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Project description:Background & Aims: Cellular responses induced by surgical procedure or ischemia-reperfusion injury (IRI) may severely alter transcriptome profiles. We have investigated this effect to obtain insight into molecular ischemia responses during surgical procedures and characterize pre-analytical effects impacting on molecular analyses. Methods: 143 non-malignant liver samples were obtained from 30 patients at different time points of ischemia during surgery from two individual cohorts, treated either with the Pringle maneuver or total vascular exclusion. Transcriptomics profiles were analyzed by Affymetrix microarrays and expression of selected mRNAs was validated by RT-qPCR. Results: Transcriptional profiles of both cohorts displayed 179 genes that were mutually deregulated confirming elevated cytokine signaling, and NFkB as the dominant pathways in ischemia response. Contrary to ischemia, reperfusion induced pro-apoptotic and pro-inflammatory cascades involving TNF, NFkB and MAPK pathways. FOS and JUN were down-regulated in steatosis compared to their up-regulation in normal livers. Surprisingly, molecular signatures of underlying primary and secondary cancers were clearly present in the non-tumor tissue. Conclusions: We identified transcripts mutually deregulated during ischemia and reperfusion injury in both cohorts that can be used to monitor ischemia during liver surgery and highlight the importance of pre-analytical quality control. The marked inter-patient variability might reflect differences in individual stress responses and impact of underlying disease conditions. Furthermore, we provide a comprehensive and pre-analytically highly standardized in vivo transcriptome profile of histologically normal liver and identified 230 genes with substantial pre-analytical robustness (<2 % covariation across both cohorts) that might serve as reference genes and could be particularly suited for future diagnostic applications. Conclusions: We identified transcripts mutually deregulated during ischemia and reperfusion injury in both cohorts that can be used to monitor ischemia during liver surgery and highlight the importance of pre-analytical quality control. The marked inter-patient variability might reflect differences in individual stress responses and impact of underlying disease conditions. Furthermore, we provide a comprehensive and pre-analytically highly standardized in vivo transcriptome profile of histologically normal liver and identified 230 genes with substantial pre-analytical robustness (<2 % covariation across both cohorts) that might serve as reference genes and could be particularly suited for future diagnostic applications.
2024-02-21 | GSE228782 | GEO
Project description:Background & Aims: Cellular responses induced by surgical procedure or ischemia-reperfusion injury (IRI) may severely alter transcriptome profiles. We have investigated this effect to obtain insight into molecular ischemia responses during surgical procedures and characterize pre-analytical effects impacting on molecular analyses. Methods: 143 non-malignant liver samples were obtained from 30 patients at different time points of ischemia during surgery from two individual cohorts, treated either with the Pringle maneuver or total vascular exclusion. Transcriptomics profiles were analyzed by Affymetrix microarrays and expression of selected mRNAs was validated by RT-qPCR. Results: Transcriptional profiles of both cohorts displayed 179 genes that were mutually deregulated confirming elevated cytokine signaling, and NFkB as the dominant pathways in ischemia response. Contrary to ischemia, reperfusion induced pro-apoptotic and pro-inflammatory cascades involving TNF, NFkB and MAPK pathways. FOS and JUN were down-regulated in steatosis compared to their up-regulation in normal livers. Surprisingly, molecular signatures of underlying primary and secondary cancers were clearly present in the non-tumor tissue. Conclusions: We identified transcripts mutually deregulated during ischemia and reperfusion injury in both cohorts that can be used to monitor ischemia during liver surgery and highlight the importance of pre-analytical quality control. The marked inter-patient variability might reflect differences in individual stress responses and impact of underlying disease conditions. Furthermore, we provide a comprehensive and pre-analytically highly standardized in vivo transcriptome profile of histologically normal liver and identified 230 genes with substantial pre-analytical robustness (<2 % covariation across both cohorts) that might serve as reference genes and could be particularly suited for future diagnostic applications. Conclusions: We identified transcripts mutually deregulated during ischemia and reperfusion injury in both cohorts that can be used to monitor ischemia during liver surgery and highlight the importance of pre-analytical quality control. The marked inter-patient variability might reflect differences in individual stress responses and impact of underlying disease conditions. Furthermore, we provide a comprehensive and pre-analytically highly standardized in vivo transcriptome profile of histologically normal liver and identified 230 genes with substantial pre-analytical robustness (<2 % covariation across both cohorts) that might serve as reference genes and could be particularly suited for future diagnostic applications.
