Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 6 de 6
Filter
Add more filters










Database
Language
Publication year range
1.
Gut ; 58(8): 1135-43, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19282305

ABSTRACT

BACKGROUND/AIM: Endotoxaemia can complicate hepatic ischaemia-reperfusion (IR) injury. Endocannabinoids appear to modulate the haemodynamic alterations and cytokine response induced by lipopolysaccharide (LPS). Thus, we aimed to determine the effect of the endocannabinoid CB1-receptor antagonist Rimonabant in a model of hepatic IR injury complicated by endotoxaemia. METHODS: Sprague-Dawley rats pre-treated with Rimonabant 3 or 10 mg/kg or vehicle underwent partial hepatic IR and lipopolysaccharide (LPS) injection at reperfusion. Liver injury was evaluated by serum alanine aminotransferase (ALT) and necrotic-cell count. The inflammatory response was investigated by assessing hepatic neutrophil infiltration, tumour necrosis factor alpha (TNFalpha), interferon gamma (IFNgamma), interleukin 6 (IL6), and suppressor of cytokine signalling (SOCS) 1 and SOCS3 gene expression by real-time polymerase chain reaction (RT-PCR). Systolic blood pressure and hepatic blood flow were measured as haemodynamic parameters. Finally, lipid peroxidation, glutathione status, and immunoreactive CB1 receptor expression in the liver were also determined. RESULTS: Liver injury and neutrophil infiltration occurring in the late-phase of LPS-enhanced IR were significantly reduced by CB1-receptor antagonism. Rimonabant-treated rats showed significantly higher gene expression of IFNgamma, IL6, SOCS1 and SOCS3 in "early" reperfusion, while that of TNFalpha was reduced. These findings were associated with increased STAT3 phosphorylation. Furthermore, CB1-receptor antagonism significantly improved the oxidative injury and haemodynamic alterations occurring during reperfusion in untreated rats. Finally, CB1-receptor immunoreactivity was upregulated early after reperfusion. CONCLUSIONS: This study demonstrates that CB1-receptor antagonism protects the liver against LPS-enhanced IR injury by interfering with the inflammatory response that causes the late, neutrophil-dependent phase of reperfusion injury, although the prevention of the transient endotoxin-related hypotension occurring early during reperfusion may be also involved.


Subject(s)
Endotoxemia/etiology , Liver/blood supply , Piperidines/therapeutic use , Pyrazoles/therapeutic use , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Reperfusion Injury/prevention & control , Alanine Transaminase/blood , Animals , Blood Pressure/drug effects , Drug Evaluation, Preclinical , Lipopolysaccharides , Liver/metabolism , Liver/pathology , Liver Circulation/drug effects , Male , Necrosis , Neutrophil Infiltration , Rats , Rats, Sprague-Dawley , Receptor, Cannabinoid, CB1/metabolism , Reperfusion Injury/complications , Reperfusion Injury/metabolism , Rimonabant
2.
Dig Liver Dis ; 39(10): 943-51, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17692581

ABSTRACT

BACKGROUND/AIM: Controversial experimental observations suggest that granulocyte colony stimulating-factor may promote hepatic regeneration after hepatectomy and chemical injury either by directly stimulating adult liver cells or facilitating the mobilization of bone marrow cells and their homing to the liver. We investigated whether different schedules of granulocyte colony stimulating-factor administration protect against experimental acute liver injury. METHODS: Acute liver injury was induced in Sprague-Dawley fed rats by injecting a single intraperitoneal dose of carbon tetrachloride. Recombinant human granulocyte colony stimulating-factor or vehicle was given daily after intoxication (4 days) or before (7 days) and after carbon tetrachloride administration. Liver injury and regeneration were assessed 2 and 4 days after damage. Bone marrow cells mobilization was evaluated by the white blood cell count and the assessment of circulating clonogenic haematopoietic progenitors (colony forming unit-cells). RESULTS: In this experimental model, although granulocyte colony stimulating-factor induced the significant mobilization of colony forming unit-cells, the study cytokine had no effect on liver injury (serum alanine amino transaminase level and necrotic index) and liver regeneration (mitotic index and bromodeoxyuridine incorporation), regardless of the administration schedule. CONCLUSIONS: This study does not support the conclusion that: (1) granulocyte colony stimulating-factor exerts a protective effect against toxic-induced, non-lethal acute liver injury and (2) promotes hepatocyte regeneration.


