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Targeting superoxide dismutase to injured tissues

Research Project

Project/Area Number 03670146
Research Category

Grant-in-Aid for General Scientific Research (C)

Allocation TypeSingle-year Grants
Research Field Pathological medical chemistry
Research InstitutionKUMAMOTO UNIVERSITY

Principal Investigator

INOUE Masayasu  熊本大学, 医学部, 助教授 (80040278)

Project Period (FY) 1991 – 1992
Project Status Completed (Fiscal Year 1992)
Budget Amount *help
¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 1992: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1991: ¥1,200,000 (Direct Cost: ¥1,200,000)
KeywordsSuperoxide dismutase / Free radicals / Oxygen stress / Heparin / Albumin / Fusion gene / Protein engineering / Gene engineering / Free radical / Heparin / 活性酸素 / SOD / タ-ゲッティング / 分子設計 / Fusion酵素 / ヘパリン
Research Abstract

Though active oxygen species have been postulated to play important roles in the pathogenesis of various diseases, critical evidence supporting this hypothesis is lacking. Since these hazardous species rapidly react with bioactive molecules, they should be scavenged at the site of generation. To localize superoxide dismutase (SOD) at the site of tissue injury, we have developed three types of SOD derivatives, SM-SOD,AC-SOD,AH-SOD,MAN-SOD,GAL-SOD, and HB-SOD. SM-SOD circulates bound to albumin with prolonged in vivo half-life and accumulates in tissues whose pH is decreased. AC-SOD is an acylated SOD that binds to membrane/lipid bilayers of cornea and other tissues. AH-SOD is a cationic SOD that selectively accumulates in the proximal tubules of the kidney. MAN-SOD and GAL-SOD are hepatophilic SOD derivatives linked with mannose and galactose residues and specifically localized in sinusoidal cells and hepatocytes, respectively. HB-SOD is a fusion gene product having a structure of human Cu/Zn-SOD and C-terminal heparin-binding domain.
When injected intravenously, SM-SOD markedly inhibited posticschemic reperfusion injury of the brain, heart, liver and other tissues. Through binding to the corneal surface, AC-SOD significantly decreased endotoxin-induced corneal injury particularly at is early stage of inflammation. The infiltration of neutrophils to the avascular cornea was also inhibited by AC-SOD. HB-SOD binds to vascular endothelial cells and undergoes transendothelial movement where it efficiently dismutates superoxide radicals. Using these SOD derivatives, the roles of superoxide radicals in the pathogenesis of various types of tissue injury were tested. HB-SOD also inhibited vasogenic tissue injury, such as brain edema, and exhibited depressor action in spontaneously hypertensive rat, an animal model of essential hypertension. These results indicate that superoxide radicals play critical roles in the pathogenesis of these diseases.

Report

(3 results)
  • 1992 Annual Research Report   Final Research Report Summary
  • 1991 Annual Research Report
  • Research Products

    (52 results)

All Other

All Publications (52 results)

