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Background & Aims: Recent studies have described the existence of endogenous cannabinoids with vasodilator activity because of their interaction with peripheral CB1 receptors, anandamide being the most extensively investigated. The study investigated whether endogenous cannabinoids are involved in the pathogenesis of the cardiovascular disturbances in experimental cirrhosis. Methods: Arterial pressure, cardiac output, and total peripheral resistance were measured before and after the administration of a cannabinoid CB1 receptor antagonist to cirrhotic rats with ascites and to control rats. Blood pressure was also assessed in normotensive recipient rats after the intravenous administration of blood cells or isolated monocytes obtained from cirrhotic and control rats. Moreover, the endogenous content of anandamide was measured in circulating monocytes of cirrhotic and control rats by gas chromatography/mass spectrometry. Results: CB1 receptor blockade did not modify systemic hemodynamics in control rats, but significantly increased arterial pressure and peripheral resistance in cirrhotic animals. Blood cell suspension or monocytes from cirrhotic animals, but not from controls, induced arterial hypotension in recipient rats. Finally, anandamide was solely detected in monocytes of cirrhotic animals. Conclusions: Monocytes of cirrhotic rats with ascites are activated to produce anandamide and this substance contributes to arterial hypotension in experimental cirrhosis.

Background & Aims: Recent studies have suggested that the kallikrein-kinin system regulates tissue fibrogenesis. We hypothesize that bradykinin (BK), the main effector peptide of this system, regulates hepatic fibrogenesis. Methods: Kallikrein-kinin system components were studied by quantitative reverse-transcription polymerase chain reaction analysis, immunohistochemistry, and Western blotting. The effect of bradykinin on liver injury was studied by infusing saline or bradykinin (1 and 100 ng/kg/min) through a subcutaneous pump into carbon tetrachloride–treated rats and mice treated with Fas-stimulating antibody. Bradykinin effects were studied in cultured hepatic stellate cells (HSCs) and hepatocytes. Results: Bradykinin receptors and kallikrein-1 were detected in both normal and fibrotic human livers and HSCs. BK receptors were up-regulated in fibrotic livers and activated HSCs. Bradykinin infusion reduced liver damage, as indicated by decreased aminotransferase serum levels and reduced histologic necroinflammatory score without inducing changes in arterial pressure. Moreover, bradykinin attenuated hepatic fibrosis, as indicated by reduced collagen accumulation, smooth muscle α-actin content, as well as decreased pro-collagen-α1(I) and transforming growth factor-β1 gene expression. Bradykinin infusion reduced hepatocellular apoptosis induced by anti–Fas-receptor antibody. HSCs responded to bradykinin with intracellular calcium mobilization. Bradykinin reduced procollagen-α1(I) and transforming growth factor-β1 gene expression and induced matrix metalloproteinase-2 activation. Finally, BK induced prosurvival and proliferative intracellular signaling in primary hepatocytes. Conclusions: Bradykinin attenuates liver damage and fibrosis development in a rat model of chronic liver injury. Therefore, activation of the kallikrein-kinin system may be a new therapeutic approach to the management of chronic liver disease.

Background & Aims Significant fibrosis (fibrosis stage [F] ≥ 2) and portal hypertension (hepatic venous pressure gradient [HVPG] ≥ 6 mm Hg) in patients 1 year after liver transplantation indicate progressive hepatitis C recurrence. This study evaluated whether serum fibrosis markers can predict hepatitis C recurrence during the first year after liver transplantation. Methods Hyaluronic acid, amino-terminal propeptide of type-III-procollagen, tissue inhibitor of matrix metalloproteinase type-1 concentrations were measured in serum samples from 133 patients infected with hepatitis C virus (HCV) at 3, 6, and 12 months after liver transplantation; routine laboratory tests were also performed. Liver biopsy samples (n = 133) and HVPGs (n = 94) were analyzed 1 year after transplantation. Sixteen patients who were not infected with HCV served as controls. Results An algorithm, including the 3 markers (3-M-ALG) and 3 published scores (aspartate aminotransferase [AST]-to-alanine aminotransferase ratio, AST-to-platelet ratio index, and Benlloch) were analyzed. One year after liver transplantation, 50 patients (38%) had significant fibrosis (F ≥ 2) and 31 (32%) had an HVPG ≥ 6 mm Hg. The area under the receiver operator characteristic curve of the 3-M-ALG used to identify F ≥ 2 at 3, 6, and 12 months after transplantation (0.67, 0.77, and 0.78) and of those with HVPG ≥ 6 at the same time points (0.75, 0.87, and 0.90) were significantly higher than values obtained with the 3 published scores. At 12 months, a 3-M-ALG ≥ 2 identified most patients at risk of decompensation/death. Conclusions Serum markers can accurately discriminate between patients with mild and progressive hepatitis C recurrence after liver transplantation.