Development of cirrhosis is associated with increased levels of placental growth factor: A descriptive study

Background and Aims: Chronic liver damage causes hepatic stellate cell activation and contraction, leading to intrahepatic microvascular and structural changes. Bosentan, an endothelin-1 receptor A and B antagonist, decreases portal pressure, however intrahepatic in vivo effects have never been studied. We will study the in vivo effects of bosentan on hepatic microcirculation in a mouse model of cirrhosis by measuring sinusoidal diameter with intravital fluorescence microscopy (IVFM).
Methods: In male Swiss mice (n = 4) cirrhosis was induced by subcutaneous (SC) injection of carbon tetrachloride (CCl4, 1:1 in olive oil; 1 ml/kg) twice weekly for 16 weeks. Control mice (n = 4) received pure olive oil (1 ml/kg) SC. Hepatic microcirculation was visualised in vivo by IVFM after intravenous (IV) infusion of sodium fluorescein. Sinusoidal diameters were measured after 0, 5, 10, 15, 20, 25, 30, 45 and 60 min of a continuous IV infusion of 10 mg/kg/h bosentan or placebo.
Results: Baseline sinusoidal diameter in CCl4 mice (5.9 mm ± 0.3) was significantly smaller than in control mice (6.7 mm ± 0.2) (PConclusions: Sinusoidal diameter in a cirrhotic mouse is significantly smaller than in a control mouse, which demonstrates in vivo the narrowing of liver sinusoids in a cirrhotic mouse model. Bosentan causes a significant sinusoidal vasodilation after 15 and 20 minutes of an IV administration in the CCl4 group. On the other hand, bosentan does not have an influence on liver sinusoids in the control group. These results demonstrate for the first time the in vivo vasodilatory effect of bosentan on liver sinusoids during cirrhosis, but there is tachyphylaxis after 20 minutes of IV infusion.

Jaar van publicatie:2008