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1.
J Hepatol ; 50(5): 937-47, 2009 May.
Article in English | MEDLINE | ID: mdl-19303157

ABSTRACT

BACKGROUND/AIMS: The efficacy of ischemic preconditioning (IPC) in preventing reperfusion injury in human liver transplants is still questioned. Phosphoinositide-3-kinase (PI3K) is essential for IPC development in rodent livers. This work investigates whether PI3K-dependent signals might account for the inconsistent responses to IPC of transplanted human livers. METHODS: Forty livers from deceased donors were randomized to receive or not IPC before recovery. PI3K activation was evaluated in biopsies obtained immediately before IPC and 2 h after reperfusion by measuring the phosphorylation of the PI3K downstream kinase PKB/Akt and the levels of the PI3K antagonist phosphatase tensin-homologue deleted from chromosome 10 (PTEN). RESULTS: IPC increased PKB/Akt phosphorylation (p = 0.01) and decreased PTEN levels (p = 0.03) in grafts, but did not significantly ameliorate post-transplant reperfusion injury. By calculating T(2h)/T(0) PKB/Akt phosphorylation ratios, 10/19 (53%) of the preconditioned grafts had ratios above the control threshold (IPC-responsive), while the remaining nine grafts showed ratios comparable to controls (IPC-non-responsive). T(2h)/T(0) PTEN ratios were also decreased (p < or = 0.03) only in IPC-responsive grafts. The patients receiving IPC-responsive organs had ameliorated (p < or = 0.05) post-transplant aminotransferase and bilirubin levels, while prothrombin activity was unchanged. CONCLUSIONS: Impaired PI3K signaling might account for the variability in the responses to IPC of human grafts from deceased donors.


Subject(s)
Ischemic Preconditioning , Liver Transplantation/physiology , Phosphatidylinositol 3-Kinases/metabolism , Reperfusion Injury/prevention & control , Adult , Aged , Aged, 80 and over , Biopsy , Female , Humans , Liver/enzymology , Liver/pathology , Male , Middle Aged , PTEN Phosphohydrolase/metabolism , PTEN Phosphohydrolase/physiology , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/physiology , Transplantation Tolerance/physiology
2.
Gastroenterology ; 137(1): 341-9, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19208344

ABSTRACT

BACKGROUND & AIMS: Endocannabinoids contribute to hemodynamic abnormalities of cirrhosis. Whether this favors renal sodium retention and ascites formation is unknown. We determined whether cannabinoid type 1 receptor antagonism prevents sodium retention and ascites formation in preascitic cirrhotic rats. METHODS: Once renal sodium handling was impaired, rats with carbon tetrachloride-induced cirrhosis were randomized to receive either vehicle or rimonabant (3 [group 1] or 10 [group 2] mg x kg(-1) x day(-1)) for 2 weeks. Natriuresis, sodium intake, and sodium balance were measured daily. At the end of the protocol, systemic hemodynamics, renal blood flow, ascites volume, and liver fibrosis were assessed. RESULTS: A significant reduction in ascites formation (group 1: 54%; group 2: 10%; vehicle: 90%) and volume (group 1: 1.6 +/- 0.3 mL; group 2: 0.5 mL; vehicle: 5.5 +/- 0.8 mL) occurred in treated rats. Rimonabant significantly improved sodium balance during week 2 (group 1: 0.98 +/- 0.08 mmol; group 2: 0.7 +/- 0.08 mmol; vehicle: 3.05 +/- 0.11 mmol). Both treated groups showed lower cardiac output and higher mean arterial pressure, peripheral vascular resistance, and renal blood flow (P < .05). Liver fibrosis was reduced in group 2 by 30% (P < .05 vs vehicle). Mean arterial pressure inversely correlated with sodium balance (R = -0.61; P = .003), but not with fibrosis score. CONCLUSIONS: Rimonabant improves sodium balance and delays decompensation in preascitic cirrhosis. This is achieved though an improvement in systemic and renal hemodynamics, although it cannot be excluded that the antifibrotic effect of the drug may play a role.


