rats, acute ingestion of high alcohol concentrations facilitated the absorption of endotoxin from the animals’ small intestine by increasing intestinal permeability—that is, the degree to which the cell wall allows the passage of various molecules, including endotoxin, into the blood. Other studies have shown that high alcohol concentrations can directly damage the cells lining the interior of the intestine (i.e., the intestinal epithelium), thereby impairing the ability of the epithelium to serve as a barrier preventing access of unwanted substances from the intestine to the bloodstream. The exact mechanism by which alcohol disrupts this protective barrier to endotoxin still is unknown, however.

Interestingly, females have higher levels of endotoxin in the blood after chronic alcohol exposure than do males, suggesting that females may be more susceptible than males to alcohol–induced increases in gut permeability to endotoxin. These variations may be related to differences between male and female hormone systems, because researchers have demonstrated that gut permeability is significantly increased in animals treated with the female hormones estradiol and progesterone. Whether this mechanism explains the long–standing observation that women are more susceptible than men to alcohol–induced liver damage, however, has yet to be determined. (1)

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