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1992 Fiscal Year Final Research Report Summary

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
KeywordsSuperoxide dismutase / Free radicals / Oxygen stress / Heparin / Albumin / Fusion gene / Protein engineering / Gene engineering
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.

  • Research Products

    (30 results)

All Other

All Publications (30 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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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

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Published: 1994-03-24  

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