taurochenodeoxycholic-acid and Reperfusion-Injury

Topics: Adenosine; Adult; Allopurinol; Cholagogues and Choleretics; Glutathione; Humans; Insulin; Liver; Liver Transplantation; Middle Aged; Organ Preservation; Organ Preservation Solutions; Raffinose; Reperfusion Injury; Taurochenodeoxycholic Acid; Transplantation, Homologous

Impaired function of the endoplasmic reticulum (ER) results in ER stress, an accumulation of proteins in the ER lumen. ER stress is a major contributor to inflammatory diseases and is part of the pathomechanism of ischemia-reperfusion injury (IRI). Since severe traumatic injury is often accompanied by remote organ damage and immune cell dysfunction, we investigated the influence of ER stress modulation on the systemic inflammatory response and liver damage after hemorrhagic shock and reperfusion (HS/R).. Male C56BL/6-mice were subjected to hemorrhagic shock with a mean arterial pressure of 30 ± 5 mm Hg. After 90 min mice were resuscitated with Ringer solution. Either the ER stress inductor tunicamycin (TM), its drug vehicle (DV), or the ER stress inhibitor tauroursodeoxycholic acid (TUDCA) were added to reperfusion solution. Animals were sacrificed 14 h after shock induction and plasma concentrations of liver transaminases as well as inflammatory cytokines were measured. In addition, liver tissue sections were embedded in paraffin. For the quantification of hepatocellular damage hematoxylin and eosin stained tissue sections were analyzed. Furthermore, the topographic patterns of ER stress marker proteins were evaluated using immunohistochemistry.. ER stress modulation influenced the topographic pattern of ER stress marker proteins. The alterations were particularly seen in the transition zone between vital liver parenchyma and cell death areas. Furthermore, the application of tunicamycin during reperfusion inhibited the secretion of pro-inflammatory cytokines and increased the hepatocellular damage significantly. However, the injection of TUDCA resulted in a significantly reduced liver damage, as seen by lower transaminases and smaller cell death areas.. ER stress modulation influences post-hemorrhagic IRI. Moreover, the ER stress inhibitor TUDCA diminished the hepatocellular damage following HS/R significantly. This may help to provide a therapeutic target to ameliorate the clinical outcome after trauma-hemorrhage.

Topics: Animals; Endoplasmic Reticulum Stress; Liver; Liver Diseases; Male; Mice; Reperfusion Injury; Shock, Hemorrhagic; Taurochenodeoxycholic Acid

Ischemia-reperfusion (I/R)-induced acute kidney injury (AKI) not only prolongs the length of hospital stay, but also seriously affects the patient's survival rate. Although our previous investigation has verified that reactive oxygen species (ROS) transferred through gap junction composed of connexin32 (Cx32) contributed to AKI, its underlying mechanisms were not fully understood and viable preventive or therapeutic regimens were still lacking. Among various mechanisms involved in organs I/R-induced injuries, endoplasmic reticulum stress (ERS)-related apoptosis is currently considered to be an important participant. Thus, in present study, we focused on the underlying mechanisms of I/R-induced AKI, and postulated that Cx32 mediated ROS/ERS/apoptosis signal pathway activation played an important part in I/R-induced AKI.. We established renal I/R models with Cx32. Renal damage was progressively exacerbated in a time-dependent manner at the reperfusion stage, that was consistent with the alternation of ERS activation, including glucose regulated protein 78 (BiP/GRP78), X box-binding protein1, and C/EBP homologous protein expression. TUDCA or 4-PBA application attenuated I/R-induced ERS activation and protected against renal tubular epithelial cells apoptosis and renal damage. Cx32 deficiency decreased ROS generation and distribution between the neighboring cells, which attenuated I/R-induced ERS activation, and improved cell apoptosis and renal damage.. Cx32 mediated ROS/ERS/apoptosis signal pathway activation played an important part in I/R-induced AKI. Cx32 deficiency, ROS elimination, and ERS inhibition all could protect against I/R-induced AKI.

