Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Orthotopic liver transplantation (OLT) continues to be the only remedy for end-stage liver disease. In an attempt to decrease the ever-widening gap between organ donor and recipient numbers, and ultimately make more livers amenable to transplantation, we characterized the healthy human liver's response to ischemia and reperfusion-induced injury during transplantation. This was carried out by transcriptional profiling using cDNA microarray to identify genes whose expression was modulated at the 1-h postreperfusion time point. We observed that the map kinase phosphatase-1/dual-specificity phosphatase-1 (MKP-1/DUSP1) mRNA was strongly and significantly upregulated. Validation of this observation was carried out using reverse transcriptase-polymerase chain reaction (RT-PCR), immunoblotting and immunohistochemistry. In addition, we characterized the signaling pathways regulating MKP-1 expression using the human hepatoma cell line HepG2. Finally, by combining MKP-1 silencing with reperfusion-associated stresses, we reveal the preferential role of this protein in attenuating the activity of the JNK and p38(MAPK) pathways, and the resulting apoptosis, making MKP-1 a potential target for therapeutic intervention.
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PMID:The MAP kinase phosphatase-1 MKP-1/DUSP1 is a regulator of human liver response to transplantation. 1903 24

According to transplant registries, grafts from elderly donors have lower survival rates. During 1999-2005, we evaluated the outcomes of 89 patients who received a liver from a donor aged > or = 60 years and managed with the low liver-damage strategy (LLDS), based on the preoperative donor liver biopsy and the shortest possible ischemia time (group D > or = 60-LLDS). Group D > or = 60-LLDS was compared with 198 matched recipients, whose grafts were not managed with this strategy (89 donors < 60 years, group D < 60-no-LLDS and 89 donors aged > or =60 years, group D > or = 60-no-LLDS). In the donors proposed from the age group of > or =60 years, the number of donors rejected decreased during the study period and the LLDS was found to be responsible for this in a significant manner (47% vs. 60%, respectively P < 0.01). Among the recipients transplanted, the clinical features (age, gender, viral infection, child and model for end-stage liver disease score) were comparable among groups, but group D > or = 60-LLDS had a lower mean ischemia time: 415 +/- 106 min vs. 465 +/- 111 (D < 60-no-LLDS), P < 0.05 and vs. 476 +/- 94 (D > or = 60-no-LLDS), P < 0.05. After a median follow-up of 3 years, the 1- and 3-year graft survival rates of group D > or = 60-LLDS (84% and 76%) were comparable with group D < 60-no-LLDS (89% and 76%) and were significantly higher than group D > or = 60-no-LLDS (71% and 54%), P < 0.005. In conclusion, the LLDS optimized the use of livers from elderly donors.
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PMID:Liver transplantations with donors aged 60 years and above: the low liver damage strategy. 1904 Apr 83

MicroRNAs are a group of small non-coding RNAs with modulator activity of gene expression. Recent studies have uncovered a profound role of microRNAs in liver diseases. This study aimed to investigate a potential relationship between microRNA-223 (miR-223) expression and hepatic ischemia/reperfusion injury in mice. Quantitative RT-PCR analysis showed that miR-223 expression levels were greatly up-regulated in the livers after 75 min ischemia followed by 120 min reperfusion when compared to sham controls (2.59 +/- 0.23 vs. 0.83 +/- 0.15; P < 0.01). Correlation analysis also revealed that hepatic miR-223 expression level was significantly positively correlated with serum markers of ischemic injury. By prediction assay of miRNA targets mRNA, acyl-CoA synthetase long-chain family member 3, ephrin A1, and ras homolog gene family member B were predicted to be downstream targets of miR-223. Thus, we conclude that hepatic ischemia/reperfusion injury might be another form of liver disease that is associated with alteration in miR-223 expression.
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PMID:Association of MicroRNA-223 expression with hepatic ischemia/reperfusion injury in mice. 1910 39