2024-02-21 | GSE228781 | GEO
Project description:Hepatic ischemia-reperfusion injury (IRI) limits access to transplantation. Heme oxygenase-1 (HO-1) is a powerful antioxidant enzyme which degrades free heme into biliverdin, free iron and carbon monoxide. HO-1 and its metabolites have the ability to modulate a wide variety of inflammatory disorders including hepatic IRI. Mechanisms of this protective effect include reduction of oxygen free radicals, alteration of macrophage and T cell phenotype. Further work is required to understand the physiological importance of the many actions of HO-1 identified experimentally, and to harness the protective effect of HO-1 for therapeutic potential.
| S-EPMC3012573 | biostudies-literature
Project description:Neutrophils play critical roles during the initial phase of hepatic ischemia/reperfusion injury (HIRI). However, the regulation of neutrophil activation, infiltration, and proinflammatory cytokine secretion has not been fully elucidated. In this study, we revealed that OX40 was expressed by neutrophils, its expression in neutrophils was time-dependently upregulated following HIRI, and Ox40 knockout markedly alleviated liver injury. Compared with wild-type neutrophils, the adoptive transfer of Ox40-/- neutrophils decreased HIRI in neutrophil-depleted Rag2/Il2rg-/- or Ox40-/- mice. Moreover, consistently, the in vitro experiments showed that Ox40 not only prolonged neutrophil survival but also promoted proinflammatory cytokines, ROS production, and even neutrophil chemotaxis. Further investigation demonstrated that the knockout of Ox40 in neutrophils inhibited NF-?B signaling via the TRAF1/2/4 and IKK?/IKK?/I?B? pathways. OX40L and OX86 stimulation could enhance neutrophil activation and survival in vitro and in vivo. In conclusion, our study provides a new understanding of OX40, which is expressed not only in adaptive immune cells but also in innate immune cells, i.e., neutrophils, contributing to the activation and survival of neutrophils. These findings provide a novel potential therapeutic target for the prevention of HIRI during liver transplantation or hepatic surgery.
| S-EPMC6948758 | biostudies-literature
Project description:Hepatic ischemia reperfusion (IR) is the leading cause of acute liver failure (ALF) during the perioperative period and patients with ALF frequently develop acute kidney injury (AKI). There is no effective therapy for AKI associated with ALF because pathomechanisms are incompletely characterized, in part due to the lack of an animal model. In this study, we characterize a novel murine model of AKI following hepatic IR. Mice subjected to approximately 70% liver IR not only developed acute liver dysfunction, but also developed severe AKI 24 h after liver injury. Mice subjected to liver IR developed histological changes of acute tubular injury including focal proximal tubular cell necrosis involving the S3 segment, cortical tubular ectasia, focal tubular simplification and granular bile/heme cast formation. In addition, there was focal interstitial edema and hyperplasia of the juxtaglomerular apparatus. Inflammatory changes in the kidney after hepatic IR included neutrophil infiltration of the interstitium and upregulation of several proinflammatory mRNAs (tumor necrosis factor-alpha, keratinocyte-derived cytokine, monocyte chemotactic protein-1, macrophage inflammatory protein-2, intercellular adhesion molecule-1). In addition, marked renal endothelial cell apoptosis was detected involving peritubular interstitial capillaries, accompanied by increased renal vascular permeability. Finally, there was severe disruption of renal proximal tubule epithelial filamentous-actin. Our results show that AKI rapidly and reproducibly develops in mice after hepatic IR and is characterized by renal tubular necrosis, inflammatory changes and interstitial capillary endothelial apoptosis. Our murine model of AKI after liver injury closely mimics human AKI associated with ALF and may be useful in delineating the mechanisms and potential therapies for this common clinical condition.