Topics: Acetylcysteine; Acute Kidney Injury; Animals; Apoptosis; Connexins; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Epithelial Cells; Gap Junction beta-1 Protein; Gene Deletion; Gene Knockout Techniques; Kidney; Male; Mice, Inbred C57BL; Phenylbutyrates; Reactive Oxygen Species; Reperfusion Injury; Signal Transduction; Taurochenodeoxycholic Acid

The aim of this study is to investigate the protective effect and the mechanism of tauroursodeoxycholic acid (TUDCA) against hepatic ischemia reperfusion (IR) injury. Male Balb/c mice were intraperitoneally injected with tauroursodeoxycholic acid (400 mg/kg) or saline solution, once per day for 3 days before surgery, and then the model of hepatic I/R injury was established. Blood and liver samples were collected from each group at 3, 6, and 24 h after surgery. Liver pathological changes, liver function, hepatocyte apoptosis and proinflammatory factors were detected. KCs were extracted, cultured and treated with TUDCA or phosphate-buffered saline (PBS) for 24 h, and then viability and phagocytosis were examined. Additionally, IRE1α/TRAF2/NF-κB pathway activity and AML cell apoptosis were detected. The results showed that TUDCA alleviated hepatic I/R injury, the level of liver function markers, and hepatocyte apoptosis in vivo. Furthermore, the proinflammatory effects of KCs were suppressed by down-regulating IRE1α/TRAF2/NF-κB pathway activity in vivo. TUDCA dose-dependently suppressed the expression of inflammatory factors and IRE1α/TRAF2/NF-κB pathway activity in vitro, consistent with the in vivo results. Therefore, TUDCA can effectively alleviate hepatic IR injury by down-regulating the activity of the IRE1α/TRAF2/NF-κB pathway to suppress the function of KCs.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Survival; Coculture Techniques; Cytokines; Cytoprotection; Disease Models, Animal; Dose-Response Relationship, Drug; Endoplasmic Reticulum Stress; Endoribonucleases; Inflammation Mediators; Kupffer Cells; Leukemia, Myeloid, Acute; Liver; Liver Diseases; Male; Mice, Inbred BALB C; NF-kappa B; Protein Serine-Threonine Kinases; Reperfusion Injury; Signal Transduction; Taurochenodeoxycholic Acid; Time Factors; TNF Receptor-Associated Factor 2

Ischemic-type biliary lesions (ITBL) are the most troublesome biliary complication after liver transplantation (LT) from non-heart-beating donors (NHBD) and frequently result in death or re-transplantation. In transplantation process, warm ischemia (WI) in the donor, cold ischemia and reperfusion injury in the recipient altogether inducing ischemia-reperfusion injury (IRI) is strongly associated with ITBL. This is a cascading injury process, involving in a complex series of inter-connecting events causing variety of cells activation and damage associated with the massive release of inflammatory cytokines and generation of reactive oxygen species (ROS). These damaged cells such as sinusoidal endothelial cells (SECs), Kupffer cells (KCs), hepatocytes and biliary epithelial cells (BECs), coupled with immunological injury and bile salt toxicity altogether contribute to ITBL in NHBD LT. Developed therapeutic strategies to attenuate IRI are essential to improve outcome after LT. Among them, single pharmaceutical interventions blocking a specific pathway of IRI in rodent models play an absolutely dominant role, and show a beneficial effect in some given controlled experiments. But this will likely prove ineffective in complex clinical setting in which more risk parameters are involved. Therefore, we intend to design a multidrug cocktail approach to block different pathways on more than one stage (WI, cold ischemia and reperfusion) of the process of IRI-induced ITBL simultaneously. This multidrug cocktail will include six drugs containing streptokinase, epoprostenol, thiazolidinediones (TZDs), N-Acetylcysteine (NAC), hemin and tauroursodeoxycholic acid (TUDC). These drugs show protective effects by targeting the different key events of IRI, such as anti-inflammatory, anti-fibrosis, anti-oxidation, anti-apoptosis and reduced bile salt toxicity. Ideally, the compounds, dosage, and method of application of drugs included in cocktail should not be definitive. We can consider removing or adding some drugs to the proposed cocktail based on further research. But given the multitude of different combinations, it is extremely difficult to determent which combination is the optimization design. Nevertheless, regardless of the difficulty, our multidrug cocktail approach designed to block different mechanisms on more than one stage of IRI simultaneously may represent a future preventive and therapeutic avenue for ITBL.

