Inhibition of ischemia/reperfusion injury and chronic graft deterioration by a single-donor treatment with cobalt-protoporphyrin for the induction of heme oxygenase-1

Tullius, Stefan G.; Nieminen-Kelhä, Melina; Buelow, Roland; Reutzel‐Selke, Anja; Martins, Paulo Ney Aguiar; Pratschke, Johann; Bachmann, U.; Lehmann, Manfred; Southard, Daniel; Iyer, Suhasani; Schmidbauer, G.; Sawitzki, Birgit; Reinke, Petra; Neuhaus, P.; Volk, Hans‐Dieter

doi:10.1097/00007890-200209150-00001

Cited by 166 publications

(123 citation statements)

References 31 publications

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“…[16][17][18][28][29][30] In most of these studies, the introduction of HO-1 in grafts is achieved by metalloporphyrin (mainly cobalt protoporphyrin), gene transfer or transgenic engineering. These methods need to treat grafts in advance or are limited on transgenic animal models.…”

Section: Discussionmentioning

confidence: 99%

A cell penetrating heme oxygenase protein protects heart graft against ischemia/reperfusion injury

Ma¹,

Lau

Obed³

et al. 2008

Gene Ther

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Ischemia/reperfusion (I/R) injury is an unavoidable barrier that significantly affects outcome of solid organ transplantation. Here, we establish a protein transduction system to extend graft preservation time and to prevent I/R injury in heart transplantation. We generated a recombinant heme oxygenase-1 (HO-1) protein containing a modified protein transduction domain (PTD). PTD could cross cover cell membrane and carry target molecule to parenchymal cells of cold-preserved heart grafts. The newly generated PTD-HO-1 protein localized mainly in subcellular membrane organelle and nucleus after delivery that significantly prolonged cold preservation of heart grafts. This effect was associated with significantly less endothelial cell activation, less neutrophil and macrophage infiltration in PTD-HO-1-transduced heart grafts after reperfusion as compared with controls. In addition, transduction of PTD-HO-1 protein to heart graft significantly suppressed the I/R injury-associated myocardiocyte apoptosis. The infarct areas of heart graft after I/R injury were significantly reduced after PTD-HO-1 protein treatment. We show here for the first time that PTD can maintain its biological activities during cold preservation. Transduction of cell penetrating HO-1 protein significantly prolongs the cold preservation time and protects the graft from the I/R injury. This approach represents a novel method for the improvement of the overall outcome of organ transplantation.

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Section: Discussionmentioning

confidence: 99%

A cell penetrating heme oxygenase protein protects heart graft against ischemia/reperfusion injury

Ma¹,

Lau

Obed³

et al. 2008

Gene Ther

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“…Recent studies reported that cobalt administration ameliorated ischemic injury of the heart (15,25) and the liver (26 -28). In the kidney, Tullius et al (29) showed that treatment with cobalt protoporphyrin improved chronic graft survival of transplant kidneys via induction of heme oxygenase-1. While they attributed improvement in graft survival to prevention of ischemic injury, no detailed information about acute phase of ischemic injury in the kidney was provided, and it remains unclear whether other mechanisms participated in their study.…”

Section: Discussionmentioning

confidence: 99%

Induction of Renoprotective Gene Expression by Cobalt Ameliorates Ischemic Injury of the Kidney in Rats

