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Title: Liver Dysfunction and Phosphatidylinositol-3-Kinase Signalling in Early Sepsis: Experimental Studies in Rodent Models of Peritonitis
Authors: Recknagel, P.Gonnert, F.A.Westermann, M.Lambeck, S.Lupp, A.Rudiger, A.Dyson, A.Carré, J.E.Kortgen, A.Krafft, C.Popp, J.Sponholz, C.Fuhrmann, V.Hilger, I.Claus, R.A.Riedemann, N.C.Wetzker, R.Singer, M.Trauner, M.Bauer, M.
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Issue Date: 2012
Published in: PLoS Medicine Vol. 9 (2012), No. 11
Publisher: San Francisco, CA : Public Library of Science
Abstract: Background: Hepatic dysfunction and jaundice are traditionally viewed as late features of sepsis and portend poor outcomes. We hypothesized that changes in liver function occur early in the onset of sepsis, yet pass undetected by standard laboratory tests. Methods and Findings: In a long-term rat model of faecal peritonitis, biotransformation and hepatobiliary transport were impaired, depending on subsequent disease severity, as early as 6 h after peritoneal contamination. Phosphatidylinositol-3-kinase (PI3K) signalling was simultaneously induced at this time point. At 15 h there was hepatocellular accumulation of bilirubin, bile acids, and xenobiotics, with disturbed bile acid conjugation and drug metabolism. Cholestasis was preceded by disruption of the bile acid and organic anion transport machinery at the canalicular pole. Inhibitors of PI3K partially prevented cytokine-induced loss of villi in cultured HepG2 cells. Notably, mice lacking the PI3Kγ gene were protected against cholestasis and impaired bile acid conjugation. This was partially confirmed by an increase in plasma bile acids (e.g., chenodeoxycholic acid [CDCA] and taurodeoxycholic acid [TDCA]) observed in 48 patients on the day severe sepsis was diagnosed; unlike bilirubin (area under the receiver-operating curve: 0.59), these bile acids predicted 28-d mortality with high sensitivity and specificity (area under the receiver-operating curve: CDCA: 0.77; TDCA: 0.72; CDCA+TDCA: 0.87). Conclusions: Liver dysfunction is an early and commonplace event in the rat model of sepsis studied here; PI3K signalling seems to play a crucial role. All aspects of hepatic biotransformation are affected, with severity relating to subsequent prognosis. Detected changes significantly precede conventional markers and are reflected by early alterations in plasma bile acids. These observations carry important implications for the diagnosis of liver dysfunction and pharmacotherapy in the critically ill. Further clinical work is necessary to extend these concepts into clinical practice. Please see later in the article for the Editors' Summary.
Keywords: 5 (6 quinoxalinylmethylene) 2, 4 thiazolidinedione; adenosine triphosphate; alanine aminotransferase; bile acid; bilirubin; carboxyfluorescein; chenodeoxycholic acid; collagenase; cytochrome P450 1A; cytochrome P450 2A; cytochrome P450 2B; cytochrome P450 2C; cytochrome P450 3A; esterase; gamma glutamyltransferase; glutathione; glutathione transferase; indocyanine green; interleukin 6; monocyte chemotactic protein 1; multidrug resistance protein 2; organic anion transporter; phosphatidylinositol 3 kinase; reduced nicotinamide adenine dinucleotide; taurodeoxycholic acid; tumor necrosis factor alpha; unclassified drug; wortmannin; aged; animal cell; animal experiment; animal model; animal tissue; article; bile flow; biotransformation; cell interaction; cholestasis; clinical article; confocal laser microscopy; controlled study; disease severity; epifluorescence microscopy; female; flow cytometry; gene expression; heart stroke volume; high performance liquid chromatography; human; human cell; immunofluorescence test; liver dysfunction; male; mass spectrometry; metabolomics; microcirculation; mouse; nonhuman; peritonitis; rat; receiver operating characteristic; scanning electron microscopy; sensitivity and specificity; sepsis; signal transduction; transthoracic echocardiography; Western blotting; Animals; Bile Acids and Salts; Biological Markers; Blotting, Western; Cholestasis; Coinfection; Feces; Gene Expression Regulation; Genome-Wide Association Study; Humans; Liver; Liver Diseases; Liver Function Tests; Male; Mice; Mice, Inbred C57BL; Microscopy, Electron, Scanning; Peritonitis; Phosphatidylinositol 3-Kinase; Rats; Rats, Wistar; Sepsis; Signal Transduction; Spectrum Analysis, Raman; Xenobiotics
DDC: 610
License: CC BY 3.0 Unported
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