Gene expression profiling of liver injury during human orthotopic liver transplantation.
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE7706 | GEO | 2008/03/01
SECONDARY ACCESSION(S): PRJNA99425
REPOSITORIES: GEO
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Project description:We have studied the genes activated in human liver transplantation to identify potential target genes for the prevention or treatment of related injuries. In a first protocol, in order to evaluate the effect of Ischemia-Reperfusion Injury (IRI) on gene expression profile, we compared gene expression levels in transplanted-reperfused livers versus basal values in donor livers, identifying 795 genes significantly modified in human liver after transplantation. Some genes are likely to be completely activated by IRI, as they are not expressed at all in basal livers. In a second protocol, in order to identify gene dysregulations already present in donor livers, which might affect gene expression profile after transplantation, gene expression evaluated in the first study was compared to control livers (espression data retrieved from ArrayExpress database). About 900 genes in donor livers are dysregulated if compared to the control condition. At least 400 of them remain dysregulated or become more and more dysregulated after transplantation. For the first protocol, two biopsies were collected from each liver: 1 biopsy before explantation from the donor, immediately after opening, before ice was applied, and 1 biopsy about 2-3 hours after liver reperfusion in the recipient organism. Gene expression of 5 transplanted livers was compared to that of 5 donor livers. In the second protocol gene expression both of transplanted and donor livers was compared to gene expression data from 5 control livers retrieved from ArrayExpress repository SAMPLE ID: E-AFMX-11. This dataset is part of the TransQST collection.
2009-10-01 | E-GEOD-14951 | biostudies-arrayexpress
Project description:We have studied the genes activated in human liver transplantation to identify potential target genes for the prevention or treatment of related injuries. In a first protocol, in order to evaluate the effect of Ischemia-Reperfusion Injury (IRI) on gene expression profile, we compared gene expression levels in transplanted-reperfused livers versus basal values in donor livers, identifying 795 genes significantly modified in human liver after transplantation. Some genes are likely to be completely activated by IRI, as they are not expressed at all in basal livers. In a second protocol, in order to identify gene dysregulations already present in donor livers, which might affect gene expression profile after transplantation, gene expression evaluated in the first study was compared to control livers (espression data retrieved from ArrayExpress database). About 900 genes in donor livers are dysregulated if compared to the control condition. At least 400 of them remain dysregulated or become more and more dysregulated after transplantation.
2009-10-01 | GSE14951 | GEO
Project description:10 biopsies from one patient undergoing a auxiliary liver and combined kidney transplantation, where one liver lobe is replaced by an auxiliary liver lobe. Thereafter the kidney is transplanted. Keywords: Time course study
2011-03-02 | GSE8941 | GEO
Project description:10 biopsies from one patient undergoing a auxiliary liver and combined kidney transplantation, where one liver lobe is replaced by an auxiliary liver lobe. Thereafter the kidney is transplanted. Keywords: Time course study 10 samples, no replicates.
2011-03-02 | E-GEOD-8941 | biostudies-arrayexpress
Project description:BACKGROUND. Orthotopic liver transplant (OLT) is the primary therapy for end-stage liver disease and acute liver failure. However, ischemia/reperfusion injury (IRI) can severely compromise allograft survival. To understand the evolution of immune responses underlying OLT-IRI, we evaluated longitudinal cytokine expression profiles from adult OLT recipients before transplant through 1 month after transplant. METHODS. We measured the expression of 38 cytokines, chemokines, and growth factors in preoperative and postoperative recipient circulating systemic blood (before transplant and 1 day, 1 week, and 1 month after transplant) and intraoperative portal blood (before and after reperfusion) of 53 OLT patients and analyzed this expression in relation to biopsy-proven IRI (n = 26 IRI+; 27 IRI-), clinical liver function tests early (days 1-7) after transplant, and expression of genes encoding cytokine receptors in biopsies of donor allograft taken before and after reperfusion. RESULTS. Bilirubin and arginine transaminase levels early after transplant correlated with IRI. Fourteen cytokines were significantly increased in the systemic and/or portal blood of IRI+ recipients that shifted from innate to adaptive-immune responses over time. Additionally, expression of cognate receptors for 10 of these cytokines was detected in donor organ biopsies by RNAseq. CONCLUSION. These results provide a mechanistic roadmap of the early immunological events both before and after IRI and suggest several candidates for patient stratification, monitoring, and treatment. FUNDING. Ruth L. Kirschstein National Research Service Award T32CA009120, Keck Foundation award 986722, and a Quantitative & Computational Biosciences Collaboratory Postdoctoral Fellowship.
| S-EPMC5135282 | biostudies-literature
Project description:BACKGROUND: Throughout the history of liver transplantation many improvements have been made in the field of surgical technique. It is beyond the scope of this paper to review all aspects of surgical technique in liver transplantation; thus, in this review we focus on the description of our current technique in most cases, which is orthotopic liver transplantation with preservation of the inferior vena cava and temporary portocaval shunt. We advocate this technique because it has been demonstrated that it achieves better haemodynamic stability during the anhepatic phase, transfusion can be reduced and renal function is improved. The different options for vascular anastomoses are described, particularly the options for arterial anastomoses in case of finding a non-adequate recipient hepatic artery. Technical possibilities for patients with preoperative portal vein thrombosis and the procedure in case of domino or sequential liver transplantation are further explained.