Matsumoto¹,

Makino

Tanaka³

et al. 2003

Journal of the American Society of Nephrology

240

172

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Abstract. Hypoxia in the tubulointerstitium has been thought to play pivotal roles in the pathophysiology of acute renal failure and the progression of chronic kidney disease. Pre-induction of hypoxia-inducible and renoprotective gene expression may protect subsequent ischemic injury. This study evaluated the efficacy of cobalt, which inhibits HIF-1 degradation and increases the expression level of hypoxia-related genes, in an acute ischemic tubulointerstitial injury model of rats. Ischemic renal injury was induced by 45-min clamping of renal pedicles with contralateral nephrectomy. Elevation of serum creatinine and morphologic injury after the ischemic insult was observed. Administration of cobalt chloride afforded striking functional improvement (mean Ϯ SEM creatinine in mg/dl: Co treatment group, 2.14 Ϯ 1.21; control, 3.69 Ϯ 1.43; P Ͻ 0.05) associated with amelioration of tubulointerstitial damage. Cobalt treatment also reduced macrophage infiltration significantly. In the kidney of rats treated with cobalt, mRNA levels of several genes that serve for tissue protection, such as HO-1, EPO, Glut-1, and VEGF, were increased before ischemic injury. Upregulation of HO-1 by cobalt was confirmed at the protein level. Subcutaneous injection of cobalt also ameliorated ischemic injury, which was associated with upregulation of renal HIF-1␣ protein expression. These results suggest that protection against hypoxic tubulointerstitial injury by cobalt administration is mediated by induction of renoprotective gene expression. HIF induction is one possible and attractive explanation for the observed effects.Hypoxia contributes significantly to the pathophysiology of major categories of human disease, including myocardial and cerebral ischemia, cancer, congenital heart disease, and chronic obstructive pulmonary disease. In the kidney, ischemic injury leads to acute renal failure (ARF). Although renal function after episodes of ARF is thought to be restored, initial ischemic injury is associated with high morbidity and mortality. Furthermore, hypoxia is crucial in progression of chronic renal disease (1). There is growing evidence that reduction of peritubular capillary density coincides with loss of renal function and results in progressive renal failure, implying a role of hypoxia in tubulointerstitial damage, which leads to eventual kidney failure (2).Improvement of the ability of organs to tolerate ischemic injury would be beneficial in case of hypoxia. An exposure to hypoxic environment is known to stimulate genes that play roles in the adaptation to oxygen deficiency. A category of them includes proteins involved in regulating glucose uptake and glucose metabolism, which allow maintaining energy synthesis under hypoxic condition. The other category includes proteins involved in angiogenesis and erythropoiesis, which increase blood vessel density and blood oxygen-carrying capacity.Many processes of adaptation to hypoxia are mediated by hypoxia inducible factor (HIF), which is a master regulator of genes activated by low o...

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“…Induction of HO-1 has previously been shown to protect rats from transplantation-related complications by preventing cytokine responses. 18 We investigated the effect of HO-1 induction by CoPP, or HO repression by SnPP, on liver damage and survival in the cytokine-dependent GalN/ LPS model of apoptotic liver damage. Measurement of plasma ALT revealed that HO-1 induction protected mice from liver injury, while repression of HO increased liver injury (Fig.…”

Section: Ho-1 Induction Protects Mice From Inflammatorymentioning

confidence: 99%

Cooperative effect of biliverdin and carbon monoxide on survival of mice in immune-mediated liver injury

et al. 2004

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Induction of the heme-degrading enzyme heme oxygenase-1 (HO-1) has been shown to be beneficial in terms of improvement of liver allograft survival and prevention of CD95-mediated apoptosis in the liver. In the present study, we investigated the effects of HO-1, and its products carbon monoxide (CO), biliverdin (BV), and iron/ferritin, in a mouse model of results in the production of carbon monoxide (CO), free iron, and biliverdin (BV). HO-1, in contrast to the second isoform HO-2, is inducible by various stimuli. 1,2 To investigate HO effects in vitro as well as in vivo, HO-1 can be induced by application of cobalt-protoporphyrin-IX (CoPP), for example, while tin-protoporphyrin-IX (SnPP) suppresses HO activity. 3,4 In the liver, administration of CoPP to mice results in HO-1 expression in hepatocytes as well as in Kupffer cells. 5 In vivo, HO-1 induction has been shown previously to protect mice from apoptotic liver damage 5 and to protect rats from liver graft rejection as well as from ischemia/reperfusion injury. 6 -8 To investigate mechanisms of cytokine-dependent liver injury, mice can be sensitized with the hepatocytespecific transcriptional inhibitor D-galactosamine (GalN) in combination with the macrophage activator lipopolysaccharide (LPS). 9 In this GalN/LPS model, mice develop severe liver injury, which is dependent on tumor necrosis factor (TNF) 10,11 and interferon ␥ (IFN-␥) 12 induction, while interleukin (IL) 10 prevents injury. 13 In the present study we show that HO-1, induced by CoPP, protects mice from GalN/LPS-induced liver injury, prolongs survival, and reduces cytokine expression. Protection from liver damage could also be achieved by pretreatment with the HO products CO and BV, but not by ferritin. Prolongation of survival and cytokine reduction was only detectable in mice pretreated with a combination of both hepatoprotective products CO and BV. Materials and MethodsAnimals. BALB/c-mice (6-8 weeks old; weight range, 18-22 g) were obtained from the animal facilities of the

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Inhibition of ischemia/reperfusion injury and chronic graft deterioration by a single-donor treatment with cobalt-protoporphyrin for the induction of heme oxygenase-1

Cited by 166 publications

References 31 publications

A cell penetrating heme oxygenase protein protects heart graft against ischemia/reperfusion injury

A cell penetrating heme oxygenase protein protects heart graft against ischemia/reperfusion injury

Induction of Renoprotective Gene Expression by Cobalt Ameliorates Ischemic Injury of the Kidney in Rats

Cooperative effect of biliverdin and carbon monoxide on survival of mice in immune-mediated liver injury

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