scholarly journals Peroxiredoxin-6 protects against mitochondrial dysfunction and liver injury during ischemia-reperfusion in mice

2009 ◽  
Vol 296 (2) ◽  
pp. G266-G274 ◽  
Author(s):  
Thorsten Eismann ◽  
Nadine Huber ◽  
Thomas Shin ◽  
Satoshi Kuboki ◽  
Elizabeth Galloway ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Knockout Mice ◽  
Ischemia Reperfusion ◽  
Protective Mechanism ◽  
Wild Type ◽  
Hepatocellular Injury ◽  
Hepatic Ischemia ◽  
Altered Expression ◽  
Peroxiredoxin 6

Hepatic ischemia-reperfusion (I/R) injury is an important complication of liver surgery and transplantation. Mitochondrial function is central to this injury. To examine alterations in mitochondrial function during I/R, we assessed the mitochondrial proteome in C57Bl/6 mice. Proteomic analysis of liver mitochondria revealed 234 proteins with significantly altered expression after I/R. From these, 13 proteins with the greatest expression differences were identified. One of these proteins, peroxiredoxin-6 (Prdx6), has never before been described in mitochondria. In hepatocytes from sham-operated mice, Prdx6 expression was found exclusively in the cytoplasm. After ischemia or I/R, Prdx6 expression disappeared from the cytoplasm and appeared in the mitochondria, suggesting mitochondrial trafficking. To explore the functional role of Prdx6 in hepatic I/R injury, wild-type and Prdx6-knockout mice were subjected to I/R injury. Prdx6-knockout mice had significantly more hepatocellular injury compared with wild-type mice. Interestingly, the increased injury in Prdx6-knockout mice occurred despite reduced inflammation and was associated with increased mitochondrial generation of H2O2 and dysfunction. The mitochondrial dysfunction appeared to be related to complex I of the electron transport chain. These data suggest that hepatocyte Prdx6 traffics to the mitochondria during I/R to limit mitochondrial dysfunction as a protective mechanism against hepatocellular injury.

Cilostazol attenuates murine hepatic ischemia and reperfusion injury via heme oxygenase-dependent activation of mitochondrial biogenesis

2015 ◽  
Vol 309 (1) ◽  
pp. G21-G29 ◽  
Author(s):  
Yeonsoo Joe ◽  
Min Zheng ◽  
Hyo Jeong Kim ◽  
Md. Jamal Uddin ◽  
Seul-Ki Kim ◽  
...  
Keyword(s):  
Liver Injury ◽  
Mitochondrial Dysfunction ◽  
Heme Oxygenase ◽  
Mitochondrial Biogenesis ◽  
Ischemia Reperfusion ◽  
Heme Oxygenase 1 ◽  
Wild Type ◽  
Hepatocellular Injury ◽  
Primary Hepatocytes ◽  
Hepatic Ischemia

Hepatic ischemia-reperfusion (I/R) can cause hepatocellular injury associated with the inflammatory response and mitochondrial dysfunction. We studied the protective effects of the phosphodiesterase inhibitor cilostazol in hepatic I/R and the roles of mitochondria and the Nrf2/heme oxygenase-1 (HO-1) system. Wild-type, Hmox1 −/−, or Nrf2 −/− mice were subjected to hepatic I/R in the absence or presence of cilostazol followed by measurements of liver injury. Primary hepatocytes were subjected to cilostazol with the HO-1 inhibitor ZnPP, or Nrf2-specific siRNA, followed by assessment of mitochondrial biogenesis. Preconditioning with cilostazol prior to hepatic I/R protected against hepatocellular injury and mitochondrial dysfunction. Cilostazol reduced the serum levels of alanine aminotransferase, TNF-α, and liver myeloperoxidase content relative to control I/R-treated mice. In primary hepatocytes, cilostazol increased the expression of HO-1, and markers of mitochondrial biogenesis, PGC-1α, NRF-1, and TFAM, induced the mitochondrial proteins COX III and COX IV and increased mtDNA and mitochondria content. Pretreatment of primary hepatocytes with ZnPP inhibited cilostazol-induced PGC-1α, NRF-1, and TFAM mRNA expression and reduced mtDNA and mitochondria content. Genetic silencing of Nrf2 prevented the induction of HO-1 and mitochondrial biogenesis by cilostazol in HepG2 cells. Cilostazol induced hepatic HO-1 production and mitochondrial biogenesis in wild-type mice, but not in Hmox1 −/− or Nrf2 −/− mice, and failed to protect against liver injury in Nrf2 −/− mice. These results suggest that I/R injury can impair hepatic mitochondrial function, which can be reversed by cilostazol treatment. These results also suggest that cilostazol-induced mitochondrial biogenesis was mediated by an Nrf-2- and HO-1-dependent pathway.

