Journal of Hepatology
Volume 47, Issue 2 , Pages 228-238, August 2007

Kupffer cell activation in normal and fibrotic livers increases portal pressure via thromboxane A2☆

  • Christian J. Steib

      Affiliations

    • Department of Medicine II, Klinikum Großhadern, Ludwig-Maximilians University, Marchioninistraße 15, 81366 Munich, Germany
    • Corresponding Author InformationCorresponding author. Tel.: +49 89 7095 3176; fax: +49 89 7095 2392.
    • ,
  • Alexander L. Gerbes

      Affiliations

    • Department of Medicine II, Klinikum Großhadern, Ludwig-Maximilians University, Marchioninistraße 15, 81366 Munich, Germany
    • ,
  • Markus Bystron

      Affiliations

    • Department of Medicine II, Klinikum Großhadern, Ludwig-Maximilians University, Marchioninistraße 15, 81366 Munich, Germany
    • ,
  • Mark op den Winkel

      Affiliations

    • Department of Medicine II, Klinikum Großhadern, Ludwig-Maximilians University, Marchioninistraße 15, 81366 Munich, Germany
    • ,
  • Josef Härtl

      Affiliations

    • Department of Medicine II, Klinikum Großhadern, Ludwig-Maximilians University, Marchioninistraße 15, 81366 Munich, Germany
    • ,
  • Frigga Roggel

      Affiliations

    • Institute of Pathology, University of Munich-Grosshadern, Munich, Germany
    • ,
  • Thomas Prüfer

      Affiliations

    • Department of Anesthesiology, University Hospital Tuebingen, Germany
    • ,
  • Burkhard Göke

      Affiliations

    • Department of Medicine II, Klinikum Großhadern, Ludwig-Maximilians University, Marchioninistraße 15, 81366 Munich, Germany
    • ,
  • Manfred Bilzer

      Affiliations

    • Department of Medicine II, Klinikum Großhadern, Ludwig-Maximilians University, Marchioninistraße 15, 81366 Munich, Germany

Received 3 August 2006; received in revised form 7 March 2007; accepted 10 March 2007. published online 09 April 2007.

Background/Aims

Cirrhotic patients show an increased risk of variceal bleeding upon bacterial infections. Kupffer cells (KC) constitute the first macrophage population to become activated by bacterial β-glucans and endotoxins derived from the gut. We therefore investigated whether and how KC activation increases portal pressure.

Methods

KC in normal and fibrotic livers from bile duct ligated (BDL) rats were activated by the β-glucan component of zymosan in vivo and during isolated rat liver perfusion.

Results

Activation of KC in normal livers resulted in a severalfold increase of portal pressure in vivo as well as in isolated perfused liver preparations. This increase and the accompanying 40-fold stimulation of hepatic prostaglandin F2α/D2 and thromboxane A2 (TxA2) production in isolated perfused livers were attenuated by KC blockade. The TxA2 synthase inhibitor furegrelate and the TxA2 receptor antagonist BM 13.177 reduced the increase of portal perfusion pressure supporting TxA2 as pivotal vasoconstrictor released by activated KC. Importantly, a more pronounced vasopressor response in fibrotic livers was related to a raise in KC density and a 10-fold increase of TxA2 production after KC activation.

Conclusions

KC activated by β-glucans increase portal pressure through the release of TxA2. This vasopressor response is augmented in BDL induced fibrosis.

Abbreviations: BDL, bile duct ligation, BM 13.177, solutroban, COX, cyclooxygenase, DMSO, dimethylsulfoxide, Dup 697, 5-bromo-2-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl)thiopene, GdCl3, gadolinium chloride, KC, Kupffer cells, LDH, lactate dehydrogenase, PG, prostaglandin, SC 560, 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole, Tx, thromboxane, U-46619, 9,11-dideoxy-9α, 11α-methanoepoxy-prostaglandin F2α, Zymosan, cell wall particles from yeast

Keywords: Kupffer cells, Inflammation, Zymosan, Portal hypertension, Thromboxane A2, Reactive oxygen species

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☆ The authors who have taken part in this study declared that they do not have a relationship with the manufacturers of the drugs involved either in the past or present and did not receive funding from the manufacturers to carry out their research. They did not receive funding from any source to carry out this study.

PII: S0168-8278(07)00192-4

doi:10.1016/j.jhep.2007.03.019

Journal of Hepatology
Volume 47, Issue 2 , Pages 228-238, August 2007

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