Subject(s)
Colony-Stimulating Factors/therapeutic use , Liver Failure, Acute/drug therapy , Animals , Carbon Tetrachloride/toxicity , Disease Models, Animal , Image Cytometry , Immunohistochemistry , Leukocyte Count , Liver Failure, Acute/chemically induced , Liver Failure, Acute/pathology , Liver Regeneration/drug effects , Male , Rats , Rats, Sprague-Dawley , Recombinant Proteins , Treatment Outcome
3.
Transplant Proc ; 38(10): 3249-50, 2006 Dec.
Article in English | MEDLINE | ID: mdl-17175238

ABSTRACT

AIM: We sought to determine whether an additional supply of oxygenated blood achieved by partial portal vein arterialization (PPVA) was protective on normal or fatty liver (FL) in rats with acute liver failure (ALF) induced by hepatectomy. METHODS: Sprague-Dawley rats with normal or FL were segregated either to receive or not to undergo PPVA after hepatectomy. FL was induced by feeding a choline-deficient diet (5 days). PPVA was performed by anactamasing the left renal artery to the splenic vein with a stent following a left nephrectomy and splenectomy; the control rats underwent left nephrectomy and splenectomy only. Liver injury was evaluated by the serum alanine aminotransferase (ALT) level. The animals were sacrificed at 24 hours, 48 hours, and 7 days to collect blood and liver tissue samples for biochemical analysis. The 7-day survival was assessed in separate experimental groups. RESULTS: PPVA significantly increased Po2 and oxygen saturation in the portal blood compared to non PPVA rats. PPVA significantly improved the 7-day survival compared with controls in both groups: hepatectomy of normal liver (90% vs 30%) and hepatectomy of FL (75% vs 25%). Serum ALT levels were slightly lower in the PPVA groups compared with the non-PPVA groups without a significant difference. Prothrombin activity decreased soon after hepatectomy in the normal and the FL liver groups but recovered rapidly thereafter without differences between the PPVA and non-PPVA treated animals. CONCLUSION: An additional supply of arterial oxygenated blood through a PPVA promotes rapid resolution of ALF after partial hepatectomy in rats with normal or fatty livers, significantly improving 7-day survivals compared to hepatectomy controls.


Subject(s)
Fatty Liver/surgery , Hepatectomy , Hepatic Artery/surgery , Liver Failure, Acute/prevention & control , Portal Vein/surgery , Anastomosis, Surgical , Animals , Choline Deficiency , Disease Models, Animal , Oxygen/blood , Oxygen Consumption , Portal System/physiology , Rats , Rats, Sprague-Dawley
4.
Transplant Proc ; 38(4): 1185-6, 2006 May.
Article in English | MEDLINE | ID: mdl-16757301

ABSTRACT

INTRODUCTION: Hyperoxygenation of the liver has been suggested to improve its regenerative capacity. Thus, this study sought to determine whether an additional supply of oxygenated blood delivered by portal vein arterialization (PVA) was protective against acute liver failure induced by hepatectomy. METHODS: Sprague-Dawley rats (six per each group) were divided to either undergo PVA or be untreated after extended hepatectomy. Liver injury was evaluated by the serum alanine aminotransferase (ALT) levels. Hepatocyte regeneration was assessed by calculating the mitotic index and bromodeoxyuridine staining. The 10-day survival was assessed in separate experimental groups. RESULTS: The pO(2) in portal blood increased significantly following PVA. Serum ALT levels were significantly reduced in arterialized versus nonarterialized rats. PVA promotes liver regeneration. Finally, PVA significantly improved host survival compared to the controls: 90% versus 30%, respectively. CONCLUSION: These data suggested that an additional supply of arterial oxygenated blood through PVA promoted a rapid regeneration, leading to a faster restoration of liver mass after partial hepatectomy in rats. Thus, PVA may represent a novel tool to optimize hepatocyte regeneration.


