Kupffer cell activation in normal and fibrotic livers increases portal pressure via thromboxane A(2).

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 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.