OLIGONUCLEOTIDE TARGETING OF THE KUPFFER CELL

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DESCRIPTION: (Adapted from the Investigator's Abstract) Tumor necrosis factor-a (TNF-alpha) is a cytokine required for cell replication. However, when its production is upregulated it triggers an inflammatory response and cell injury. Kupffer cells are the main producers of TNF-alpha. In endothelial cells and hepatocytes, TNF-alpha: (i) activates the production of leukocyte chemoattractants and (ii) increases the expression of intercellular adhesion molecules (ICAM-1) which anchors leukocytes. Anchored leukocytes (neutrophils/monocytes) are stimulated to (iii) release latent proteolytic enzymes that become activated by the concerted action of myeloperoxidase and hydrogen peroxide, leading to cell damage. Several approaches can prevent cell injury. Obliteration of Kupffer cells reduces liver injury elicited by a number of hepatotoxins. Antibodies that bind TNF-a, ICAM-1, or anchoring receptors in neutrophils and monocytes (CD11b/CD18) protect against cell injury in different experimental conditions in vitro and in vivo, including liver injury induced by chronic ethanol administration. While these approaches have contributed an important insight to the pathogenesis of liver injury they cannot be used clinically in chronic conditions. Recent studies show that antisense oligonucleotides are viable therapeutic alternatives in chronic inflammatory conditions. Studies proposed test the general hypothesis that liver injury induced by chronic ethanol treatment can be suppressed by antisense oligonucleotides that act at three steps of the cytotoxic cascade: (i) TNF-alpha production by Kupffer cells (ii) ICAM-1 generation by hepatocytes and endothelial cells and (iii) myeloperoxidase-mediated cytotoxicity. Overall, the proposed research investigates the effectiveness of new genotypic drugs that act on central mechanisms of hepatocellular injury that may have therapeutic potential for alcoholic liver disease.