Alcoholic liver disease (ALD) is an important health problem. There is increasing evidence that many of the clinical manifestations and, at least, part of the liver injury in ALD are mediated by cytokines such as tumor necrosis factor (TNF), interleukin-6 (IL-6) and interleukin-8 (IL-8). Regulation of these cytokines has become a focal point for therapeutic intervention in many diseases including ALD. Nuclear factor kappa B (NFkappaB) is a transcription factor for these cytokines. NFkappaB is activated by reactive oxygen intermediates and endotoxin. We postulate that chronic alcohol abuse causes increased gut permeability and endotoxemia, depletion of many nutrient antioxidants, inadequate macrophage prostaglandin concentrations, generation of reactive oxygen intermediates, activation of NFkappaB, increased TNF production, increased IL-8 production with neutrophil infiltration, mitochondrial dysfunction with mitochondrial GSH depletion, increased susceptibility to hepatic TNF cytotoxicity, and liver injury. The overall goals of my laboratory are to further characterize cytokine mediated nutritional/metabolic events and mechanisms of cytokine induced liver injury, with the ultimate goal being the development of effective """"""""anticytokine"""""""" therapy for ALD. The """"""""anticytokine"""""""" therapy to be studied in this proposal is the prostaglandin E1 analogue misoprostol. We postulated that misoprostol will both inhibit cytokine production and improve gut permeability. The specific objectives of this proposal are: 1. Determine the dose of misoprostol that most effectively decreases ex vivo cytokine production when given orally for a 14 day period to normal volunteers. 2. Determine that the optimal dose of misoprostol that effectively decreases ex vivo cytokine production in normal volunteers also effectively decreases ex vivo cytokine production in patients with stable alcoholic cirrhosis and is well tolerated by them when given orally over a 14 day period. 3.A. Determined whether misoprostol treatment of patients with acute alcoholic hepatitis is well tolerated and effective in decreasing gut permeability, endotoxemia, plasma cytokine levels, ex vivo cytokine production and lipid peroxidation. 3.B. Determine the relationship between plasma cytokine levels and putative cytokine mediated clinical manifestations of alcoholic liver disease includings: measures of liver injury/function, neutrophilia/acute phase reactants, fever/metabolic rate and appetite/nutritional parameters.
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