This is a revised R29 FIRST Award application investigating the hypothesis that polyunsaturated fatty acids alter the hepatic response to repetitive insults. The study will utilize an in vivo assessment of kupffer cell mediated effects on liver acute phase protein synthesis and cytokine production after repeated bolus LPS treatment to prime the inflammatory response (low dose) or to induce tolerance (high dose). The impact of decreasing kupffer cells by gadolinium treatment vs increasing kupffer cells by GM-CSF treatment on the inflammatory response will be examined. The effect of modifying kupffer cell fatty acid composition by treating with omega-3 polyunsaturated fatty acid enriched and control liposomes in response to repeated bolus LPS treatment will be examined. The changes in response will be evaluated by examining CD 14 expression, protein kinase C activity, protein tyrosine kinase activity and lipid peroxidation. Acute phase protein synthesis will be evaluated at the protein and message level, and TNF, IL-6 and eicosanoid production will be evaluated. The in vivo responses will be correlated with an in vitro KC-hepatocyte co-culture system.