  • [Publications] R.Kunitomo: "Synthesis of a cytochrome c derivative with prolonged in vivo half-life and determination of ascorbyl radicals in the circulation." J.Biol.Chem.267. 8732-8738 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] E.Sato: "Dynamic aspects of ovarian SOD isozymes during ovulation in the rat." FEBS.Lett.303. 121-125 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] M.Neihoerster: "A link between extracellular reactive oxygen and endotoxin-induced release of TNFa in vivo." Biochem.Pharmacol.43. 1151-1154 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] A.Komatsu: "Neutrophil accumulation in ischemic reperfused liver." Am.J.Physiol.262. G669-676 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] M.Inoue: "Expression of hybrid Cu/Zn-SOD with high affinity for heparin on vascular endothelial cells." J.Biol.Chem.266. 16409-16414 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] K.Nakazono: "Does superoxide underlie the pathogenesis of hypertention?" Proc.Natl.Acad.Sci.USA. 88. 10045-10048 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] M.Inoue: "Method in Enzymology:Targeting superoxide dismutase by gene-and protein-engineering." L.Packer(Academic Press), (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] 井上 正康: "活性酸素と病態" 学会出版センター, 777 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Y. Ando M. Inoue S. Araki Y. Morino: "Inhitition of carragcenin-induced paw edema by a superoxide dismutase derivative that circulates bound to albumin" Biochem. Biophys Acta. 1073. 374-379 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] A. Yasutake K. Hirayama M. Inoue: "Interaction of methylmercury compounds with bovine serum albumin." Arch. toxicol.64. 639-643 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] H. Obayashi S. Koshi Y. Miyauchi M. Inoue: "Inhibition of posthaemorrhagic transfusion-induced gastric mucosal injury by a long acting superoxide dismutase derivative." Proc. Soc. Exp. Biol. Med.196. 164-169 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] R. Takahashi K. Edashige E. Sato M. Inoue: "Luminol chemiluminescence and reactive oxygen generation by activated neutrophiles." Arch. Biochem. Biophys.285. 325-330 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] K. Okajima W. Yand M. Inoue H. Okabe: "Role of leukocytes in the activation of intravascular coagulation in patients with septicaemia." Am. J. Haematol.36. 265-271 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Y. Oyanagui S. Sato M. Inoue: "Inhibition of carrageenan paw edema by superoxide dismutase that binds to heparan sulfate on vascular endothelial cells." Biochem. Pharmacol. 42. 991-995 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] M. Inoue N. Watanabe K. Matsuno J. Sasaki: "Expression of a hybrid Cu,Zn-type superoxide dismutase which has high affinity for heparin-like proteoglycans on vascular endothelial cells." J. Biol. Chem.266. 16409-16414 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] K. Matsuno N. Watanabe K. Nakazono J. Sasaki: "Does superoxide underlies the pathogenesis of essential hypertension?" Proc. Natl. Acad. Sci. USA. 88. 10045-10048 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] S. Kawamoto Y. Miyauchi M. Inoue: "Mechanism of entero-hepatic injury caused by circulatory disturbance of hepatic vessels in the rat." Proc. Soc. Exp. Biol. Med.198. 629-635 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] S. Koshi H. Obayashi Y. Miyauchi M. Inoue: "Inhibition of postischemic reperfusion injury of the small intestine by diamine oxidase." Biochem. Biophys. Acta. 1075. 231-236 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] M. Neihoerster M. Inoue A. Wendel: "A link between extracellular reactive oxygen and endotoxin-induced release of tumor necrosis factor a in vivo." Biochem. Pharmacol.43. 1154-1158 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] M. Takahashi E. Sato K. Akimaru E. Edamatu: "Stimulus-specific enhancement of luminol chemiluminescence in neutrophils by phosphatidylserine liposomes." Arch. Biochem. Biophys.(1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] E. Sato H. Kobuchi K. Edashige M. Takahashi: "Dynamic aspects of superoxide dismutase isozymes during the ovulation in the rat" FEBS Lett.303. 121-125 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] R. Kunitomo Y. Miyauchi M. Inoue: "Synthesis of a cytochrome C derivative with prolonged in vivo half life and determination of ascorbyl radicals in the circulation of the rat." J.Biol.Chem.267. 8732-8738 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] H. Komatsu A. Koo P. Guth M. Inoue: "Neutrophil accumulation in ischemic reperfused liver: Evidence for a role of superoxide free radicals." Am. J. Physiolo. 262. G669-676 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] AK. Koo H. Komatsu M. Inoue P. Guth: "Contribution of the non-reflow phenomenon to hepatic injury following ischemia-reperfusion: Evidence for a role of superoxide anions and leukocyte adhesion in the microcirculation." Hepatology. 15. 507-514 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] H. Araki M. Jougasaki K. Nishi J. Muramoto: "Heparin adheres to the damaged arterial wall and inhibites its thrombogenicity." Circulation Res.(1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] T. Kitamura J. Alroy Z. Gatmation M. Inoue: "The pathogenesis of black liver in mutant (TR-) rats with conjugated hyperbilirubinemia." Hepatology. (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] M. Inoue N. Watanabe: "Inhibition of lethal arrhythmias by targeting superoxide dismutase to heparan sulfates on vascular endothelial cell surface." Arch. Biochem. Biophys.(1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] M.Inoue: "Targeting superoxide dismutase to renal proximal tubule cells." J. Biol. Chem.(1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] K. Nakazono S. Fujiyama T. Sato M. Inoue: "Superoxide radicals play critical roles in the pathogenesis of hypertension with genetic and nongenetic etiology" Arch. Biochem. Biophys. (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Y. Nishimura M. Nakayama T. Sato M. Inoue: "Inhibition of renal injury induced by puromycin aminonucleotide in the rat" Arch. Biochem. Biophys.(1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] R.Kunitomo: "Synthesis of a cytochrome c derivative with prolonged in vivo half-life and determination of ascorbyl radicals in the circulation." J.Biol.Chem.267. 8732-8738 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] E.Sato: "Dynamic aspects of ovarian SOD isozymes during ovulation in the rat." FEBS.Lett.303. 121-125 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] M.Neihoerster: "A link between extracellular reactive oxygen and endotoxin-induced release of TNFa in vivo." Biochem.Pharmacol.43. 1151-1154 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] A.Komatsu: "Neutrophil accumulation in ischemic reperfused liver." Am.J.Physiol.262. G669-676 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] M.Inoue: "Expression of hybrid Cu/Zn-SOD with high affinity for heparin on vascular endothelial cells." J.Biol.Chem.266. 16409-16414 (1991)

