Our recent studies have indicated that depression in hepatocellular function occurs very early after the onset of polymicrobial sepsis (as induced by cecal ligation and puncture). This depression is associated with increased norepinephrine (NE) production and Kupffer cell (KC)-derived TNF-alpha release. The gut appears to be the major source of NE release during early sepsis, as evidenced by the increased intestinal tyrosine hydroxylase and dopamine beta- hydroxylase (enzymes responsible for NE biosynthesis) and significantly higher levels of NE in portal than in systemic blood. Administration of NE via the portal vein or in the isolated perfused liver preparation increases TNF-alpha release and depressed hepatocellular function. In contrast, alpha2-adrenergic antagonists rauwolscine or yohimbine attenuate TNF-alpha production and prevent hepatocellular depression in early sepsis as well as after NE infusion. Enterectomy prior to the onset of sepsis also reduces circulating levels of NE and TNF-alpha and prevents hepatocellular depression. In addition, alpha2-adrenergic agonists NE or clonidine increases TNF-alpha release in vivo as well as in isolated KC. Moreover, the number and affinity of alpha2-adrenoceptors in KC appear to be increased in early sepsis. We therefore hypothesize that the increased gut-derived NE during early sepsis upregulates TNF-alpha production in KC through an alpha2-adrenoceptor pathway and is responsible for producing hepatocellular depression. Since administration of glycines at the early state of sepsis decreases TNF-alpha release and protects hepatocellular function, we further hypothesize that modulation of KC responsiveness to NE by reducing intracellular calcium in KC and/or reducing gut-derived NE release are the mechanisms responsible for the beneficial effect of this amino acid on hepatocellular function during sepsis. Studies are proposed to determine the mechanisms: 1) responsible for the increased NE biosynthesis in the gut during the early stage of sepsis; 2) by which gut-derived NE upregulates TNF-alpha production in KC and depresses hepatocellular function in sepsis; 3) responsible for the beneficial effect of glycines on hepatocellular function under such conditions. The proposed studies should provide useful information not only for better understanding the precise mechanisms responsible for hepatocellular depression during the early stage of polymicrobial sepsis, but also for intercepting such depression and preventing subsequent multiple organ dysfunction and mortality.
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