Mechanism of hepatocellular dysfunction during early sepsis. Key role of increased gene expression and release of proinflammatory cytokines tumor necrosis factor and interleukin-6.

BACKGROUND Hepatocellular dysfunction occurs at 1.5 hours after cecal ligation and puncture (CLP [ie, sepsis model]), despite normal cardiac output and hepatic perfusion. OBJECTIVE To determine whether proinflammatory cytokines such as tumor necrosis factor (TNF) and interleukin-6 (IL-6) are up-regulated before the occurrence of hepatocellular dysfunction during sepsis. DESIGN, INTERVENTION, AND MAIN OUTCOME MEASURE: Rats were subjected to sepsis by CLP, followed by administration of normal saline solution, 3 mL/100 g of body weight, to these and animals undergoing sham operation. At 0.5, 1, 1.5, or 2 hours after CLP, circulating levels of TNF and IL-6 were measured by enzyme-linked immunosorbent assay and bioassay, respectively. In additional animals, Kupffer cells were isolated at 1, 2, or 5 hours after CLP or sham operation. Kupffer cell TNF and IL-6 messenger RNA levels were determined by reverse-transcription polymerase chain reaction technique. RESULTS Plasma levels of TNF and IL-6 increased significantly at 1.5 hours and persisted at 2 hours after CLP. Levels of TNF and IL-6 messenger RNA in Kupffer cells increased as early as 1 hour after CLP. The up-regulated gene expression also persisted at 2 and 5 hours after the onset of sepsis. CONCLUSIONS We have previously shown that TNF-alpha infusion produces hepatocellular dysfunction and that pharmacological inhibition of TNF production prevents it. Since the present study demonstrated that upregulation of proinflammatory cytokine gene expression occurs before hepatocellular dysfunction during sepsis, TNF and/or IL-6 may be responsible for producing hepatocellular dysfunction. Thus, administration of pharmacologic agents that selectively block or inhibit proinflammatory cytokine release may be useful in preventing cellular dysfunction during early sepsis.