Heme oxygenase system in hepatic ischemia-reperfusion injury.
Ontology highlight
ABSTRACT:
SUBMITTER: Richards JA
PROVIDER: S-EPMC3012573 | biostudies-literature | 2010 Dec
REPOSITORIES: biostudies-literature
Publications
Heme oxygenase system in hepatic ischemia-reperfusion injury.
Richards James A JA Wigmore Stephen J SJ Devey Luke R LR
World journal of gastroenterology 20101201 48
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 physio ...[more]
Similar Datasets
Project description:Acute kidney injury has a high mortality and lacks specific therapies, with ischemia/reperfusion injury (IRI) being the predominant cause. Macrophages (M phi) have been used successfully in cell therapy to deliver targeted therapeutic genes in models of inflammatory kidney disease. Heme oxygenase-1 (HO-1) catalyzes heme breakdown and has important cytoprotective functions. We hypothesized that administration of M phi modified to overexpress HO-1 would protect from renal IRI. Using an adenoviral construct (Ad-HO-1), HO-1 was overexpressed in primary bone marrow-derived M phi (BMDM). In vitro Ad-HO-1 M phi showed an anti-inflammatory phenotype with increased phagocytosis of apoptotic cells (ACs) and increased interleukin (IL)-10 but reduced TNF-alpha and nitric oxide (NO) following lipopolysaccharide/interferon-gamma (IFN gamma) stimulation compared to control transduced or unmodified M phi. In vivo, intravenously (IV) injected M phi homed preferentially to the post-IRI kidney compared to uninjured control following experimental IRI. At 24 hours postinjury, despite equivalent levels of tubular necrosis, apoptosis, and capillary density between groups, the injection of Ad-HO-1 M phi resulted in preserved renal function (serum creatinine reduced by 46%), and reduced microvascular platelet deposition. These data demonstrate that genetically modified M phi improve the outcomes in IRI when administered after the establishment of structural injury, raising the prospect of targeted cell therapy to support the function of the acutely injured kidney.
| S-EPMC2956932 | biostudies-literature
Project description:Ischemia/reperfusion (I/R) injury is the main cause of primary graft dysfunction of liver allografts. Cobalt-protoporphyrin (CoPP)-dependent induction of heme oxygenase (HO)-1 has been shown to protect the liver from I/R injury. This study analyzes the apoptotic mechanisms of HO-1-mediated cytoprotection in mouse liver exposed to I/R injury. HO-1 induction was achieved by the administration of CoPP (1.5 mg/kg body weight i.p.). Mice were studied in in vivo model of hepatic segmental (70 %) ischemia for 60 min and reperfusion injury. Mice were randomly allocated to four main experimental groups (n = 10 each): (1) A control group undergoing sham operation. (2) Similar to group 1 but with the administration of CoPP 72 h before the operation. (3) Mice undergoing in vivo hepatic I/R. (4) Similar to group 3 but with the administration of CoPP 72 h before ischemia induction. When compared with the I/R mice group, in the I/R+CoPP mice group, the increased hepatic expression of HO-1 was associated with a significant reduction in liver enzyme levels, fewer apoptotic hepatocytes cells were identified by morphological criteria and by immunohistochemistry for caspase-3, there was a decreased mean number of proliferating cells (positively stained for Ki67), and a reduced hepatic expression of: C/EBP homologous protein (an index of endoplasmic reticulum stress), the NF-κB's regulated genes (CIAP2, MCP-1 and IL-6), and increased hepatic expression of IκBa (the inhibitory protein of NF-κB). HO-1 over-expression plays a pivotal role in reducing the hepatic apoptotic IR injury. HO-1 may serve as a potential target for therapeutic intervention in hepatic I/R injury during liver transplantation.
| S-EPMC5560494 | biostudies-other
Project description:Renal ischemia-reperfusion injury (IRI) is a major risk factor for delayed graft function in renal transplantation. Compelling evidence exists that the stress-responsive enzyme, heme oxygenase-1 (HO-1) mediates protection against IRI. However, the role of myeloid HO-1 during IRI remains poorly characterized. Mice with myeloid-restricted deletion of HO-1 (HO-1M-KO), littermate (LT), and wild-type (WT) mice were subjected to renal IRI or sham procedures and sacrificed after 24 hours or 7 days. In comparison to LT, HO-1M-KO exhibited significant renal histological damage, pro-inflammatory responses and oxidative stress 24 hours after reperfusion. HO-1M-KO mice also displayed impaired tubular repair and increased renal fibrosis 7 days after IRI. In WT mice, HO-1 induction with hemin specifically upregulated HO-1 within the CD11b+ F4/80lo subset of the renal myeloid cells. Prior administration of hemin to renal IRI was associated with significant increase of the renal HO-1+ CD11b+ F4/80lo myeloid cells in comparison to control mice. In contrast, this hemin-mediated protection was abolished in HO-1M-KO mice. In conclusion, myeloid HO-1 appears as a critical protective pathway against renal IRI and could be an interesting therapeutic target in renal transplantation.