| S-EPMC2020659 | biostudies-other
Project description:Sotraustaurin (STN), a small molecule, targeted protein kinase C (PKC) inhibitor that prevents T-lymphocyte activation via a calcineurin-independent pathway, is currently being tested in Phase II renal and liver transplantation clinical trials. We have documented the key role of activated T cells in the inflammation cascade leading to liver ischemia/reperfusion injury (IRI). This study explores putative cytoprotective functions of STN in a clinically relevant rat model of hepatic cold ischemia followed by orthotopic liver transplantation (OLT). Livers from Sprague-Dawley rats were stored for 30 h at 4°C in UW solution, and then transplanted to syngeneic recipients. STN treatment of liver donors/recipients or recipients only prolonged OLT survival to >90% (vs. 40% in controls), decreased hepatocellular damage and improved histological features of IRI. STN treatment decreased activation of T cells, and diminished macrophage/neutrophil accumulation in OLTs. These beneficial effects were accompanied by diminished apoptosis, NF-?B/ERK signaling, depressed proapoptotic cleaved caspase-3, yet upregulated antiapoptotic Bcl-2/Bcl-xl and hepatic cell proliferation. In vitro, STN decreased PKC?/I?B? activation and IL-2/IFN-? production in ConA-stimulated spleen T cells, and diminished TNF-?/IL-1? in macrophage-T cell cocultures. This study documents positive effects of STN on liver IRI in OLT rat model that may translate as an additional benefit of STN in clinical liver transplantation.
| S-EPMC3625141 | biostudies-literature
Project description:BACKGROUND: Hepatic osteodystrophy occurs in the majority of patients with advanced chronic liver disease with the abnormalities in bone metabolism accelerating following orthotopic liver transplantation (OLT). AIMS: To examine changes in bone mineral density (BMD) following OLT and to investigate factors that lead to bone loss. METHODS: Twelve patients had BMD (at both the lumbar spine (LS) and femoral neck (FN)) and biochemical markers measured preoperatively and for 24 months following OLT. RESULTS: BMD was low in 75% of patients prior to OLT and decreased significantly from baseline at the LS at three months and the FN at six months. BMD began to increase thereafter at both sites, approaching baseline values at the LS by 12 months. Bone formation markers, osteocalcin and procollagen type I carboxy propeptide, decreased immediately post-OLT, with a concomitant increase seen in the resorption markers pyridinoline and deoxypyridinoline. This resulted in a negative uncoupling index early post-OLT, that rebounded to positive values after six months. There was a significant correlation between the change in the uncoupling index between six and three months which preceded the increase in BMD at 12 months. The decrease in BMD recorded early post-OLT correlated with vitamin D levels at three months. CONCLUSIONS: Results suggest that increased resorption and inadequate formation are the major contributors to additional bone loss following OLT. Non-invasive biochemical markers precede later changes in BMD in this patient group following OLT and may have a role in investigating and planning intervention strategies to prevent bone loss in future studies.
| S-EPMC1727429 | biostudies-other
Project description:BackgroundAcute kidney injury (AKI) occurs commonly in the setting of orthotopic liver transplantation (OLT). To date, the correlation between AKI post-OLT and pre-operative changes in renal function has not been rigorously examined.MethodsTo determine the impact of pre-OLT changes in renal function on AKI post-OLT, as well as to identify risk factors for AKI, we analyzed the prospectively maintained NIDDK Liver Transplantation Database, which includes patients who received their first OLT between April 15, 1990, and June 30, 1994. We used the AKI Network definition of AKI.ResultsSurprisingly, univariate analysis revealed that worsening renal function while awaiting OLT was protective to the development of AKI post-OLT. Independent predictors of AKI were increased body mass index, increased Childs-Pugh-Turcott score, decreased urine output during cross-clamp, improved renal function while awaiting OLT, increased post-operative stroke volume, non-Caucasian race, and post-operative use of tacrolimus.ConclusionsThe correlation between improving renal function pre-OLT and AKI post-OLT may represent true protection (via ischemic pre-conditioning) or, alternatively, a masking of milder forms of AKI (via improved renal perfusion through correction of the cirrhotic milieu). These results highlight the complex interaction between liver and kidney disease, and suggest that not only the etiology but also the course of pre-OLT renal dysfunction may be a critical determinant of renal function post-OLT.
| S-EPMC2991287 | biostudies-literature
Project description:The increased use of older and/or marginal donor organs in liver transplantation over the last decade calls for strategies to minimize ischaemic reperfusion (I/R) injury to prevent early graft failure. Tacrolimus, a very potent and effective calcineurin inhibitor, was selected because of its ability to ameliorate I/R injury. A randomized, blinded, controlled single-centre trial of 26 liver transplant recipients was performed between February 2008 and December 2009. Donor organs were randomized to be perfused intraportally during liver transplantation with 1.5 l 5% albumin infusion containing either 20 ng/ml tacrolimus or placebo. The primary end point was liver function as assessed by aspartate transaminase (AST) or alanine transaminase (ALT) levels 6 days after transplantation. Treatment effectiveness was tested by transcriptome-wide analysis of biopsies. There was no difference in the primary end point, i.e. AST (IU/l) and ALT (IU/l) at day 6 after transplantation between groups. Furthermore, choleastatic parameters as well as parameters of liver synthesis were not different between groups. However, tacrolimus treatment suppressed inflammation and immune response in the transplanted liver on a genome-wide basis. Intrahepatic administration of tacrolimus did not result in a reduction of AST and ALT within the first week after transplantation.
| S-EPMC3359429 | biostudies-literature