The transcription factor interferon regulatory factor-1 mediates liver damage during ischemia-reperfusion injury

2006 ◽  
Vol 290 (6) ◽  
pp. G1261-G1268 ◽  
Author(s):  
Allan Tsung ◽  
Michael T. Stang ◽  
Atsushi Ikeda ◽  
Nathan D. Critchlow ◽  
Kunihiko Izuishi ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Liver Injury ◽  
Liver Damage ◽  
Knockout Mice ◽  
Ischemia Reperfusion ◽  
Wild Type ◽  
Regulatory Factor ◽  
Hepatic Ischemia ◽  
Adenoviral Delivery ◽  
Tnf Α

Hepatic ischemia occurs in the settings of trauma, transplantation, and elective liver resections. The initiating events that account for local organ damage are only partially understood. Interferon (IFN) regulatory factor-1 (IRF-1) is a transcription factor that regulates the expression of a number of genes involved in both innate and acquired immunity; however, its function in liver injury is unknown. Therefore, the purpose of this study was to investigate the role of IRF-1 in hepatic ischemia-reperfusion (I/R) injury. In C57BL/6 mice undergoing 60 min of hepatic ischemia, IRF-1 protein expression increased as early as 1 h after reperfusion. IRF-1 knockout mice were significantly protected from hepatic I/R-induced damage compared with their wild-type controls. Hepatic I/R injury resulted in marked activation of the MAP kinase c-Jun NH2-terminal kinase (JNK) in wild-type mice but not IRF-1 knockout mice. IRF-1 knockout mice also exhibited significantly lower hepatic expression of TNF-α, IL-6, ICAM-1, and inducible nitric oxide synthase (iNOS) mRNA. Adenoviral delivery of IRF-1 into C57BL/6 mice resulted in increased liver damage even without an ischemic insult. This injury was associated with increased JNK activation and hepatic iNOS expression. Because IRF-1 contributed to liver injury, we also examined for inflammatory signals that regulated IRF-1 gene expression in cultured hepatocytes. Whereas IFN-γ and IFN-β were strong inducers of IRF-1 mRNA (>10-fold) in a time- and dose-dependent manner, TNF-α and IL-1β also induced IRF-1 mRNA to a lesser extent (2- to 3-fold). IL-6 and lipopolysaccharide had no effect on IRF-1 expression. This study demonstrates that IRF-1 exerts a harmful role in hepatic I/R injury by modulating the expression of multiple inflammatory mediators. We further show that IRF-1-mediated injury involves the activation of JNK and that hepatocellular IRF-1 expression itself is regulated by specific cytokines.

scholarly journals Distinct contributions of CD4+ T cell subsets in hepatic ischemia/reperfusion injury

2009 ◽  
Vol 296 (5) ◽  
pp. G1054-G1059 ◽  
Author(s):  
Satoshi Kuboki ◽  
Nozomu Sakai ◽  
Johannes Tschöp ◽  
Michael J. Edwards ◽  
Alex B. Lentsch ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Ischemia Reperfusion ◽  
Γδ T Cells ◽  
Nkt Cells ◽  
T Cell Subsets ◽  
Wild Type ◽  
Hepatic Ischemia ◽  
Hepatic Ischemia Reperfusion

Helper T cells are known to mediate hepatic ischemia/reperfusion (I/R) injury. However, the precise mechanisms and subsets of CD4+ T cells that contribute to this injury are still controversial. Therefore, we sought to determine the contributions of different CD4+ T cell subsets during hepatic I/R injury. Wild-type, OT-II, or T cell receptor (TCR)-δ-deficient mice were subjected to 90 min of partial hepatic ischemia followed by 8 h of reperfusion. Additionally, wild-type mice were pretreated with anti-CD1d, -NK1.1, or -IL-2R-α antibodies before I/R injury. OT-II mice had diminished liver injury compared with wild-type mice, implicating that antigen-dependent activation of CD4+ T cells through TCRs is involved in hepatic I/R injury. TCR-δ knockout mice had decreased hepatic neutrophil accumulation, suggesting that γδ T cells regulate neutrophil recruitment. We found that natural killer T (NKT) cells, but not NK cells, contribute to hepatic I/R injury via CD1d-dependent activation of their TCRs, as depletion of NKT cells by anti-CD1d antibody or depletion of both NKT cells and NK cells by anti-NK1.1 attenuated liver injury. Although regulatory T cells (Treg) are known to suppress T cell-dependent inflammation, depletion of Treg cells had little effect on hepatic I/R injury. The data suggest that antigen-dependent activation of CD4+ T cells contributes to hepatic I/R injury. Among the subsets of CD4+ T cells, it appears that γδ T cells contribute to neutrophil recruitment and that NKT cells directly injure the liver. In contrast, NK cells and Treg have little effects on hepatic I/R injury.

