Kupffer cell activation in normal and fibrotic livers increases portal pressure via thromboxane A(2).
OBJECTIVE
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 beta-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 beta-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 F(2alpha)/D(2) and thromboxane A(2) (TxA(2)) production in isolated perfused livers were attenuated by KC blockade. The TxA(2) synthase inhibitor furegrelate and the TxA(2) receptor antagonist BM 13.177 reduced the increase of portal perfusion pressure supporting TxA(2) 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 TxA(2) production after KC activation.


CONCLUSIONS
KC activated by beta-glucans increase portal pressure through the release of TxA(2). This vasopressor response is augmented in BDL induced fibrosis.
Steib
Christian J
CJ
Department of Medicine II, Klinikum Grosshadern, Ludwig-Maximilians University, Marchioninistrasse 15, 81366 Munich, Germany. christian.steib@med.uni-muenchen.de
Gerbes
Alexander L
AL
Bystron
Markus
M
Op den Winkel
Mark
M
Härtl
Josef
J
Roggel
Frigga
F
Prüfer
Thomas
T
Göke
Burkhard
B
Bilzer
Manfred
M
D000818:Animals; D001652:Bile Ducts; D001794:Blood Pressure; D051545:Cyclooxygenase 1 / Q000378:metabolism; D007728:Kupffer Cells / Q000378:metabolism; D008026:Ligation; D008099:Liver / Q000473:pathology / Q000503:physiopathology*; D008103:Liver Cirrhosis / Q000503:physiopathology*; D008297:Male; D011168:Portal System / Q000503:physiopathology*; D011453:Prostaglandins / Q000378:metabolism; D011509:Proteoglycans / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018125:Receptors, Transforming Growth Factor beta; D013928:Thromboxane A2 / Q000378:metabolism*; D014662:Vasoconstrictor Agents / Q000378:metabolism; D015054:Zymosan / Q000737:chemistry / Q000494:pharmacology
D011453:Prostaglandins; D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; D014662:Vasoconstrictor Agents; C071736:betaglycan; D013928:Thromboxane A2; D015054:Zymosan; D051545:Cyclooxygenase 1