Cirrhosis is often associated with
portal hypertension and portal-systemic collateral vessels formation attributed to angiogenesis, which leads to severe complications as
hepatic encephalopathy.
Sirolimus has anti-
fibrosis and
anti-angiogenesis effects, but whether it influences the severity of portal-systemic collaterals and
hepatic encephalopathy is unknown. This study was thus designed to address this issue in rats with common bile duct
ligation-induced
liver cirrhosis.
Sham-operated rats were surgical controls. Rats were intraperitoneally administered with 0.5 and 2 mg/kg/day
sirolimus or vehicle for 2 weeks. Four weeks post operations, motor activities,
body weight, biochemistry and hemodynamic data were measured. The liver was dissected for histopathology, immunohistochemical stains and
protein analysis. On the parallel cirrhotic groups, the portal-systemic shunting was determined. The results showed that the
body weight gain was significantly lower in
sirolimus-treated rats.
Sirolimus reduced portal pressure and plasma levels of
alanine aminotransferase,
aspartate aminotransferase and
ammonia, and attenuated hepatic
inflammation and
fibrosis in cirrhotic rats. In addition, the hepatic phosphorylated
mammalian target of rapamycin (mTOR) and
P70S6K protein expressions were significantly downregulated and
endothelial nitric oxide synthase (eNOS) expression upregulated by
sirolimus.
Sirolimus did not influence portal-systemic shunting and motor activities of cirrhotic rats. In conclusion,
sirolimus significantly improved hepatic
inflammation and
fibrosis accompanied by portal pressure reduction in cirrhotic rats, in which down-regulated mTOR/
P70S6K and up-regulated eNOS expressions might play a role. However,
sirolimus did not significantly change the severity of portal-systemic collaterals and motor activities, suggesting that the multifactorial pathogenesis of
hepatic encephalopathy could not be fully overcome by
sirolimus.