| S-EPMC2632727 | biostudies-literature
Project description:The mononuclear phagocyte system (MPS, e.g., liver, spleen) is often treated as a "blackbox" by nanoresearchers in translating nanomedicines. Often, most of the injected nanomaterials are sequestered by the MPS, preventing their delivery to the desired disease areas. Here, this imperfection is exploited by applying nano-antioxidants with preferential liver uptake to directly prevent hepatic ischemia-reperfusion injury (IRI), which is a reactive oxygen species (ROS)-related disease. Ceria nanoparticles (NPs) are selected as a representative nano-antioxidant and the detailed mechanism of preventing IRI is investigated. It is found that ceria NPs effectively alleviate the clinical symptoms of hepatic IRI by scavenging ROS, inhibiting activation of Kupffer cells and monocyte/macrophage cells. The released pro-inflammatory cytokines are then significantly reduced and the recruitment and infiltration of neutrophils are minimized, which suppress subsequent inflammatory reaction involved in the liver. The protective effect of nano-antioxidants against hepatic IRI in living animals and the revealed mechanism herein suggests their future use for the treatment of hepatic IRI in the clinic.
| S-EPMC6773480 | biostudies-literature
Project description:IntroductionIRI results from the interruption then reinstatement of an organ's blood supply, and this poses a significant problem in liver transplantation and resectional surgery. In this paper, we explore the role T cells play in the pathogenesis of this injury.Materials & methodsWe used an in vivo murine model of warm partial hepatic IRI, genetically-modified mice, in vivo antibody depletion, adoptive cell transfer and flow cytometry to determine which lymphocyte subsets contribute to pathology. Injury was assessed by measuring serum alanine aminotransfersase (ALT) and by histological examination of liver tissue sections.ResultsThe absence of T cells (CD3?KO) is associated with significant protection from injury (p=0.010). Through a strategy of antibody depletion it appears that NKT cells (p=0.0025), rather than conventional T (CD4+ or CD8+) (p=0.11) cells that are the key mediators of injury.DiscussionOur results indicate that tissue-resident NKT cells, but not other lymphocyte populations are responsible for the injury in hepatic IRI. Targeting the activation of NKT cells and/or their effector apparatus would be a novel approach in protecting the liver during transplantation and resection surgery; this may allow us to expand our current criteria for surgery.
| S-EPMC5694034 | biostudies-literature
Project description:Tumor necrosis factor receptor-associated factor 1 (TRAF1), an adapter in signal transduction, is involved in immunity and in apoptotic processes in various cell types. However, little is known about its function and the molecular mechanism of its activation during liver injury. This study tested the hypothesis that TRAF1 is a mediator of cell injury after hepatic ischemia/reperfusion injury (I/R). In a mouse hepatic I/R injury model, we found that TRAF1 expression was highly induced. TRAF1 deficiency was liver protective, whereas sustained TRAF1 overexpression aggravated liver injury in response to hepatic I/R injury. Mechanistic studies demonstrated that a deficiency of TRAF1 in cultured hepatocytes led to the inhibition of NF-?B-mediated inflammatory responses, suppression of the ASK/JNK pro-death pathway and promotion of cellular regeneration capacity. In contrast, the converse occurred in hepatocyte-specific TRAF1 transgenic mice. TRAF1 activated the ASK1/JNK pathway and promoted hepatic injury. Our study demonstrates that TRAF1 is a crucial early mediator of hepatic I/R injury and suggests that TRAF1 may be a potential gene therapy target for the treatment of liver injury.
| S-EPMC4649517 | biostudies-literature
Project description:Hepatic ischemia-reperfusion injury (IRI), which mainly results from excessive reactive oxygen species (ROS) generated by a reperfusion burst of oxygen, has long been a major cause of liver dysfunction and failure after surgical procedures. Here, a monodispersed hydrophilic carbohydrate-derived nanoparticle (C-NP) was synthesized as a nanoantioxidant that could effectively prevent hepatic IRI. The spherical C-NPs had a size of ∼78 ± 11.3 nm covered with polar surface groups. They were well dispersible in water with good colloidal stability, nontoxicity, and good ROS scavenging capability. The C-NPs also exhibited good circulation lifetime, effective delivery to liver, and gradual degradability with an ability to assist the IRI group maintaining a normal and healthy liver status. The pathology mechanism of C-NPs in hepatic IRI was confirmed to be scavenging of excessive ROS by C-NPs. The effective therapeutic treatment of C-NPs in living animals revealed a great potential in clinical prevention for hepatic IRI.
| S-EPMC7484346 | biostudies-literature
Project description:To find the genes with significant expression changes after liver ischemia-reperfusion injury,we established a hypoxia-reoxygenation model using AML12 cells. We then performed gene expression profiling analysis using data obtained from RNA-seq under normoxia and hypoxia-reoxygenation conditions.
2022-10-30 | GSE216522 | GEO