Liver, which plays a major role in regulating bodily metabolic functions, is often the target of systemic insults arising from endotoxins, xenobiotics etc., resulting in hepatic injury. Recent studies have shown that hepatic injury is closely linked to the way Kupffer cells react to such insults and that obliteration of Kupffer cells can prevent liver injury. The Kupffer cell-mediated liver injury has been attributed to the excessive release of cytokines like tumor necrosis factor-alpha, interleuken-1, IL-6 and prostanoids, during endotoxemia. Endotoxins have been implicated in alcoholic liver diseases, since, high levels of endotoxins have been reported in the blood of alcoholic patients with liver disease. The objective of this proposal therefore, is to develop a method by which to control the production of cytokines and prostanoids in Kupffer cells. To achieve this goal, a method will be developed in which antisense and/antigene molecules, which are specifically targetted to the inflammatory cytokine/prostanoid-gene products will be encapsulated in anionic liposomes and delivered in vivo to Kupffer cells. The efficacy of delivery will be assessed by monitoring a) the tissue distribution of the delivered molecule, b) its biological half-life and c) cellular levels of targetted mRNA. Based on other reports, during the final year of the fellowship period, the molecular species of the liposomes will be modified to target other cell types such as hepatocytes and splenic macrophages. Positive data from such exploratory experiments will set the stage for future investigations with wider scope.