Topics: Acetylcysteine; Animals; Biliary Tract Diseases; Drug Therapy, Combination; Epithelial Cells; Epoprostenol; Female; Hemin; Hepatocytes; Humans; Inflammation; Ischemia; Kupffer Cells; Liver; Liver Failure; Liver Transplantation; Models, Theoretical; Organ Preservation; Reactive Oxygen Species; Reoperation; Reperfusion Injury; Streptokinase; Swine; Taurochenodeoxycholic Acid; Thiazolidinediones; Tissue Donors; Warm Ischemia

Inevitable warm ischemia time before organ procurement aggravates posttransplantation ischemia-reperfusion injury. Endoplasmic reticulum (ER) stress is involved in ischemia-reperfusion injury, but its role in donation after cardiac death (DCD) liver transplantation is not clear and the effect of ER stress inhibitors, tauroursodeoxycholic acid (TUDCA) and 4-phenyl butyric acid (PBA), on the prognosis of recipient of DCD liver transplantation remains unclear.. Male Sprague-Dawley rats (8-10 weeks) were randomly divided into the control group: liver grafts without warm ischemia were implanted; DCD group: warm ischemia time of the liver grafts was 60 minutes; TUDCA and PBA groups: based on the DCD group, donors were intraperitoneally injected with TUDCA or PBA 30 minutes before the organ procurements. Serum aminotransferase levels, oxidative stress activation and expression of ER stress signal molecules were evaluated. Pathological examinations were performed. The survivals of the recipients in each group were compared for 14 days.. Compared with the control group, DCD rats had significantly higher levels of serum aminotransferase at 6 hours, 1 day and 3 days after operation (P<0.01, 0.01 and 0.05, respectively) and oxidative indices (P<0.01 for both malondialdehyde and 8-hydroxy deoxyguanosine), more severe liver damage (P<0.01) and up-regulated ER stress signal expressions (P<0.01 for GRP78, phos-eIF2alpha1, CHOP, ATF-4, ATF-6, PERK, XBP-1 and pro-caspase-12). All recipients died within 3 days after liver transplantation. Administration of TUDCA or PBA significantly decreased aminotransferase levels (P<0.05), increased superoxide dismutase activities (P<0.01), alleviated liver damage (P<0.01), down-regulated ER stress signal expressions (P<0.01) and improved postoperative survivals (P<0.01).. ER stress was involved with DCD liver transplantation in rats. Preoperative intraperitoneally injection of TUDCA or PBA protected ER stress and improved prognosis.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Cholagogues and Choleretics; Death; Delayed Graft Function; Endoplasmic Reticulum Stress; Liver Transplantation; Male; Models, Animal; Oxidative Stress; Phenylbutyrates; Prognosis; Rats, Sprague-Dawley; Reperfusion Injury; Survival Rate; Taurochenodeoxycholic Acid

The incidence of acute kidney injury (AKI) is very high, and multiple physiopathological processes are involved, including endoplasmic reticulum stress (ERS). Tauroursodeoxycholic acid (TUDCA) is an endogenous bile acid derivative that has been reported to inhibit ERS. To determine whether TUDCA had a nephroprotective effect on AKI and to explore the exact mechanism, an ischaemia/reperfusion (I/R)-induced AKI mouse model and a tunicamycin-pre-treated TCMK-1 cell model were established. It was found that the renal tubular necrosis score and cell apoptosis index reached their peak 24 hr after I/R. GRP78 and C/EBP homologous protein (CHOP) expression and Caspase 12 activation were enhanced, reaching their peaks at 4 and 12 hr, respectively. TUDCA intervention not only decreased the renal tubular necrosis score and the cell apoptosis index but also down-regulated GRP78 and CHOP expression and Caspase 12 activation. The survival rate of TCMK-1 cells pre-treated with TUDCA was significantly higher than that of TCMK-1 cells without TUDCA pre-treatment. In conclusion, TUDCA had a nephroprotective effect on IR-induced AKI by inhibiting ERS and by blocking GRP78 and CHOP expression, reducing Caspase 12 activation and inhibiting cell apoptosis.

