title: Phosphodiesterase-4 inhibition with rolipram attenuates hepatocellular injury in hyperinflammation in vivo and in vitro without influencing inflammation and HO-1 expression.
abstract: OBJECTIVE
  To investigate the impact of the phophodiesterase-4 inhibition (PD-4-I) with rolipram on hepatic integrity in lipopolysaccharide (LPS) induced hyperinflammation.
  
  
  METHODS
  Liver microcirculation in rats was obtained using intravital microscopy. Macrohemodynamic parameters, blood assays, and organs were harvested to determine organ function and injury. Hyperinflammation was induced by LPS and PD-4-I rolipram was administered intravenously one hour after LPS application. Cell viability of HepG2 cells was measured by EZ4U-kit based on the dye XTT. Experiments were carried out assessing the influence of different concentrations of tumor necrosis factor alpha (TNF-α) and LPS with or without PD-4-I.
  
  
  RESULTS
  Untreated LPS-induced rats showed significantly decreased liver microcirculation and increased hepatic cell death, whereas LPS + PD-4-I treatment could improve hepatic volumetric flow and cell death to control level whithout influencing the inflammatory impact. In HepG2 cells TNF-α and LPS significantly reduced cell viability. Coincubation with PD-4-I increased HepG2 viability to control levels. The heme oxygenase 1 (HO-1) pathway did not induce the protective effect of PD-4-I.
  
  
  CONCLUSIONS
  Intravenous PD-4-I treatment was effective in improving hepatic microcirculation and hepatic integrity, while it had a direct protective effect on HepG2 viability during inflammation.
authors.affiliation: Department of Anaesthesia and Critical Care, University Hospital Würzburg, Germany.
authors.forename: Jakob
authors.initials: J
authors.lastname: Wollborn
authors.affiliation: Department of Anaesthesia and Critical Care, University Hospital Würzburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Wunder
authors.affiliation: Department of Pathology, Klinikum Nürnberg, Nürnberg, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Stix
authors.affiliation: Department of Anaesthesia and Critical Care, University Hospital Würzburg, Germany ; Department of Medicinal Chemistry, University of Vienna, Vienna, Austria.
authors.forename: Winfried
authors.initials: W
authors.lastname: Neuhaus
authors.affiliation: Department of Anaesthesia and Critical Care, University Hospital Würzburg, Germany.
authors.forename: Rapahel R
authors.initials: RR
authors.lastname: Bruno
authors.affiliation: Department of Anaesthesia and Critical Care, University Hospital Würzburg, Germany ; Department of Anesthesiology and Critical Care Medicine, University Medical Center, Freiburg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baar
authors.affiliation: Department of General, Visceral, Vascular, and Paediatric Surgery (Department of Surgery I), University of Würzburg, Würzburg, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Flemming
authors.affiliation: Department of Anaesthesia and Critical Care, University Hospital Würzburg, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Roewer
authors.affiliation: Department of General, Visceral, Vascular, and Paediatric Surgery (Department of Surgery I), University of Würzburg, Würzburg, Germany.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Schlegel
authors.affiliation: Department of Anaesthesia and Critical Care, University Hospital Würzburg, Germany.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Schick
keywords: Acute liver failure; endotoxemia; phosphodiesterase; rolipram; sepsis