OBJECTIVE: The liver is an early target organ in sepsis, severe sepsis, and septic shock, contributing to multiple organ failure, and both lipopolysaccharide and gut-derived catecholamines are implicated in the occurrence of hepatocellular dysfunction. Treatment of septic shock involves administration of vasoactive agents such as exogenous catecholamines or vasopressin in order to reestablish blood pressure. As a prelude to clinical application, we tested the hypothesis that catecholamines could modulate the lipopolysaccharide-induced inflammatory response and function in human liver. DESIGN: An in vitro human cell culture study. SETTING: Research laboratory of an academic institution. SUBJECTS: Primary human hepatocytes and human hepatoma HepaRG cells. INTERVENTIONS: Primary human hepatocytes and human hepatoma HepaRG cells were exposed to lipopolysaccharide to evaluate effects of epinephrine and several other compounds (norepinephrine, dobutamine, dopamine, dopexamine, phenylephrine, clonidine, salbutamol, and vasopressin). Markers of inflammation (interleukin-6, C-reactive protein) and drug metabolism (cytochrome P450 [CYP] 3A4, CYP2B6, CYP1A2, CYP2E1, constitutive androstane receptor, pregnane X receptor) were analyzed. MEASUREMENTS AND MAIN RESULTS: Transcripts of C-reactive protein and CYP3A4 were strongly increased and depressed respectively after a 24-hr treatment with 10 ng/mL lipopolysaccharide. Co-treatment with either of the catecholamines failed to reverse lipopolysaccharide effects, whereas when added alone, epinephrine, and to a lesser extent norepinephrine, salbutamol, and dobutamine, mimicked lipopolysaccharide effects. Suppression of CYP3A4 implicated beta-adrenergic receptors and was mediated through overproduction of interleukin-6. By contrast, vasopressin did not elicit an inflammatory response or modify CYP3A4 expression. CONCLUSIONS: Some catecholamines can induce an inflammatory response and exacerbate the hepatic dysfunction observed during sepsis, favoring the idea that catecholamines could alter the biotransformation of drugs metabolized by CYP3A4 and that alternative vasoactive agents, such as vasopressin, merit further investigation in septic shock patients.
OBJECTIVE: The liver is an early target organ in sepsis, severe sepsis, and septic shock, contributing to multiple organ failure, and both lipopolysaccharide and gut-derived catecholamines are implicated in the occurrence of hepatocellular dysfunction. Treatment of septic shock involves administration of vasoactive agents such as exogenous catecholamines or vasopressin in order to reestablish blood pressure. As a prelude to clinical application, we tested the hypothesis that catecholamines could modulate the lipopolysaccharide-induced inflammatory response and function in human liver. DESIGN: An in vitro human cell culture study. SETTING: Research laboratory of an academic institution. SUBJECTS: Primary human hepatocytes and humanhepatoma HepaRG cells. INTERVENTIONS: Primary human hepatocytes and humanhepatoma HepaRG cells were exposed to lipopolysaccharide to evaluate effects of epinephrine and several other compounds (norepinephrine, dobutamine, dopamine, dopexamine, phenylephrine, clonidine, salbutamol, and vasopressin). Markers of inflammation (interleukin-6, C-reactive protein) and drug metabolism (cytochrome P450 [CYP] 3A4, CYP2B6, CYP1A2, CYP2E1, constitutive androstane receptor, pregnane X receptor) were analyzed. MEASUREMENTS AND MAIN RESULTS: Transcripts of C-reactive protein and CYP3A4 were strongly increased and depressed respectively after a 24-hr treatment with 10 ng/mL lipopolysaccharide. Co-treatment with either of the catecholamines failed to reverse lipopolysaccharide effects, whereas when added alone, epinephrine, and to a lesser extent norepinephrine, salbutamol, and dobutamine, mimicked lipopolysaccharide effects. Suppression of CYP3A4 implicated beta-adrenergic receptors and was mediated through overproduction of interleukin-6. By contrast, vasopressin did not elicit an inflammatory response or modify CYP3A4 expression. CONCLUSIONS: Some catecholamines can induce an inflammatory response and exacerbate the hepatic dysfunction observed during sepsis, favoring the idea that catecholamines could alter the biotransformation of drugs metabolized by CYP3A4 and that alternative vasoactive agents, such as vasopressin, merit further investigation in septic shockpatients.
Authors: Valentin Fuhrmann; Nikolaus Kneidinger; Harald Herkner; Gottfried Heinz; Mariam Nikfardjam; Anja Bojic; Peter Schellongowski; Bernhard Angermayr; Maximilian Schöniger-Hekele; Christian Madl; Peter Schenk Journal: Intensive Care Med Date: 2011-06-07 Impact factor: 17.440
Authors: J R Coppeta; M J Mescher; B C Isenberg; A J Spencer; E S Kim; A R Lever; T J Mulhern; R Prantil-Baun; J C Comolli; J T Borenstein Journal: Lab Chip Date: 2016-12-20 Impact factor: 6.799
Authors: Florian Simon; Ricardo Giudici; Angelika Scheuerle; Michael Gröger; Pierre Asfar; Josef A Vogt; Ulrich Wachter; Franz Ploner; Michael Georgieff; Peter Möller; Régent Laporte; Peter Radermacher; Enrico Calzia; Balázs Hauser Journal: Crit Care Date: 2009-07-10 Impact factor: 9.097
Authors: Peter S Kruger; Noelle M Freir; Bala Venkatesh; Thomas A Robertson; Michael S Roberts; Mark Jones Journal: Intensive Care Med Date: 2008-11-26 Impact factor: 17.440
Authors: Valentin Fuhrmann; Nikolaus Kneidinger; Harald Herkner; Gottfried Heinz; Mariam Nikfardjam; Anja Bojic; Peter Schellongowski; Bernhard Angermayr; Reinhard Kitzberger; Joanna Warszawska; Ulrike Holzinger; Peter Schenk; Christian Madl Journal: Intensive Care Med Date: 2009-06-09 Impact factor: 17.440