L-selectin and ICAM-1 mediate reperfusion injury and neutrophil adhesion in the warm ischemic mouse liver

1998 ◽  
Vol 275 (6) ◽  
pp. G1341-G1352 ◽  
Author(s):  
Surinder S. Yadav ◽  
David N. Howell ◽  
Wenshi Gao ◽  
Douglas A. Steeber ◽  
Robert C. Harland ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Leukocyte Adhesion ◽  
Ischemia Reperfusion ◽  
Mutant Mice ◽  
Intercellular Adhesion Molecule ◽  
Wild Type ◽  
Intercellular Adhesion Molecule 1 ◽  
Hepatic Ischemia ◽  
Hepatic Ischemia Reperfusion

Leukocytes recruited during ischemia-reperfusion to the liver are important mediators of injury. However, the mechanisms of leukocyte adhesion and the role of adhesion receptors in hepatic vasculature remain elusive. L-selectin may critically contribute to injury, priming adhesion for later action of intercellular adhesion molecule-1 (ICAM-1). Paired experiments were performed using mutant mice (L-selectin −/−, ICAM-1 −/−, and L-selectin/ICAM-1 −/−) and wild-type mice (C57BL/6) to investigate leukocyte adhesion in the ischemic liver. Leukocyte adhesion and infiltration were assessed histologically. Aspartate aminotransferase levels were significantly reduced (2- to 3-fold) in mutant vs. wild-type mice in most groups but most significantly after 90 min of partial hepatic ischemia. Leukocyte adhesion was significantly reduced in all mutant mice. Areas of microcirculatory failure, visualized by intravital microscopy, were prevalent in wild-type but virtually absent in L-selectin-deficient mice. After total hepatic ischemia for 75 or 90 min, survival was better in mutant L-selectin and L-selectin/ICAM-1 mice vs. wild-type mice and ICAM-1 mutants. In conclusion, L-selectin is critical in the pathogenesis of hepatic ischemia-reperfusion injury. Poor sinusoidal perfusion due to leukocyte adhesion and clot formation is a factor of injury and appears to involve L-selectin and ICAM-1 receptors.

scholarly journals Kynurenic Acid Protects Against Ischemia/Reperfusion-Induced Retinal Ganglion Cell Death in Mice

2020 ◽  
Vol 21 (5) ◽  
pp. 1795 ◽  
Author(s):  
Rooban B. Nahomi ◽  
Mi-Hyun Nam ◽  
Johanna Rankenberg ◽  
Stefan Rakete ◽  
Julie A. Houck ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Kynurenic Acid ◽  
Ganglion Cells ◽  
Ischemia Reperfusion ◽  
Fasting Blood Glucose ◽  
Kynurenine Pathway ◽  
Retinal Ganglion ◽  
Diabetic Mice ◽  
Wild Type ◽  
Ganglion Cell Death

Background: Glaucoma is an optic neuropathy and involves the progressive degeneration of retinal ganglion cells (RGCs), which leads to blindness in patients. We investigated the role of the neuroprotective kynurenic acid (KYNA) in RGC death against retinal ischemia/reperfusion (I/R) injury. Methods: We injected KYNA intravenously or intravitreally to mice. We generated a knockout mouse strain of kynurenine 3-monooxygenase (KMO), an enzyme in the kynurenine pathway that produces neurotoxic 3-hydroxykynurenine. To test the effect of mild hyperglycemia on RGC protection, we used streptozotocin (STZ) induced diabetic mice. Retinal I/R injury was induced by increasing intraocular pressure for 60 min followed by reperfusion and RGC numbers were counted in the retinal flat mounts. Results: Intravenous or intravitreal administration of KYNA protected RGCs against I/R injury. The I/R injury caused a greater loss of RGCs in wild type than in KMO knockout mice. KMO knockout mice had mildly higher levels of fasting blood glucose than wild type mice. Diabetic mice showed significantly lower loss of RGCs when compared with non-diabetic mice subjected to I/R injury. Conclusion: Together, our study suggests that the absence of KMO protects RGCs against I/R injury, through mechanisms that likely involve higher levels of KYNA and glucose.