Subject(s)
Ascites/prevention & control , Kidney/drug effects , Liver Cirrhosis, Experimental/drug therapy , Piperidines/pharmacology , Pyrazoles/pharmacology , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Animals , Ascites/etiology , Ascites/metabolism , Ascites/physiopathology , Blood Pressure/drug effects , Carbon Tetrachloride , Cardiac Output/drug effects , Diuresis/drug effects , Dose-Response Relationship, Drug , Kidney/blood supply , Kidney/metabolism , Kidney/physiopathology , Liver Cirrhosis, Experimental/chemically induced , Liver Cirrhosis, Experimental/complications , Liver Cirrhosis, Experimental/metabolism , Liver Cirrhosis, Experimental/physiopathology , Male , Natriuresis/drug effects , Rats , Rats, Wistar , Receptor, Cannabinoid, CB1/metabolism , Renal Circulation/drug effects , Rimonabant , Sodium/urine , Sodium, Dietary/metabolism , Time Factors , Vascular Resistance/drug effects
3.
J Surg Res ; 135(2): 394-401, 2006 Oct.
Article in English | MEDLINE | ID: mdl-16780880

ABSTRACT

BACKGROUND: Optimization of the conditions for regeneration is a major goal in the management of patients with acute liver failure (ALF). Previous observations suggested that hyperoxygenation of the liver may improve its regenerative capacity. Thus, this study aimed to determine whether an additional supply of oxygenated blood achieved by portal vein arterialization (PVA) is protective in rat ALF caused by toxin administration or hepatectomy. METHODS: Sprague-Dawley rats were subjected or not to PVA after CCl(4) intoxication or extended hepatectomy. PVA was performed by interposing a stent between the left renal artery and splenic vein after left nephrectomy and splenectomy. Liver injury was evaluated by the serum ALT level and necrotic cell count. Hepatocyte regeneration was assessed by calculating the mitotic index and bromodeoxyuridine (BrdU) staining. The 10-day survival was assessed in separate experimental groups. RESULTS: The pO(2) in portal blood increased significantly following PVA. In the CCl(4)-induced ALF, serum ALT levels and necrosis were significantly reduced in arterialized than non-arterialized rats. PVA greatly promotes liver regeneration in both models. Finally, PVA significantly improved survival compared to controls (CCl(4): 100 versus 40%; 90% hepatectomy: 90 versus 30%). Interestingly, in the CCl(4)-induced ALF, survival was 100% even when the shunt was closed after 48 h. CONCLUSION: These data indicate that the additional supply of arterial oxygenated blood through PVA promotes a rapid regeneration leading to the resolution of toxic-induced massive liver necrosis and a faster restoration of liver mass after partial hepatectomy in rats. Thus, PVA may represent a novel tool for optimizing hepatocyte regeneration.


Subject(s)
Carbon Tetrachloride/toxicity , Liver Circulation , Liver Failure/chemically induced , Liver Failure/surgery , Portal Vein/surgery , Alanine Transaminase/blood , Analysis of Variance , Animals , Aspartate Aminotransferases/blood , Creatine/blood , Hepatectomy , Image Cytometry , Immunohistochemistry , Liver Failure/pathology , Liver Function Tests , Liver Regeneration/physiology , Male , Oxygen/blood , Prothrombin Time , Rats , Rats, Sprague-Dawley
4.
J Hepatol ; 43(1): 92-7, 2005 Jul.
Article in English | MEDLINE | ID: mdl-15893844

ABSTRACT

BACKGROUND/AIMS: We aimed to develop a non-invasive test to identify the initial alterations of sodium homeostasis and prospectively predict decompensation in preascitic cirrhotic rats. METHODS: The sodium overload test (SOT) was performed in control (CT) and CCl4-induced cirrhotic rats (CH) by calculating the percentage of sodium excreted in the urine after NaCl oral administration (0.5 g/kg). Liver fibrosis was quantified by image cytometry. RESULTS: From the 8th week of CCl4 intoxication, while the daily sodium balance did not change in CH and CT, SOT became significantly lower in the former (62.1+/-13.2 vs 78.8+/-13.2%; P=0.035). At sacrifice, ascites was only present in one animal. The degree of liver fibrosis correlated with SOT. In subsequent experiments, 17 cirrhotic rats developed ascites between the 9th and 14th weeks. SOT remained stable up to 3 weeks before ascites appearance, while it fell significantly to 35+/-19 and 26+/-21% at 2 and 1 week before ascites diagnosis, respectively. Nearly all the rats (95%) with a SOT<60% developed ascites within 3 weeks. CONCLUSIONS: In preascitic cirrhotic rats, SOT unveils sodium metabolism abnormalities earlier than the daily sodium balance and prospectively predicts ascites appearance, identifying rats in a homogeneous stage of cirrhosis, which is essential in pathophysiological studies on sodium retention.


Subject(s)
Ascites/etiology , Ascites/physiopathology , Liver Cirrhosis, Experimental/complications , Liver Cirrhosis, Experimental/metabolism , Sodium/metabolism , Animals , Carbon Tetrachloride , Dose-Response Relationship, Drug , Hemodynamics , Homeostasis , Liver Cirrhosis, Experimental/chemically induced , Liver Cirrhosis, Experimental/pathology , Male , Rats , Rats, Wistar , Sodium Chloride/administration & dosage , Sodium Chloride/metabolism , Sodium Chloride/pharmacology , Survival Analysis
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