Global gene expression profiles of ischemic preconditioning in deceased donor liver transplantation

Raza, Ali; Dikdan, George; Desai, Kunj K.; Shareef, A Raja; Fernandes, Helen; Aris, Virginie; Torre, Andrew N. de la; Wilson, Dorian; Fisher, Adrian; Soteropoulos, Patricia; Koneru, Baburao

doi:10.1002/lt.22049

Cited by 15 publications

(13 citation statements)

References 59 publications

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“…Our work has shown profound modifications of HP and LSEC proteome and enzymatic activities, highlighting critical processes involved in IR injury and liver preconditioning, and implementing and dissecting previous observation obtained in the liver [5,[23][24][25][26][27][28].…”

Section: Discussionsupporting

confidence: 60%

“…We detected several proteins involved in liver cell response to oxidative stress. Many of these proteins (GRP75, GSTP1, SBP2, PPIA, GSTM1, CATA, PRDX6, CH60, PDIA3) were already known to be involved in IR and preconditioning processes [5,[24][25][26][27][28]. Catalase, GSTP1, GSTP2, and GSTM1 are directly linked to detoxification of ROS, and GSH is known as a highly effective antioxidant present in elevated concentrations in HP [33].…”

Section: Discussionmentioning

confidence: 98%

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Mouse hepatocytes and LSEC proteome reveal novel mechanisms of ischemia/reperfusion damage and protection by A2aR stimulation

Mandili

Alchera

Merlin

et al. 2015

Journal of Hepatology

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IR and A2aR stimulation produces pathological and protected liver cell phenotypes, respectively characterized by down- and upregulation of proteins involved in the response to O2 and nutrients deprivation during ischemia, oxidative stress, and reactivation of aerobic energy synthesis at reperfusion. This provides novel insights into IR hepatocellular damage and protection, and suggests additional therapeutic options.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 98%

Mouse hepatocytes and LSEC proteome reveal novel mechanisms of ischemia/reperfusion damage and protection by A2aR stimulation

Mandili

Alchera

Merlin

et al. 2015

Journal of Hepatology

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“…Though there have been gene expression profiling studies that have addressed I/R injury (11)(12)(13)28), there is a paucity of gene expression literature that paints a global picture of clinically-defined EAD. The only study addressing molecular aspects of EAD in humans is an early study using PCR to analyze quantitative gene expression in postperfusion biopsies after liver transplantation (29).…”

Section: Discussionmentioning

confidence: 99%

“…The authors conclude that ischemic preconditioning induces changes in gene expression, some of which are potentially beneficial but others that are possibly injurious to the graft (13).…”

Section: Introductionmentioning

confidence: 99%

Genomic Profiles and Predictors of Early Allograft Dysfunction After Human Liver Transplantation

Kurian

Fouraschen

Langfelder

et al. 2015

American Journal of Transplantation

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y These authors contributed equally to this manuscript.Early hepatic allograft dysfunction (EAD) manifests posttransplantation with high serum transaminases, persistent cholestasis, and coagulopathy. The biological mechanisms are poorly understood. This study investigates the molecular mechanisms involved in EAD and defines a gene expression signature revealing different biological pathways in subjects with EAD from those without EAD, a potential first step in developing a molecular classifier as a potential clinical diagnostic. Global gene expression profiles of 30 liver transplant recipients of deceased donor grafts with EAD and 26 recipients without graft dysfunction were investigated using microarrays of liver biopsies performed at the end of cold storage and after graft reperfusion prior to closure. Results reveal a shift in inflammatory and metabolic responses between the two time points and differences between EAD and non-EAD. We identified relevant pathways (PPARa and NF-kB) and targets (such as CXCL1, IL1, TRAF6, TIPARP, and TNFRSF1B) associated with the phenotype of EAD. Preliminary proof of concept gene expression classifiers that distinguish EAD from non-EAD patients, with Area Under the Curve (AUC) >0.80 were also identified. This data may have mechanistic and diagnostic implications for EAD.

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“…IP-induced overexpression of glutathione S-transferase mu transcripts could contribute to decreased oxidative stress. However, the overexpression of fatty acid synthase may increase oxidative stress and the TNF ligand superfamily member 10 may enhance apoptotic pathways [82]. Thus, the clinical effectiveness of IP is still under discussion.…”

Section: Identifying Future Potential Treatment Strategiesmentioning

confidence: 99%

Genomics of liver transplant injury and regeneration

Hashmi

Baranov

González

et al. 2015

Transplantation Reviews

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While improved surgical techniques, post-operative care, and immunosuppression regimens have reduced morbidity and mortality associated with orthotopic liver transplantation (OLT), further improvement of outcomes requires personalized treatment and a better understanding of genomic mechanisms involved. Gene expression profiles of ischemia/reperfusion (I/R) injury, regeneration, and rejection, may suggest mechanisms for development of better predictive tools and treatments. The liver is unique in its regenerative potential, recovering lost mass and function after injury from ischemia, resection, and rejection. I/R injury, an inevitable consequence of perfusion cessation, cold storage, and reperfusion, is regulated by the interaction of the immune system, inflammatory cytokines, and reduced microcirculatory blood flow in the liver. Rejection, a common postoperative complication, is mediated by the recipient's immune system through T-cell-dependent responses activating proinflammatory and apoptotic pathways. Characterizing distinctive gene expression signatures for these events can identify therapies to reduce injury, promote regeneration, and improve outcomes. While certain markers of liver injury and regeneration have been observed in animals, many of these are unverified in human studies. Further investigation of these genomic signatures and mechanisms through new technology offers promise, but continues to pose a significant challenge. An overview of the current fund of knowledge in this area is reviewed.

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Global gene expression profiles of ischemic preconditioning in deceased donor liver transplantation

Cited by 15 publications

References 59 publications

Mouse hepatocytes and LSEC proteome reveal novel mechanisms of ischemia/reperfusion damage and protection by A2aR stimulation

Mouse hepatocytes and LSEC proteome reveal novel mechanisms of ischemia/reperfusion damage and protection by A2aR stimulation

Genomic Profiles and Predictors of Early Allograft Dysfunction After Human Liver Transplantation

Genomics of liver transplant injury and regeneration

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