Topics: Acute Kidney Injury; Animals; Apoptosis; Caspase 12; Cells, Cultured; Disease Models, Animal; Down-Regulation; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Heat-Shock Proteins; Male; Mice; Mice, Inbred C57BL; Reperfusion Injury; Stress, Physiological; Taurochenodeoxycholic Acid; Transcription Factor CHOP

Numerous steatotic livers are discarded for transplantation because of their poor tolerance to ischemia-reperfusion (I/R). We examined whether tauroursodeoxycholic acid (TUDCA), a known inhibitor of endoplasmic reticulum (ER) stress, protects steatotic and nonsteatotic liver grafts preserved during 6 h in University of Wisconsin (UW) solution and transplanted. The protective mechanisms of TUDCA were also examined. Neither unfolded protein response (UPR) induction nor ER stress was evidenced in steatotic and nonsteatotic liver grafts after 6 h in UW preservation solution. TUDCA only protected steatotic livers grafts and did so through a mechanism independent of ER stress. It reduced proliferator-activated receptor-γ (PPARγ) and damage. When PPARγ was activated, TUDCA did not reduce damage. TUDCA, which inhibited PPARγ, and the PPARγ antagonist treatment up-regulated toll-like receptor 4 (TLR4), specifically the TIR domain-containing adaptor inducing IFNβ (TRIF) pathway. TLR4 agonist treatment reduced damage in steatotic liver grafts. When TLR4 action was inhibited, PPARγ antagonists did not protect steatotic liver grafts. In conclusion, TUDCA reduced PPARγ and this in turn up-regulated the TLR4 pathway, thus protecting steatotic liver grafts. TLR4 activating-based strategies could reduce the inherent risk of steatotic liver failure after transplantation.

Topics: Animals; Antiviral Agents; Blotting, Western; Endoplasmic Reticulum; Fatty Liver; Liver Transplantation; Male; Obesity; Organ Preservation; PPAR gamma; Rats; Rats, Sprague-Dawley; Rats, Wistar; Rats, Zucker; Reperfusion Injury; Taurochenodeoxycholic Acid; Toll-Like Receptor 4; Transplantation, Isogeneic; Unfolded Protein Response

Hepatic steatosis continues to present a major challenge in liver transplantation. These organs have been shown to have increased susceptibility to cold ischemia/reperfusion (CIR) injury in comparison with otherwise comparable lean livers; the mechanisms governing this increased susceptibility to CIR injury are not fully understood. Endoplasmic reticulum (ER) stress is an important link between hepatic steatosis, insulin resistance, and metabolic syndrome. In this study, we investigated ER stress signaling and blockade in the mediation of CIR injury in severely steatotic rodent allografts. Steatotic allografts from genetically leptin-resistant rodents had increased ER stress responses and increased markers of hepatocellular injury after liver transplantation into strain-matched lean recipients. ER stress response components were reduced by the chemical chaperone taurine-conjugated ursodeoxycholic acid (TUDCA), and this resulted in an improvement in the allograft injury. TUDCA treatment decreased nuclear factor kappa B activation and the proinflammatory cytokines interleukin-6 and interleukin-1β. However, the predominant response was decreased expression of the ER stress cell death mediator [CCAAT/enhancer-binding protein homologous protein (CHOP)]. Furthermore, activation of inflammation-associated caspase-11 was decreased, and this linked ER stress/CHOP to proinflammatory cytokine production after steatotic liver transplantation. These data confirm ER stress in steatotic allografts and implicate this as a mediating mechanism of inflammation and hepatocyte death in the steatotic liver allograft.

Topics: Activating Transcription Factor 4; Animals; Caspases; Disease Models, Animal; Endoplasmic Reticulum; Fatty Liver; Heat-Shock Proteins; Inflammation Mediators; Interleukin-1beta; Interleukin-6; Liver; Liver Transplantation; NF-kappa B; Non-alcoholic Fatty Liver Disease; Rats; Rats, Zucker; Reperfusion Injury; Signal Transduction; Stress, Physiological; Taurochenodeoxycholic Acid; Time Factors; Transcription Factor CHOP; Transplantation, Homologous