Liver transplantation is currently the only established treatment of end-stage liver disease, but it is limited by a severe shortage of viable donor livers. Donors after cardiac death (DCD) are an untapped source that could significantly increase the pool of available livers. Preservation of these DCD livers by conventional static cold storage (SCS) is associated with an unacceptable risk of primary nonfunction and delayed graft failure. Normothermic extracorporeal liver perfusion (NELP) has been suggested as an improvement over SCS. Livers recovered from male Lewis rats were subjected to 1 hr of warm ischemia and preserved with 5 hr of SCS or NELP, and transplanted into syngeneic recipients. As additional controls, non-ischemic livers preserved with 6 hr of SCS or NELP and unpreserved ischemic livers were transplanted. After NELP, ischemically damaged livers could be orthotopically transplanted into syngeneic recipients with 92% survival (n=13) after 4 weeks, which was comparable with control animals that received healthy livers preserved by SCS (n=9) or NELP (n=11) for 6 hr. On the other hand, animals from ischemia/SCS control group all died within 12 hr postoperatively (n=6). Similarly, animals that received ischemic livers without preservation all died within 24 hr after transplantation (n=6). These results suggest that NELP has the potential to reclaim warm ischemic livers that would not be transplantable otherwise. The rat model in this study is a useful platform to further optimize NELP as a method of recovery and preservation of DCD livers.
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PMID:Recovery of warm ischemic rat liver grafts by normothermic extracorporeal perfusion. 1915 70

Farnesoid X receptor (FXR), a member of the nuclear receptor superfamily, has been shown to play pivotal roles in bile acid homeostasis by regulating the biosynthesis, conjugation, secretion and absorption of bile acids. Accumulating data suggest that FXR signaling is involved in the pathogenesis of liver and metabolic disorders. Here we show that FXR expression is significantly suppressed in HepG2 cells exposed to hypoxia. Concomitantly, the expression of the bile salt export pump, known as an FXR target gene product and responsible for the excretion of bile acids from the liver, is also decreased under hypoxia. Overexpression of hypoxia-inducible factor (HIF)-1alpha does not mimic the suppressive effect of hypoxia on FXR expression. Furthermore, simultaneous knockdown of HIF-1alpha, HIF-2alpha and HIF-3alpha fails to restore the FXR expression level under hypoxia, indicating that HIF is not involved in hypoxia-evoked FXR downregulation. Instead, we demonstrate that p38 mitogen-activated protein kinase is an indispensable factor for FXR downregulation under hypoxia. Thus, we propose a novel liver disorder model in which two signaling molecules, p38 mitogen-activated protein kinase and FXR, may contribute to the linkage of two pathogenic conditions, i.e. ischemia, a condition accompanying hypoxia, and cholestasis, a condition with intrahepatic accumulation of cytotoxic bile acids.
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PMID:Hypoxia downregulates farnesoid X receptor via a hypoxia-inducible factor-independent but p38 mitogen-activated protein kinase-dependent pathway. 1918 29

Despite recent advances in the understanding of mechanisms underlying the pathogenesis of liver diseases, therapeutic agents are still needed in several instances such as nonalcoholic fatty liver disease, alcoholic liver disease or fibrogenesis associated with chronic liver injury. Over the past decades, cannabinoid receptors have emerged as critical mediators of acute and chronic liver injury, and pharmacological modulation of these receptors has demonstrated efficacy in preclinical models of nonalcoholic and alcoholic fatty liver, fibrosis, liver ischemia reperfusion and of complications of cirrhosis, including cirrhotic portal hypertension, cirrhotic cardiomyopathy and hepatic encephalopathy. Moreover, CB(1) antagonists have entered clinical trials for the management of nonalcoholic steatohepatitis. This review will depict the pleiotropic functions of cannabinoid receptors in liver disease and highlight potential therapeutic applications, some of which may be available in the near future.
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PMID:Cannabinoid receptors as therapeutic targets in the management of liver diseases. 1925 49

There is a lack of universally accepted clinical parameters to guide the utilization of donation after cardiac death (DCD) donor livers and it is unclear as to which patients would benefit most from these organs. We reviewed our experience in 141 patients who underwent liver transplantation using DCD allografts from 1993 to 2007. Patient outcomes were analyzed in comparison to a matched cohort of 282 patients who received livers from donation after brain death (DBD) donors. Patient survival was similar, but 1-, 5- and 10-year graft survival was significantly lower in DCD (69%, 56%, 44%) versus DBD (82%, 73%, 63%) subjects (p < 0.0001). Primary nonfunction and biliary complications were more common in DCD patients, accounting for 67% of early graft failures. A donor warm ischemia time >20 min, cold ischemia time >8 h and donor age >60 were associated with poorer DCD outcomes. There was a lack of survival benefit in DCD livers utilized in patients with model for end-stage liver disease (MELD) < or =30 or those not on organ-perfusion support, as graft survival was significantly lower compared to DBD patients. However, DCD and DBD subjects transplanted with MELD >30 or on organ-perfusion support had similar graft survival, suggesting a potentially greater benefit of DCD livers in critically ill patients.
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PMID:Liver transplantation using donation after cardiac death donors: long-term follow-up from a single center. 1934 66

