Hepatic Gene Expression During Endotoxemia
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PURPOSE: During the course of sepsis, endotoxins and cytokines activate Kupffer cells, induce the liberation and synthesis of adhesion molecules, and damage hepatocytes, which leads to septic liver failure. The interaction of the different hepatic cell types during these processes is not completely understood and may be clarified by microarray technology. MATERIALS AND METHODS: Seven Sprague Dawley rats received either an intraperitoneal injection of lipopolysaccharides (LPS) of 3 mg/kg body weight (n = 4) or sodium chloride (SC) 0.9% (n = 3). Animals were sacrificed 24 h after LPS or SC injection. RNA from liver tissue was isolated and hybridized on GeneChips (RAE 230A; Affymetrix, Santa Clara, CA). Expression of interleukin-1beta, tumor necrosis factor-alpha, and signal transducer and activator of transcription 3 was controlled by reverse transcription-polymerase chain reaction analysis. Immunohistochemical staining for intercellular adhesion molecule-1 of liver tissue was performed. RESULTS: We detected 508 differentially expressed genes between LPS and SC. Two hundred forty-eight genes were up-regulated and 260 genes were down-regulated in the LPS versus the SC group. Mainly genes involved in immune response and receptor activity were up-regulated in the LPS group. Genes enrolled in catalytic, transferase activity, and metabolisms were down-regulated in the LPS group. The microarray findings could be verified by reverse transcription-polymerase chain reaction analysis and immunohistochemical staining. CONCLUSIONS: The contemporaneous differential regulation of genes involved in metabolism, hepatocellular synthesis, and immune response reflect the liver's central role as immune organ during the course of sepsis. A switch from metabolic to immunological activity is obvious, which aggravates the hepatic damage. The functional interaction of the single genes identified during this process must be further clarified.
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