During partial hepatectomy, ischemia-reperfusion (I/R) is commonly applied in clinical practice to reduce blood flow. Steatotic livers show impaired regenerative response and reduced tolerance to hepatic injury. We examined the effects of tauroursodeoxycholic acid (TUDCA) and 4-phenyl butyric acid (PBA) in steatotic and non-steatotic livers during partial hepatectomy under I/R (PH+I/R). Their effects on the induction of unfolded protein response (UPR) and endoplasmic reticulum (ER) stress were also evaluated. We report that PBA, and especially TUDCA, reduced inflammation, apoptosis and necrosis, and improved liver regeneration in both liver types. Both compounds, especially TUDCA, protected both liver types against ER damage, as they reduced the activation of two of the three pathways of UPR (namely inositol-requiring enzyme and PKR-like ER kinase) and their target molecules caspase 12, c-Jun N-terminal kinase and C/EBP homologous protein-10. Only TUDCA, possibly mediated by extracellular signal-regulated kinase upregulation, inactivated glycogen synthase kinase-3β. This is turn, inactivated mitochondrial voltage-dependent anion channel, reduced cytochrome c release from the mitochondria and caspase 9 activation and protected both liver types against mitochondrial damage. These findings indicate that chemical chaperones, especially TUDCA, could protect steatotic and non-steatotic livers against injury and regeneration failure after PH+I/R.

Topics: Activating Transcription Factor 6; Animals; Caspase 12; Cytochromes c; Endoplasmic Reticulum; Fatty Liver; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Heat-Shock Proteins; Hepatectomy; JNK Mitogen-Activated Protein Kinases; Liver; Mitochondria; Phenylbutyrates; Rats; Rats, Zucker; Reperfusion Injury; Taurochenodeoxycholic Acid; Unfolded Protein Response; Voltage-Dependent Anion Channels

Cholestasis, induced by liver ischemia-reperfusion injury (IRI), is characterized by dilatation of bile canaliculi and loss of microvilli. Tauroursodeoxycholic acid (TUDCA) is an anti-cholestatic agent, modulating protein kinase C (PKC) alpha pathway. PKC reduces ischemic damage in several organs, its isoform alpha modulates ezrin, a key protein in the maintenance of cell lamellipoidal extensions. We evaluated the effects of TUDCA on cholestasis, canalicular changes and PKCalpha-ezrin expression in a rat model of liver IRI. Livers flushed and stored with Belzer solution or Belzer + 10 mm TUDCA (4 degrees C for 6 h) were reperfused (37 degrees C with O(2)) with Krebs-Ringer bicarbonate + 2.5 micromol/min of Taurocholate or TUDCA. Bile was harvested for bile flow assessment. Liver tissue was employed for Electron Microscopy (EM) and for PKCalpha and ezrin immunoblot and immunofluorescence. The same experiments were conducted with the PKCalpha inhibitor Go-6976. TUDCA-treated livers showed increased bile flow (0.25+/-0.17 vs. 0.042+/-0.02 microl/min/g liver, P<0.05) and better preservation of microvilli and bile canalicular area at EM. These effects were associated with increased PKCalpha and ezrin expression (P=0.03 and P=0.04 vs. control respectively), as also confirmed by immunofluorescence data. PKCalpha inhibition abolished these TUDCA effects. TUDCA administration during IRI reduces cholestasis and canalicular damage in the liver modulating PKCalpha-ezrin pathway.

Topics: Animals; Bile; Bile Canaliculi; Carbazoles; Cholagogues and Choleretics; Cholestasis; Cytoskeletal Proteins; Enzyme Inhibitors; L-Lactate Dehydrogenase; Liver; Male; Microscopy, Electron, Scanning; Protein Kinase C-alpha; Rats; Rats, Wistar; Reperfusion Injury; Taurochenodeoxycholic Acid

Topics: Apoptosis; Cryopreservation; Humans; Liver Transplantation; Reperfusion Injury; Taurochenodeoxycholic Acid

