Our recent studies indicate that depression in hepatocellular function occurs early in sepsis (i.e., cecal ligation and puncture). This depression appears to be caused by Kupffer cell-derived TNF-alpha in the liver as a result of the increased release of the sympathetic neurotransmitter norepinephrine (NE) from the gut. NE also potentiates endotoxin-induced TNF-alpha production. We have discovered that a subtype of alpha2-adrenoceptors (i.e., alpha2A-AR) is responsible for NE-induced TNF-alpha release and an alpha2A-AR antagonist is beneficial in sepsis. In addition, we have shown that production of a novel peptide, ghrelin, is reduced in sepsis. Administration of ghrelin in sepsis downregulates proinflammatory cytokines, attenuates hepatic and other organ damage, and improves survival. The beneficial effects of ghrelin appear to be mediated by inhibition of the sympathetic nervous system, as evidenced by the reduced gut-derived NE release in sepsis after ghrelin treatment. Sepsis activates sympathostimulatory neurons in the hypothalamus (e.g., the periventricular hypothalamic nucleus), as determined by c-fos expression, and ghrelin inhibits this activation. Intracerebro- ventricular injection of ghrelin also reduces TNF-alpha in endotoxemia. Moreover, a specific ghrelin receptor antagonist increases NE and TNF-alpha production in normal animals and worsens sepsis-induced mortality. We therefore hypothesize that downregulation of ghrelin in sepsis plays an important role in activating sympathostimulatory nuclei in the brain, thereby increasing NE release from the sympathetic nerve fibers in the gut, resulting in upregulation of proinflammatory cytokines (TNF-alpha, IL-1beta, HMGB-1) and subsequent injuries to the liver and other organs (the brain-gut-liver axis hypothesis). We further hypothesize that the beneficial effects of ghrelin in sepsis are due to its modulation of the over-stimulated sympathetic nerve activation. The proposed studies will: 1) confirm the role of the downregulated ghrelin in activating the sympathetic nervous system via the brain in sepsis; 2) determine the mechanisms of ghrelin downregulation in sepsis; and 3) determine the mechanisms responsible for the beneficial effect of ghrelin in sepsis. The proposed studies will provide novel information about the mechanisms responsible for hepatic and other organ dysfunction in sepsis, and identify new therapeutic approaches to reduce sepsis-induced lethality.