TY - JOUR
T1 - The relationship between endotoxemia and hepatic endocannabinoids in cirrhotic rats with portal hypertension
AU - Lin, Han Chieh
AU - Yang, Ying Ying
AU - Tsai, Tung Hu
AU - Huang, Chih Ming
AU - Huang, Yi Tsau
AU - Lee, Fa Yauh
AU - Liu, Tze Tze
AU - Lee, Shou Dong
N1 - Funding Information:
The authors thank the National Science Council of the Republic of China, Taiwan (Contract No. NSC95–2314-B-075–018-MY3 and NSC97–2314-B-075–033-MY3) and the Taipei Veterans General Hospital (Contract No.V99C1–001 and VGH99B2–002) for financially supporting this research.
PY - 2011/6
Y1 - 2011/6
N2 - Background & Aims: Cirrhosis is characterized by endotoxemia and increased intrahepatic resistance, which is caused by hepatic fibrosis and endothelial dysfunction, as well as the activated endocannabinoids system, including cannabinoid (CB1 and CB2) receptors. Besides accelerating hepatic fibrogenesis, endotoxins induce the release of circulating endocannabinoids and portal hypertension in cirrhosis. This study examines how suppression of endotoxemia by antibiotics affects intrahepatic resistance and the hepatic endocannabinoid system in bile-duct-ligated (BDL) rats. Methods: Measurements were performed that included: mean arterial pressure, cardiac index (CI), systemic vascular resistance, superior mesenteric arterial blood flow and resistance, PVP, plasma endotoxin and hepatic tumor necrosis factor-α (TNFα), anandamide and 2-arachidonylglycerol, hepatic expression of cannabinoid receptors, endothelial nitric oxide synthase (eNOS), phospho-eNOS, Akt, phospho-Akt and thromboxane synthase (TXS), matrix metalloproteinase-2 (MMP-2), tissue inhibitor of metalloproteinase-2 (TIMP-2), hepatic fibrosis, and leukocyte infiltration. Hepatic endothelial dysfunction was evaluated in BDL rats receiving vehicle (BDL-V) or 2-weeks of ciprofloxacin (BDL-cipro). Results: Plasma endotoxin and hepatic TNFα, anandamide and 2-arachidonylglycerol, expression of TXS, MMP-2, TIMP-2, hepatic fibrosis and infiltration of hepatic leukocytes, CI, PVP and intrahepatic resistance were significantly lower in BDL-cipro than in BDL-V rats. Conversely, systemic vascular resistance, eNOS and Akt phosphorylation were significantly higher in BDL-cipro than in BDL-V rats. Improvement of hepatic endothelial dysfunction was associated with lower expression of hepatic CB1 and a higher expression of hepatic CB 2 in BDL-cipro rats. Conclusions: In cirrhotic rats, ciprofloxacin suppressed endotoxemia and the hepatic endocannabinoid system thus ameliorating hyperdynamic circulation and decreased intrahepatic resistance by preventing hepatic fibrogenesis and endothelial dysfunction.
AB - Background & Aims: Cirrhosis is characterized by endotoxemia and increased intrahepatic resistance, which is caused by hepatic fibrosis and endothelial dysfunction, as well as the activated endocannabinoids system, including cannabinoid (CB1 and CB2) receptors. Besides accelerating hepatic fibrogenesis, endotoxins induce the release of circulating endocannabinoids and portal hypertension in cirrhosis. This study examines how suppression of endotoxemia by antibiotics affects intrahepatic resistance and the hepatic endocannabinoid system in bile-duct-ligated (BDL) rats. Methods: Measurements were performed that included: mean arterial pressure, cardiac index (CI), systemic vascular resistance, superior mesenteric arterial blood flow and resistance, PVP, plasma endotoxin and hepatic tumor necrosis factor-α (TNFα), anandamide and 2-arachidonylglycerol, hepatic expression of cannabinoid receptors, endothelial nitric oxide synthase (eNOS), phospho-eNOS, Akt, phospho-Akt and thromboxane synthase (TXS), matrix metalloproteinase-2 (MMP-2), tissue inhibitor of metalloproteinase-2 (TIMP-2), hepatic fibrosis, and leukocyte infiltration. Hepatic endothelial dysfunction was evaluated in BDL rats receiving vehicle (BDL-V) or 2-weeks of ciprofloxacin (BDL-cipro). Results: Plasma endotoxin and hepatic TNFα, anandamide and 2-arachidonylglycerol, expression of TXS, MMP-2, TIMP-2, hepatic fibrosis and infiltration of hepatic leukocytes, CI, PVP and intrahepatic resistance were significantly lower in BDL-cipro than in BDL-V rats. Conversely, systemic vascular resistance, eNOS and Akt phosphorylation were significantly higher in BDL-cipro than in BDL-V rats. Improvement of hepatic endothelial dysfunction was associated with lower expression of hepatic CB1 and a higher expression of hepatic CB 2 in BDL-cipro rats. Conclusions: In cirrhotic rats, ciprofloxacin suppressed endotoxemia and the hepatic endocannabinoid system thus ameliorating hyperdynamic circulation and decreased intrahepatic resistance by preventing hepatic fibrogenesis and endothelial dysfunction.
KW - Antibiotics
KW - Biliary cirrhosis
KW - Portal hypertension
UR - http://www.scopus.com/inward/record.url?scp=79956089082&partnerID=8YFLogxK
U2 - 10.1016/j.jhep.2010.09.026
DO - 10.1016/j.jhep.2010.09.026
M3 - Article
C2 - 21145843
AN - SCOPUS:79956089082
SN - 0168-8278
VL - 54
SP - 1145
EP - 1153
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 6
ER -