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1993 Fiscal Year Final Research Report Summary

Role of Endotoxin-binding proteins in Non-specific Protection to Infection

Research Project

Project/Area Number 04670250
Research Category

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

Allocation TypeSingle-year Grants
Research Field 細菌学
Research InstitutionIwate Medical University

Principal Investigator

HIRATA Michimasa  Department of Bacteriology, Lecturer, 医学部, 講師 (20048359)

Co-Investigator(Kenkyū-buntansha) SHIMOMURA Yuko  Department of Bacteriology, Assistant, 医学部, 助手 (90206251)
Project Period (FY) 1992 – 1993
KeywordsLipopolysaccharide(LPS) / LPS-binding protein / Tissue factor / Disseminated intravascular coagulation / Anticoagulant / Antibacteria / LPS-neutralization
Research Abstract

Endotoxin(lipopolysaccharide=LPS), cell wall component of gram-negative bacteria, activates monocytes and macrophages to release cytokines, reactive nitrogen intermediates (RNI), and to generate tissue factor(TF) which initiate coagulation. We have purified 7kDa and 18kDa cationic antibacterial proteins (CAP-7 and CAP-18) with LPS-binding and LPS-neutralizing activities from rabbit granulocytes using as an assay the agglutination of erythrocytes coated with Re-LPS.From protein sequencing, CAP-7 was identified as the C-terminal 37 amino acid fragment of CAP-18. Synthetic peptide #197(identical sequence to CAP-7, Gly1-Try37) and #36-1 (a truncation of CAP consisting of 32 amino acid residues, Gly1-Ala32) showed LPS-binding activity. Each peptide inhibited LPS-induced tissue factor(TF) generation by murine peritoneal macrophages, even added 1 hour after stimulation of cells with LPS.C57BL/6 mice treated with #197 were significantly protected from lethal LPS challenge. Peptide #36 also blo … More cked the LPS-induced lethality. These peptides had antibacterial activity to gram-negative bacteria, such as E.coli, S.typhimurium, K.pneumonia, Ps.aeruginosa and also to gram-positive S.aureus(Methicllin sensitive and resistant strains). Both peptides inhibited TF-and Xa-induced plasma clotting. Using synthetic chromogenic substrates, both CAP7 peptides blocked the coagulation cascade at two sites, activation of factor X to Xa and conversion of Factor II(prothrombin) to factor IIa(prothrombin). In vivo treatment of peptide #197 prevented acute lethality in mice injected with tissue factor (rabbit brain thromboplastin). Two other peptides, #32(Gly1-Phe9) and #50(lle13-Typ37) failed to demonstrate LPS-binding, LPS-neutralizing, antibacterial and anticoagulant activities. The active peptides but not the inactive peptide maintain a putative heparin binding domain at their N-termini. This heparin binding domain is participate in the LPS-binding, LPS neutralizing, antibacterial and anticoa
These active peptides may have a therapeutic potential for treatment for DIC due to sepsis and endotoxin shock. Less

  • Research Products

    (14 results)

All Other

All Publications (14 results)

  • [Publications] Hirata M.,Shimomura Y et al: "Endotoxin-neutralizing,antibacterial and anticoagulant activities rabbit CAP18-derived peptides." Gram Negative Sepsis:Basic Science to clinical Investigation. (in press). (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Hirata M.,Shimomura Y et al: "Characterization of a rabbit cationic protein(CAP18)with lipopolyscccharide-inhibitory activity." Inf.Immun. 62(in press). (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Larrick,J.W.,Hirata,M et al: "A Novel granulocyte-derived peptide with LPS neutralizing activity" J Immunol. 152. 231-240 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Larrick,J.W,Hirata,M et al: "Antimicrobial activity of rabbit CAP18-derived peptides." Antimicrob.Agents.Chemother. 37. 2534-2539 (1993)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 平田陸正 下村有子: "エンドトキシン結合性合成ペプチドの抗凝固活性" 血栓止血誌. 5. 17-27 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 平田陸正,下村有子ほか: "エンドトキシンの活性を中和する新しい蛋白質:マクロファージから、組織因子産生を指標として" 血栓止血誌. 4. 153-162 (1993)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 平田陸正(分担): "エンドトシキン最新の研究成果とその検査,診断,治療への応用" 南江堂(1994年10月刊行予定), 300-400 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Hirata, M., Shimomura, Y., Yoshida, M., Morgan, J.G., Palings, I., Wilson D., Yen, M.H. : and Larrick, J.W.: "Characterization of a rabbit cationic protein (CAP-18) with lipopolysaccharide-inhibitory activity" Infect.Immun. (in press). (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Hirata, M., Shimomura, Y., Yoshida, M., Wright, S.C., Larrick, J.W.: "Endotoxin-neutralizing, antibacteria and anticoagulant activities of rabbit CAP-18 derived peptides" Gram Negative Spesis : Basic Science to Clinical Investigation, Edited by J.Levin, A,Sturk, T.van der Poll and S.J.H.Deventer. (in press). (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Hirata, M.and Shimomura, Y.: "Anticoagulant activity of endotoxin-binding synthetic peptides" Japan J.Thromb.Haemostas. 5(1)(in press). (1993)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Hirata, M.and Shimomura, Y.and Yoshida, M.: "Unique endotoxin-neutralizing protein ; Inhibition of endotoxin-induced tissue factor generation" Japan J.Thromb.Haemostas. 4. 153-162 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Larrick, J.W.Hirata, M., Shimomura, Y., Yoshida, M., Zheng, H., Zhomng, J., and Wright S.C.: "Antimicrobial activity of rabbit CAP18-derived peptides Antimicrob" Agents Chemother. 37. 2534-2539 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Larrick, J.W.Hirata, M.Zheng, H., Zhomng, J., Bolin, D., Cavaillon, J.C., Warren, H.S.and Wright S.C.: "A novel granulocyte-derived peptide with LPS neutralizing activity" J.Immunol. 152. 231-240 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Larrick, J.W.Hirata, M., Shimomura, Y., Yoshida, M., Zheng, H., Zhomng, J., and Wright S.C.: "Rabbit CAP18 derived peptides inhibit gram negative and gram positive bacteria." Gram Negative Sepsis : Basic Science to Clinical Investigation. Edited by j.Levin, A.Sturk, T.van der Poll and S.J.H.Deventer. (in press). (1994)

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      「研究成果報告書概要(欧文)」より

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Published: 1995-03-27  

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