A1 adenosine receptor knockout mice exhibit increased mortality, renal dysfunction, and hepatic injury in murine septic peritonitis

2005 ◽  
Vol 289 (2) ◽  
pp. F369-F376 ◽  
Author(s):  
George Gallos ◽  
Thomas D. Ruyle ◽  
Charles W. Emala ◽  
H. Thomas Lee
Keyword(s):  
Organ Dysfunction ◽  
Knockout Mice ◽  
Adenosine Receptor ◽  
Ischemia Reperfusion ◽  
Cecal Ligation ◽  
Intercellular Adhesion Molecule ◽  
Myeloperoxidase Activity ◽  
Wild Type ◽  
Wild Type Littermate ◽  
Septic Peritonitis

Sepsis is a leading cause of multiorgan dysfunction and death in hospitalized patients. Dysregulated inflammatory processes and apoptosis contribute to the pathogenesis of sepsis-induced organ dysfunction and death. A1 adenosine receptor (A1AR) activation reduces inflammation and apoptosis after ischemia-reperfusion injury. Therefore, we questioned whether A1AR-mediated reduction of inflammation and apoptosis could improve mortality and organ dysfunction in a murine model of sepsis. A1AR knockout mice (A1 knockout) and their wild-type (A1 wild-type) littermate controls were subjected to cecal ligation and double puncture (CLP) with a 20-gauge needle. A1 knockout mice or A1 wild-type mice treated with 1,3-dipropyl-8-cyclopentylxanthine (a selective A1AR antagonist) had a significantly higher mortality rate compared with A1 wild-type mice following CLP. Mice lacking endogenous A1ARs demonstrated significant elevations in plasma creatinine, alanine aminotransferase, aspartate aminotransferase, keratinocyte-derived chemokine, and tumor necrosis factor-α 24 h after induction of sepsis compared with wild-type mice. The renal corticomedullary junction from A1 knockout mice also exhibited increased myeloperoxidase activity, intercellular adhesion molecule-1 protein, and mRNA encoding proinflammatory cytokines compared with renal samples from A1 wild-type littermate controls. No difference in renal tubular apoptosis was detected between A1 knockout and A1 wild-type mice. We conclude that endogenous A1AR activation confers a protective effect in mice from septic peritonitis primarily by attenuating the hyperacute inflammatory response in sepsis.

Activation of the MyD88 signaling pathway inhibits ischemia-reperfusion injury in the small intestine

2012 ◽  
Vol 303 (3) ◽  
pp. G324-G334 ◽  
Author(s):  
Toshio Watanabe ◽  
Atsushi Kobata ◽  
Tetsuya Tanigawa ◽  
Yuji Nadatani ◽  
Hirokazu Yamagami ◽  
...  
Keyword(s):  
Small Intestine ◽  
Signaling Pathway ◽  
Knockout Mice ◽  
Ischemia Reperfusion ◽  
Adaptor Protein ◽  
Myeloperoxidase Activity ◽  
Wild Type ◽  
Tnf Α ◽  
Cox 2 ◽  
Myd88 Signaling

Toll-like receptors (TLRs) recognize microbial components and trigger the signaling cascade that activates innate and adaptive immunity. Recent studies have shown that the activation of TLR-dependent signaling pathways plays important roles in the pathogenesis of ischemia-reperfusion (I/R) injuries in many organs. All TLRs, except TLR3, use a common adaptor protein, MyD88, to transduce activation signals. We investigated the role of MyD88 in I/R injury of the small intestine. MyD88 and cyclooxygenase-2 (COX-2) knockout and wild-type mice were subjected to intestinal I/R injury. I/R-induced small intestinal injury was characterized by infiltration of inflammatory cells, disruption of the mucosal epithelium, destruction of villi, and increases in myeloperoxidase activity and mRNA levels of TNF-α and the IL-8 homolog KC. MyD88 deficiency worsened the severity of I/R injury, as assessed using the histological grading system, measuring luminal contents of hemoglobin (a marker of intestinal bleeding), and counting apoptotic epithelial cells, while it inhibited the increase in mRNA expression of TNF-α and KC. I/R significantly enhanced COX-2 expression and increased PGE2 concentration in the small intestine of wild-type mice, which were markedly inhibited by MyD88 deficiency. COX-2 knockout mice were also highly susceptible to intestinal I/R injury. Exogenous PGE2 reduced the severity of injury in both MyD88 and COX-2 knockout mice to the level of wild-type mice. These findings suggest that the MyD88 signaling pathway may inhibit I/R injury in the small intestine by inducing COX-2 expression.

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