    • Related Report
      1992 Annual Research Report
  • [Publications] K.Nakazono: "Does superoxide underlie the pathogenesis of hypertention?" Proc.Natl.Acad.Sci.USA. 88. 10045-10048 (1991)

    • Related Report
      1992 Annual Research Report
  • [Publications] M.Inoue: "Method in Enzymology:Targeting superoxide dismutase by gene-and protein-engineering." L.Packer(Academic Press), (1993)

    • Related Report
      1992 Annual Research Report
  • [Publications] 井上 正康: "活性酸素と病態" 学会出版センター, 777 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] R.Kunitomo: "Synthesis of a cytochrome C‐derivative with prolonged in vivo halflife and determination of ascorbyl radicals in the circulation." J.Biol.Chem.(1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] M.Inoue: "Expression of a hybrid Cu/Zn‐type superoxide dismutase which has high affinity for heparin‐like proteoglycans on vascular endothelial cells." J.Biol.Chem.266. 16409-16414 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] K.Nakazono: "Does superoxide underlie the pathogenesis of hypertension?" Proc.Natl Acad.Sci.USA,. 88. (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] S.Kawamoto: "Mechanism for enterohepatic injury caused by circulatory disturbance of hepatic vessels in the rat." Proc.Soc.Exp.Biol.Med.198. (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] S.Koshi: "Inhibition of postischemic reperfusion injury of the small intestine by diamine oxidase." Biochim.Biophys.Acta.(1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] H.Obayashi: "Inhibition of posthemorrhagic transfusion‐induced gastric mucosal injury by a long acting superoxide dismutase derivative." Proc.Soc.Exp.Biol.Med.196. 164-169 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Y.Oyanagui: "Inhibition of carrageenan paw edema by superoxide dismutase that binds to heparan sulfate on vascular endothelial cell." Biochem.Pharmacol.42. 991-995 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] K.Okajima: "Studies on the role of leukocytes in the activation of intravascular coagulation in patients with septicaemia." Am.J.Haematol. 36. 265-271 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] M.Inoue: "Inhibition of oxygen toxicity by targeting superoxide dismutase to endothelial cell surface." FEBS Lett.269. 89-92 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] R.Takahashi: "Luminol chemiluminescence and reactive oxygen generation by activated neutrophiles." Arch.Biochem.Biophys.285. 325-330 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] A.Yasutake: "Interaction of methylmercury compounds with serum albumin." Arch.Toxicol. 64.639-643 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] M.Inoue: "Role of interorgan metabolism and transport of GSH in the regulation of circulatory status." (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] M.Inoue: "Excerpta Medica." Frontias of Mucosal Immunology, 500 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] 井上 正康: "活性酸素と病態" 学会出版センタ-, 600 (1991)

    • Related Report
      1991 Annual Research Report

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Published: 1991-04-01   Modified: 2016-04-21  

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