Tauroursodeoxycholic acid (TUDC) is a hydrophilic bile acid that has a cytoprotective effect in primary biliary cirrhosis and primary sclerosing cholangitis. TUDC also protects hepatocytes from hydrophobic bile acid-induced apoptosis. The aim of this study was to determine whether TUDC ameliorates hepatocyte apoptosis during ischemia-reperfusion injury.. We used a rat model of hepatic warm ischemia-reperfusion injury to assess the effects of TUDC. Male Sprague-Dawley rats were subjected to 1 or 2 hr of normothermic ischemia followed by 3 or 6 hr of reperfusion. The treatment group received TUDC (50 mg/kg) by bolus intravenous injection 30 min before initiation of ischemia, whereas the control group received saline only. Blood samples for biochemical analysis were obtained after 6 hr of reperfusion. Liver biopsies for histological assessment were obtained 3 and 6 hr after reperfusion. Hepatocyte apoptosis was determined by terminal dUTP nick-end labeling. The pro-apoptotic protein Bax was quantified at the mRNA and protein level.. Treatment with TUDC significantly reduced serum transaminase levels. This was associated with a significant amelioration in the levels of hepatocyte apoptosis in the TUDC-treated group compared with control. Furthermore, Western blot analysis of Bax expression in liver tissue indicated that TUDC inhibited the translocation of Bax from the cytosol to the mitochondria.. TUDC significantly reduced hepatic injury in this model. The beneficial effects of TUDC upon hepatocyte apoptosis were related to the modulation of Bax protein translocation.

Topics: Animals; Aspartate Aminotransferases; bcl-2-Associated X Protein; Biological Transport; Blotting, Western; Cytoprotection; Gene Expression; In Situ Nick-End Labeling; Ischemia; Liver; Liver Circulation; Male; Mitochondria, Liver; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Taurochenodeoxycholic Acid

Tauroursodeoxycholate (TUDC) is used routinely in the treatment of cholestatic liver disease. The present study was designed to determine whether it would mitigate ischemia/reperfusion injury in an in vivo pig liver-transplantation model.. Transplantation was performed in 12 animals after a preservation time of 8 h. In the control group (n=6), 0.9% saline was infused into the donor. In the experimental group (n=6), TUDC was given intravenously at a rate of 2 micromol/kg body weight per minute. In the recipient, infusion was started at the time of reperfusion; saline was infused for 400 min in the control group, TUDC for the same duration at a rate of 0.2 micromol/kg body weight per minute in the experimental group. Blood was drawn for determination of liver enzymes. Bile samples were collected and bile flow (BF) and bile salt secretion rate (BSSR) were determined.. One-week survival was 92% and not different among groups. Liver enzymes were lower in the TUDC group than the saline group. Prior to TUDC infusion in the donor animals, there were no differences in BF and BSSR. After infusion of TUDC, BF and BSSR were highly significantly different than the control group.. Infusion of TUDC in pig livers protects against ischemia/reperfusion injury in vivo. This might be due to the membrane-stabilizing effect of TUDC. Preconditioning of liver grafts with TUDC could potentially lead to improved liver function post-transplantation.

Topics: Analysis of Variance; Animals; Bile Acids and Salts; Cholagogues and Choleretics; Infusions, Intravenous; Liver; Liver Transplantation; Male; Organ Preservation; Reperfusion Injury; Swine; Taurochenodeoxycholic Acid

Reperfusion injury is a serious problem after clinical liver transplantation, often leading to dys- or even non-function of grafts. The present study was designed to determine whether the hydrophilic bile salt tauroursodeoxycholate (TUDC), known to be hepatoprotective in cholestatic liver disease, mitigates reperfusion injury in an in vivo pig liver transplantation model. Liver transplantation was performed in 12 pigs after a preservation time of 8 h. TUDC was administered to donor and recipient animals, and saline to controls. Blood was drawn at different time points for determination of liver enzymes. Bile samples were collected, and bile flow (BF), and bile salt secretion rate (BSSR) determined. Samples of liver tissue and bile ducts were taken for assessment by light and electron microscopy. Liver enzymes were significantly lower in the TUDC group. BF and BSSR were significantly higher. Microscopy revealed better preservation of bile duct architecture of the TUDC-infused animals. We can conclude that infusions of TUDC in pig livers ameliorate reperfusion injury in vivo. The molecular basis for this finding may be the membrane stabilizing effect of TUDC. Further studies are warranted to clarify its effect.