Although combined liver-kidney (LK) transplantation has been effectively used in patients with end-stage liver disease and concurrent renal failure, a small animal model has been rarely described because of the technical difficulties. Herein, we have described techniques of a modified simultaneous LK transplantation model in rats. We have modified the techniques to perform 47 combined LK transplants in rats with reconstructed hepatic artery and renal vessels by a microvascular sleeve method and an end-to-end anastomosis technique without cross-clamping the vena cava and abdominal aorta, respectively. An average donor operation time was 34.4+/-6.3 min with cold ischemia times of 49.7+/-6.5 min and 61.3+/-4.1 min for liver and kidney grafts, respectively. The total time for recipient operation was 96.8+/-9.4 min with a 4-wk survival rate of 92.3% (36/39). A cumulative hepatic and renal arterial patency rate reached 90.2% (37/41). Normal grafts function tests were observed within the first week post-transplant, as well as normal histopathology studies of the 2 grafts in wk 4 post-transplant. Our method proves to be practical and may contribute to a wider use of the model in the studies of allograft rejection and tolerance induction during combined LK transplantation.
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PMID:Simultaneous orthotopic liver-kidney transplantation with hepatic arterial reconstitution in rats. 1956 28

Introduction of the model of end-stage liver disease (MELD) for organ allocation has changed the waiting-list management. Despite reports of unaffected survival after orthotopic liver transplantation (OLT) in the MELD era, survival rates have decreased in our center. The aim of this study was to identify factors contributing to reduced survival. Three-month survival, recipient and graft parameters of all 323 OLT between 2004 and 2008, which fall into a pre- (N = 220) and a post-MELD (n = 103) era, were analysed by Kaplan-Meier-, Mann-Whitney- and Fisher tests. After the introduction of MELD, mean scores at OLT increased (14.8 vs. 18.6, P = 0.002). The main indications for OLT were not statistically different between eras. Post-MELD recipients were older (47.9 vs. 50.9 years, P = 0.025), donors younger (NS), cold ischemia time shorter (696 vs. 635 min., P = 0.001), and duration of surgery longer (218 vs. 245 min., P = 0.001). Procedure time significantly correlated with MELD and international normalized ratio (INR). Three-month survival dropped (from 88.6% to 79.6%, P = 0.03). Independent variables of survival were creatinine, urea and duration of surgery. Reduced 3-month survival was associated with longer surgery duration, higher creatinine and urea likely reflecting higher recipient morbidity. Survival probability should be incorporated into MELD-based graft allocation.
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PMID:The introduction of MELD-based organ allocation impacts 3-month survival after liver transplantation by influencing pretransplant patient characteristics. 1974 Feb 45

This study assesses the relation between the anhepatic phase duration and the outcome after liver transplantation. Of 645 patients who underwent transplantation between 1994 and 2006, 194 were recipients of consecutive adult primary piggyback liver transplants using heart-beating donors. The anhepatic phase was defined as the time from the physical removal of the liver from the recipient to recirculation of the graft. Other noted study variables were the cold and warm ischemia times, donor and recipient age, donor and recipient body mass index, perioperative red blood cell (RBC) transfusion, indication for transplantation, and Model for End-Stage Liver Disease score. The primary outcome parameter was graft dysfunction, which was defined as either primary nonfunction or initial poor function according to the Ploeg-Maring criteria. The median anhepatic phase was 71 minutes (37-321 minutes). Graft dysfunction occurred in 27 patients (14%). Logistic regression analysis showed an anhepatic phase over 100 minutes [odds ratio (OR), 4.28], a recipient body mass index over 25 kg/m(2) (OR, 3.21), and perioperative RBC transfusion (OR, 3.04) to be independently significant predictive factors for graft dysfunction. One-year patient survival in patients with graft dysfunction was 67% versus 92% in patients without graft dysfunction (P < 0.001). A direct relation between the anhepatic phase duration and patient survival could, however, not be established. In conclusion, this study shows that liver transplant patients with an anhepatic phase over 100 minutes have a higher incidence of graft dysfunction. Patients with graft dysfunction have significantly worse 1-year patient survival.
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PMID:The clinical relevance of the anhepatic phase during liver transplantation. 1971 49


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