| S-EPMC5428056 | biostudies-literature
Project description:BACKGROUND & AIMS:Hepatic ischemia-reperfusion injury (IRI), characterized by exogenous antigen-independent local inflammation and hepatocellular death, represents a risk factor for acute and chronic rejection in liver transplantation. We aimed to investigate the molecular communication involved in the mechanism of liver IRI. METHODS:We analyzed human liver transplants, primary murine macrophage cell cultures and IR-stressed livers in myeloid-specific heme oxygenase-1 (HO-1) gene mutant mice, for anti-inflammatory and cytoprotective functions of macrophage-specific HO-1/SIRT1 (sirtuin 1)/p53 (tumor suppressor protein) signaling. RESULTS:Decreased HO-1 expression in human post-reperfusion liver transplant biopsies correlated with a deterioration in hepatocellular function (serum ALT; p<0.05) and inferior patient survival (p<0.05). In the low HO-1 liver transplant biopsy group, SIRT1/Arf (alternative reading frame)/p53/MDM2 (murine double minute 2) expression levels decreased (p<0.05) while cleaved caspase 3 and frequency of TUNEL+cells simultaneously increased (p<0.05). Immunofluorescence showed macrophages were the principal source of HO-1 in human and mouse IR-stressed livers. In vitro macrophage cultures revealed that HO-1 induction positively regulated SIRT1 signaling, whereas SIRT1-induced Arf inhibited ubiquitinating activity of MDM2 against p53, which in turn attenuated macrophage activation. In a murine model of hepatic warm IRI, myeloid-specific HO-1 deletion lacked SIRT1/p53, exacerbated liver inflammation and IR-hepatocellular death, whereas adjunctive SIRT1 activation restored p53 signaling and rescued livers from IR-damage. CONCLUSION:This bench-to-bedside study identifies a new class of macrophages activated via the HO-1-SIRT1-p53 signaling axis in the mechanism of hepatic sterile inflammation. This mechanism could be a target for novel therapeutic strategies in liver transplant recipients. LAY SUMMARY:Post-transplant low macrophage HO-1 expression in human liver transplants correlates with reduced hepatocellular function and survival. HO-1 regulates macrophage activation via the SIRT1-p53 signaling network and regulates hepatocellular death in liver ischemia-reperfusion injury. Thus targeting this pathway in liver transplant recipients could be of therapeutic benefit.
| S-EPMC5884687 | biostudies-literature
Project description:BackgroundIschemia-reperfusion injury (IRI) is an important cause of graft dysfunction post-liver transplantation, where donor liver with severe steatosis is more sensitive to IRI. Liver IRI involves ferroptosis and can be alleviated by heme oxygenase-1-modified bone marrow mesenchymal stem cells (HO-1/BMMSCs).AimsTo explore the role and mechanism of HO-1/BMMSCs in severe steatotic liver IRI.MethodsA severe steatotic liver IRI rat model and a hypoxia/reoxygenation (H/R) of severe steatosis hepatocyte model were established. Liver and hepatocyte damage was evaluated via liver histopathology and cell activity. Ferroptosis was evaluated through ferroptosis indexes. Nuclear factor erythroid 2-related factor 2 (Nrf2) was knocked down in severe steatotic hepatocytes. The role of Nrf2 and AMPK in HO-1/BMMSC inhibition of ferroptosis was examined using the AMP-activated protein kinase (AMPK) pathway inhibitor Compound C.ResultsThe HO-1/BMMSCs alleviated severe steatotic liver IRI and ferroptosis. HO-1/BMMSCs promoted ferritin heavy chain 1(FTH1), Nrf2, and phosphorylated (p)-AMPK expression in the H/R severe steatotic hepatocytes. Nrf2 knockdown decreased FTH1 expression levels but did not significantly affect p-AMPK expression levels. The protective effect of HO-1/BMMSCs against H/R injury in severe steatotic hepatocytes and the inhibitory effect on ferroptosis were reduced. Compound C decreased p-AMPK, Nrf2, and FTH1 expression levels, weakened the HO-1/BMMSC protective effect against severe steatotic liver IRI and H/R-injured severe steatotic hepatocytes, and reduced the inhibition of ferroptosis.ConclusionsFerroptosis was involved in HO-1/BMMSC reduction of severe steatotic liver IRI. HO-1/BMMSCs protected against severe steatotic liver IRI by inhibiting ferroptosis through the AMPK-Nrf2-FTH1 pathway. HO-1/BMMSCs activate AMPK, which activates Nrf2, promotes its nuclear transcription, then promotes the expression of its downstream protein FTH1, thereby inhibiting ferroptosis and attenuating severe steatotic liver IRI in rats. Glu: glutamic acid; Cys: cystine; GSH: glutathione; GPX4: glutathione peroxidase 4; HO-1/BMMSCs: HO-1-modified BMMSCs; Fer-1: ferrostatin-1; DFO: deferoxamine; FTH1: ferritin heavy chain1; p-AMPK: phosphorylated AMP-activated protein kinase; Nrf2: nuclear factor erythroid 2-related factor 2; IRI: ischemia-reperfusion injury; MCD: methionine-choline deficiency.
