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 cardia c output and hepatic perfusion. Objective:To determine whether proinfl ammatory cytokines such as tumor necrosis factor (TNF) and interleukin -6 (IL-6) are up-regulated before the occurrence of hepatocellular dys function 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 animal s undergoing sham operation. At 0.5, 1, 1.5, or 2 hours after CLP, cir culating levels of TNF and IL-6 were measured by enzyme-linked immunos orbent assay and bioassay, respectively. In additional animals, Kupffe r 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 rev erse-transcription polymerase chain reaction technique. Results: Plasm a levels of TNF and IL-6 increased significantly at 1.5 hours and pers isted at 2 hours after CLP. Levels of TNF and IL-6 messenger RNA in Ku pffer cells increased as early as 1 hour after CLP. The up-regulated g ene expression also persisted at 2 and 5 hours after the onset of seps is. Conclusions: We have previously shown that TNF-alpha infusion prod uces hepatocellular dysfunction and that pharmacological inhibition of TNF production prevents it. Since the present study demonstrated that upregulation of proinflammatory cytokine gene expression occurs befor e hepatocellular dysfunction during sepsis, TNF and/or IL-6 may be res ponsible for producing hepatocellular dysfunction. Thus, administratio n of pharmacologic agents that selectively block or inhibit proinflamm atory cytokine release may be useful in preventing cellular dysfunctio n during early sepsis.