These include injections of vitamin B1, supplements of vitamins B2 and B6, and increasing folic acid levels[8]. When nutritional changes are not working for these patients, various compounds have had some success. to shed some insight into HSP28 how the immune system is involved in the development and/or progression of ALD. studies[56]. These responses were determined to be to the adduct and protein carrier conjugate. It was also determined that scavenger receptors were involved in the uptake of the MAA-adduct and presentation to T-cells[30]. Recent studies in our laboratory have shown that MAA-modified self proteins can become immunogenic, potentially modifying liver proteins, and increasing the risk MDA 19 of specific organ damage. Pro-fibrotic response to MAA-adducts Hepatic fibrosis is the start of the wound-healing process resulting from the injury to the liver caused by years of alcohol consumption. This process can be reversed should ethanol consumption be eliminated. However, if ethanol consumption continues, fibrosis will occur, followed by scarring and finally the development of cirrhosis[57,58]. Fibrosis is the build up of excessive depositions of extracellular matrix (ECM) proteins, which consists of collagen and fibronectin[59]. These ECM proteins may cause the characteristic scar tissue formed in the liver after an injury has occurred. Byproducts of ethanol metabolism have been shown to increase the release of these products. Hepatic stellate cells up-regulate collagen genes in response to stimulation with acetaldehyde[60,61]. Also of interest is the finding that SECs MDA 19 secrete the isoform (EIIIA) of fibronectin MDA 19 in response to MAA-adducts, which are capable of causing stellate cells to release collagen[62]. Activation of the stellate cells is the key component in the fibrogenic process, providing the main production of fibrillar collagen. The build up of modified protein adducts causes disability of effective clearance, thereby increasing the activation of SECs and stellate cells, resulting in a fibrogenic response. The only way to intervene MDA 19 in the continual response form fibrosis to cirrhosis is to remove the ethanol from the system. Some anti-fibrotic drugs have been experimentally tested, yet there are still problems concerning delivery and concentration[63-65]. IMMUNE FUNCTION AND ALCOHOL Innate immune response Ethanol affects many functions of the innate immune system. The cell types involved in this early response include: macrophage, neutrophils, and natural killer cells. One of the most active cells, the macrophage, is designed to respond to bacterial cell wall antigens by releasing cytokines, and engulfing foreign agents. In alcoholic liver disease, kupffer cells in the liver are activated by lipopolysaccaride (LPS) caused from a breakdown in the intestinal wall permeability. This phenomenon has been called leaky gut and occurs when alcohol increases gut permeability, causing bacteria from the intestinal tract to escape into the blood stream[66,67]. When LPS is present, it activates kupffer cells to release TNF-alpha and superoxides that result in an inflammatory response. Recent studies in our laboratory have shown that adducts and very small amounts of LPS can stimulate kupffer cells and SECs to release these pro-inflammatory cytokines[42]. Once these cytokines are initiated, inflammation and necrosis occurs to hepatocytes and other cell types of the liver. Neutrophils are the cell type that is predominantly recruited to the liver in response to the increase in cytokine concentrations. When these cells infiltrate into the site of infection, they phagocytose antigens and release proteolytic enzymes capable of destroying cell walls. They also release more chemoattractants to expedite the inflammatory process[68]. In alcoholic liver disease, these cells play a role in the propagation of the disease by infiltrating and cleaning up dead or dying cells. In fact, it has been shown that IL-8, a known neutrophil chemoattractant, is.

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