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

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.