| S-EPMC10570260 | biostudies-literature
Project description:Hypercapnic acidosis (HCA) has protective effects in animal models of acute lung injury, but the mechanism underlying the effect of HCA is unclear. Heme oxygenase-1 (HO-1) is an antioxidant enzyme that protects tissue from inflammation injury. We investigated whether HO-1 contributes to the protective effects of HCA in ischemia-reperfusion (IR)-induced lung injury. Typical acute lung injury in rats was successfully induced by 40 min of ischemia and 90 min of reperfusion in an isolated perfused lung model. The rat lungs were randomly assigned to the control group, IR group or IR + HCA group with or without zinc protoporphyrin IX (ZnPP), an HO-1 activity inhibitor. At the end of the experiment, bronchoalveolar lavage fluid (BALF) and lung tissues were collected to evaluate the degree of lung injury. In in vitro experiments, HO-1 siRNA transfected A549 cells were exposed to a normoxic or hypoxia-reoxygenation (H/R) environment in the presence or absence of HCA. IR caused significant increases in the pulmonary arterial pressure, lung weight to body weight and wet/dry ratios, lung weight gain, capillary filtration coefficient, lung injury scores, neutrophil infiltration, and concentrations of protein and TNF-? in the BALF. IR also induced degradation of inhibitor of nuclear factor (NF)-?B-?, increased I?B kinase (IKK)-? phosphorylation and nuclear translocation of NF-?B, and up-regulated HO-1 expression and activity. Furthermore, IR decreased Bcl-2 protein expression and increased the number of active caspase-3 stained cells. HCA treatment enhanced HO-1 expression and activity, and accordingly reduced IKK-NF-?B signaling, inhibited apoptosis, and significantly attenuated IR-induced changes. Treatment with ZnPP partially blocked the protective effect of HCA. In addition, HO-1 siRNA significantly reversed HCA-mediated inhibition of NF-?B signaling in A549 cells subjected to H/R. In conclusion, the protective effect of HCA in IR lung injury in rats was mediated in part by the anti-inflammatory and anti-apoptotic action of HO-1.
| S-EPMC3769390 | biostudies-literature
Project description:The aim of the present study was to identify the effect of heme oxygenase (HO)-1 gene on cerebral ischemia-reperfusion injury. Sprague-Dawley rats were divided randomly into four groups: Sham group, vehicle group, empty adenovirus vector (Ad) group and recombinant HO-1 adenovirus (Ad-HO-1) transfection group. Rats in the vehicle, Ad and Ad-HO-1 groups were respectively injected with saline, Ad or Ad-HO-1 for 3 days prior to cerebral ischemia-reperfusion injury. Subsequently, the middle cerebral artery occlusion method was used to establish the model of cerebral ischemia-reperfusion injury. Following the assessment of neurological function, rats were sacrificed, and the infarction volume and apoptotic index in rat brains were measured. Furthermore, the protein expression levels of HO-1 in brain tissues were detected using western blot analysis. Results indicated that the neurological score of the Ad-HO-1 group was significantly increased compared with the Ad or vehicle groups, respectively (P<0.001). The volume of cerebral infarction and the index score of neuronal apoptosis in the vehicle and Ad groups was significantly increased compared with the Ad-HO-1 group (P<0.01). The death of neuronal cells following cerebral ischemia-reperfusion injury reduced remarkably induced by over-expression of HO-1. These findings suggest a neuroprotective role of HO-1 against brain injury induced by transient cerebral ischemia-reperfusion injury.
| S-EPMC5958683 | 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 (I/R) injury is one of the leading causes of mortality following partial hepatectomy, liver transplantation, hypovolemic shock and trauma; however, effective therapeutic targets for the treatment of hepatic I/R injury are lacking. Recent studies have shown that diminazene aceturate (DIZE) has protective effects against inflammation, oxidative stress and cell death, which are the main pathogenetic mechanisms associated with hepatic I/R injury. However, the mechanistic effects DIZE exerts on hepatic I/R remain unknown. C57BL/6 male mice were pretreated with either 15 mg/kg DIZE or vehicle control (saline) and subjected to partial liver ischemia for 60 min. One day after induction of hepatic I/R, liver damage, inflammatory responses, oxidative stress and apoptosis were analyzed. By evaluating plasma alanine aminotransferase levels and histology, we found that DIZE treatment attenuated liver failure and was associated with a reduction in histologically-apparent liver damage. We also found that DIZE-treated mice had milder inflammatory responses, less reactive oxidative damage and less apoptosis following hepatic I/R compared to vehicle-treated mice. Taken together, our study demonstrates that DIZE protects against ischemic liver injury by attenuating inflammation and oxidative damage and may be a potential therapeutic agent for the prevention and treatment of ischemic liver failure.
| S-EPMC9616812 | 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