Subject(s)
Hepatic Artery/surgery , Liver Circulation , Liver Failure/surgery , Portal Vein/surgery , Alanine Transaminase/blood , Animals , Blood Flow Velocity , Disease Models, Animal , Oxygen/blood , Partial Pressure , Rats , Rats, Sprague-Dawley
5.
Transplant Proc ; 38(4): 1187-9, 2006 May.
Article in English | MEDLINE | ID: mdl-16757302

ABSTRACT

INTRODUCTION: Optimization of the conditions for regeneration of the native diseased liver is a major goal in patients with acute liver failure. This study sought to determine whether portal vein arterialization (PVA), which increases the oxygen supply to the liver, was protective in a rat model of liver failure. METHODS: At 24 hours after CCl(4) intoxication, Sprague-Dawley rats (six per group) were assigned to receive PVA or as controls. We determined blood tests, histology, and 10-day survivals. Hepatocyte regeneration was assessed by the mitotic index and bromodeoxyuridine (BrdU) incorporation. RESULTS: Serum transaminases were significantly lower in PVA-treated rats than in control animals: liver necrosis resolved rapidly after PVA. The BrdU staining and mitotic index were severalfold higher among PVA-treated than in untreated rats. Survival was 100% among rats with PVA and 40% in untreated animals (P < .01). CONCLUSIONS: PVA led to resolution of CCl(4)-induced massive liver necrosis in the rat. This effect was probably mediated by activation of rapid and extensive hepatocyte regeneration. PVA might provide a novel, alternative approach to treat acute liver failure.


Subject(s)
Carbon Tetrachloride Poisoning/surgery , Liver Circulation , Liver Failure/surgery , Portal Vein/surgery , Alanine Transaminase/blood , Animals , Aspartate Aminotransferases/blood , Disease Models, Animal , Liver Function Tests , Male , Prothrombin Time , Rats , Rats, Sprague-Dawley
6.
Dig Liver Dis ; 37(9): 689-97, 2005 Sep.
Article in English | MEDLINE | ID: mdl-15935746

ABSTRACT

BACKGROUND AND AIMS: Oxidative stress contributes to ischemia-reperfusion injury in fatty livers. This study aimed to determine whether glycogen depletion influences this oxidative injury and whether the administration of glucose can be protective. METHODS: Rats with choline deficiency-induced fatty liver underwent hepatic ischemia-reperfusion. Experimental groups: (1) fed rats; (2) 18 h fasted rats; (3) 18 h fasted rats supplemented with glucose prior to surgery. The thiobarbituric acid-reactive substances, protein carbonyls and total glutathione concentrations were measured in liver tissue and isolated mitochondria as parameters of oxidative stress before and after ischemia and during reperfusion. The mitochondrial F1-ATPase content and the serum alanine transaminase were also determined. RESULTS: With respect to fed rats, fasted rats exhibited an increased oxidative injury in both liver tissue and isolated mitochondria throughout the experiment with the only exception of thiobarbituric acid-reactive substances, which were not affected by the nutritional status in liver tissue. Fasted rats showed a significantly lower F1-ATPase content and higher alanine transaminase levels. Glucose supplementation significantly reduced the fasting-associated exacerbation of oxidative stress and liver injury and the F1-ATPase exhaustion. CONCLUSIONS: These data indicate that the pre-existing hepatic glycogen content modulates the oxidative damage in rat fatty livers exposed to ischemia-reperfusion injury and that the energetic substrate supplementation may represent a clinically feasible protective strategy.


Subject(s)
Fatty Liver/pathology , Glucose/pharmacology , Oxidative Stress/physiology , Reperfusion Injury/physiopathology , Alanine Transaminase/blood , Alanine Transaminase/metabolism , Animals , Dietary Supplements , Fatty Liver/metabolism , Glucose/administration & dosage , Glutathione/metabolism , Liver/drug effects , Liver/metabolism , Liver/pathology , Male , Nutritional Status , Oxidative Stress/drug effects , Protein Carbonylation , Proton-Translocating ATPases/metabolism , Rats , Rats, Sprague-Dawley , Reperfusion Injury/prevention & control , Thiobarbituric Acid Reactive Substances/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL
...