Topics: Animals; Cholagogues and Choleretics; Cyclosporine; Immunosuppressive Agents; Liver; Liver Function Tests; Liver Transplantation; Male; Postoperative Complications; Reperfusion Injury; Swine; Taurochenodeoxycholic Acid

Tauroursodeoxycholic acid (TUDCA) is of potential benefit in cholestatic disorders. However, the effect of TUDCA on hepatic ischemia-reperfusion injury is unknown. We studied this subject with particular regard to its roles in hepatic calcium mobilization. Three doses of TUDCA were used with continuous intravenous infusion (1.0, 0.1, and 0.01 micromol/kg body weight/min). At 3 hr after 1 hr of ischemia and reperfusion in 70% rat liver, high-dose TUDCA reduced hepatic reperfused injury according to biochemical and histological findings and significantly increased bile flow after reperfusion. It significantly increased tissue calcium content and serum calcium concentration after reperfusion. Furthermore, it also enhanced biliary calcium concentration and total output during reperfusion. In conclusion, TUDCA has a salutary effect on ischemia-reperfusion injury of the liver. However, it is still unclear how the calcium mobilization induced by TUDCA is associated with the hepatoprotection against ischemia-reperfusion injury.

Topics: Animals; Bile; Calcium; Cholestasis; Liver; Liver Diseases; Male; Peroxidase; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Taurochenodeoxycholic Acid

Tauroursodeoxycholic acid is known to have a hepatoprotective action in cholestatic disorders. We evaluated whether oral pretreatment with tauroursodeoxycholic acid could protect the liver from ischemia-reperfusion injury, with particular regard to its effect on bile flow and biliary calcium excretion.. A 1-hour in vivo ischemia-reperfusion model of 70% of the lobes of rat liver was used. Animals were divided into six groups (each group; n = 8); a non-ischemia sham group (CS), a control group without bile acids (CON), and 4 bile acid groups; 10 mg/kg and 50 mg/kg (U10, U50), taurocholic acid 10 mg/kg (CA10) and tauroursodeoxycholic acid 10 mg/kg (CD10). Bile acids were given orally for 7 days before operation.. Three hours after reperfusion, oral bile acid pretreatment failed to reduce the hepatic ischemia-reperfusion injury biochemically, but histological improvement was observed in the tauroursodeoxycholic acid groups. After reperfusion, tauroursodeoxycholic acid significantly increased bile flow from the ischemic liver, and also significantly increased serum calcium concentration. Although tauroursodeoxycholic acid did not change biliary calcium concentration, it significantly enhanced total biliary calcium output during reperfusion.. Thus, tauroursodeoxycholic acid inhibited tissue calcium accumulation and enhanced sinusoidal and biliary calcium output during hepatic ischemia-reperfusion. However, it is still unclear if calcium mobilization is part of the protective mechanisms of tauroursodeoxycholic acid in ischemia-reperfusion injury of the liver.

Topics: Analysis of Variance; Animals; Bile Acids and Salts; Calcium; Cholestasis; Evaluation Studies as Topic; Isomerism; Liver; Male; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Stimulation, Chemical; Taurochenodeoxycholic Acid

We investigated whether stimulation of bile flow by taurocholic acid (TCA), ursodeoxycholic acid (UDCA) or its taurine conjugate (TUDCA) could protect the liver from ischemia-reperfusion injury. The isolated perfused rat liver model was used. In livers perfused without bile acids (n = 8), 60 min of ischemia induced a significant reduction in bile flow and in portal flow, together with a marked increase in LDH, AST and uric acid release in the perfusate. These alterations were maximal at the beginning of reperfusion. In livers perfused with TCA (n = 6), UDCA (n = 7) or TUDCA (n = 6), bile flow was significantly increased as compared to controls during the pre-ischemic phase, as well as during the reperfusion phase. However, no significant improvement was observed in any of the biochemical, hemodynamic or histologic parameters studied. The results show that stimulation of bile flow either by TCA, UDCA or TUDCA does not reduce ischemia-reperfusion liver injury. Furthermore, the results do not provide evidence for a cytoprotective effect of UDCA or TUDCA in this model of liver injury.

Topics: Animals; Aspartate Aminotransferases; Bile; Ischemia; Isomerism; L-Lactate Dehydrogenase; Liver Circulation; Male; Perfusion; Rats; Rats, Inbred Strains; Reperfusion Injury; Taurochenodeoxycholic Acid; Taurocholic Acid; Uric Acid; Ursodeoxycholic Acid