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A breakthrough in paraquat-induced pulmonary fibrosis

Research Project

Project/Area Number 10670405
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Legal medicine
Research InstitutionKAWASAKI MEDICAL SCHOOL

Principal Investigator

TOMITA Masafumi  Kawasaki Medical School, Legal Medicine, Lecturer, 医学部, 講師 (50113197)

Co-Investigator(Kenkyū-buntansha) ISHIKAWA Tetsuya  Kawasaki Medical School, Biochemistry, Assistant, 医学部, 助手 (90221754)
HIDAKA Kazuo  Kawasaki Medical School, Biochemistry, Lecturer, 医学部, 講師 (00069064)
Project Period (FY) 1998 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2000: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1999: ¥800,000 (Direct Cost: ¥800,000)
KeywordsParaquat / Pulmonary fibrosis / Nitric oxide (NO) / Cytokine / Glutathione / Oxidative stress / gene expression / Differential display / 肺線維化 / グルタチオンレベル / 遺伝子発現 / differential display / ラット / 中毒学 / 脂質過酸化 / A549細胞 / ラット組織 / 中毒機序 / Peroxynitrite / Cytokine / 膜脂質過酸化
Research Abstract

First, we studied the effect of nitric oxide (NO) and glutathione (GSH) levels on PQ toxicity in A549 cells and rat organs exposed to PQ.Our in vitro models demonstrated that NO showed both beneficial and deleterious actions, depending on the concentrations produced and model system used. We detected, in vivo models, a remarkable increase in iNOS mRNA level and deposit of nitrotyrosine in liver tissues, whereas gene expressions for cytokines increased in lung tissues, suggesting that the mechanisms of PQ poisoning are different among organs exposed to PQ.We found a specific increase in GSH levels, the activities and the expression levels of the rate-limiting enzymes in GSH synthesis ; γ-glutamylcysteine synthetase (γ-GCS) and γ-glutamyl transpeptidase (γ-GT) in lungs exposed to PQ.Also, the GSH levels in A549 cells slightly increased by incubation with PQ.Next, by analyzing cholesterol-derived hydroperoxide, we found 7 α-OOH and 7 β-OOH accumulations in rat liver and kidney exposed to low dose of PQ, especially they reflected greater oxidative stress in the pathology of kidney. Finally, to identify genes that are differentially expressed in response to oxidative stress due to PQ, we carried out RT-PCR based differential display experiments using cDNAs from rat lungs that were treated for 3 hrs with 20 mg/kg PQ.Numerous cDNA bands were identified that were up-regulated and down-regulated ; a few clone were homologous to known genes and the remainders were unknown. Unknown six different cDNA clones were isolated and sequenced. The differential mRNA expression of these clones could be verified using RT-PCR method. These results may prove useful in elucidating the molecular changes during pulmonary fibrosis evoked by PQ intake.

Report

(4 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • 1998 Annual Research Report
  • Research Products

    (32 results)

All Other

All Publications (32 results)

  • [Publications] M.Tomita et al.: "Changes in mRNAs of inducible nitric oxide synthase and interleukin-1 β in the liver, kidney and lung tissues of rats acutely exposed to paraquat"Legal Medicine. 1. 127-134 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] M.Tomita et al.: "Enhancement of DNA fragmentation in PC12 cells by methamphetamine under serum-free conditions"Res.Pract.Forens.Med.. 42. 75-79 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] M.Tomita: "Effect of paraquat on the glutathione metabolism in lungs"Proceedings of Int.Assoc.Forensic Sci. (UCLA, CA). 258-259 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] J.Adachi,M.Tomita et al.: "7-Hydroxycholesterol as a marker of oxidative stress in rat kidney induced by paraquat"Free Rad.Res. 33. 321-327 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] W.Xu,S.Humphries,M.Tomita et al.: "Survey of the allelic frequency of a NOS2A promoter microsatellite in human populations ; Assessment of the NOS2A gene and predisposition to infectious disease."Nitric Oxide. 4. 379-383 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] M.Tomita et al.: "The role of nitric oxide in paraquat-induced cytotoxicity in the human A549 lung carcinoma cell line."Free Rad.Res. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tomita, M, Okuyama, T and Hidaka, K.: "Changes in mRNAs of inducible nitric oxide synthase and interleukin-1 b in the liver, kidney and lung tissues of rats acutely exposed to paraquat."Legal Med.. 1. 127-134 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tomita, M.and Okuyama, T.: "Enhancement of DNA fragmentation in PC12 cells by methamphetamine under serum-free conditions."Res. Pract. Forens. Med.. 42. 75-79 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tomita, M.and Okuyama, T.: "Does paraquat affect the mRNA expression for nitric oxide synthase and cytokines ?"Proceeding of 6th Indo Pacific Congresson Legal Medicine and Forensic Sciences. 812-815 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tomita, M.: "Effect of paraquat on the glutathione metabolism in lungs."Proceeding of the 15 Int. Assoc. Forens. Sci.. 258-259 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Xu, W., Humphries, S.Tomita, M.et al.: "Survey of the allelic frequency of a NOS2A promoter microsatellite in human populations ; Assessment of the NOS2A gene and predisposition to infectious disease."Nitric Oxide. 4. 379-383 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Adachi, J., Tomita, M., Yamakawa, S., Asano, M., Naito, T.Ueno, Y.: "7-Hydroperoxycholesterol as a marker of oxidative stress in rat kidney induced by paraquat."Free Rad. Res.. 33. 321-327 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tomita, M., Okuyama, T., Nishimatsu, S., Ishikawa, T.and Nohno, T.: "Differential gene expression in rat lungs exposed to paraquat."Abst. of 10th Biennial Meeting of the Society for Free Radical Research International (SFRRI). 148 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tomita, M., Okuyama, T., Hidaka, K., Ishikawa, T.and Adachi, J.: "Changes in glutathione level and gene expression for defense system against oxidative stress by paraquat."Abst. of 10th Biennial Meeting of SFRRI. 184 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tomita, M., Okuyama, T., Ishikawa, T., Hidaka, K.and Nohno, T.: "The role of nitric oxide in paraquat-induced cytotoxicity in the human A549 lung carcinom a cell line."Free Rad. Res.. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] J.Adachi,M.Tomita et al.: "7-Hydroxycholesterol as a marker of oxidative stress in rat kidney induced by paraquat"Free Rad.Res. 33・. 321-327 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] W.Xu,S.Humphries,M.Tomita et al.: "Survey of the allelic frequency of a NOS2A promoter microsatellite in human populations ; Assessment of the NOS2A gene and predisposition to infectious disease."Nitric Oxide. 4・. 379-383 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] M.Tomita et al.: "Differential gene expression in rat lungs exposed to paraquat"Abstract of 10th Meeting of SFRRI. 148-148 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] M.Tomita et al.: "Changes in glutathione leveland gene expression for defense system against oxidative stress by paraquat"Abstract of 10th Meeting of SFRRI. 184-184 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] M.Tomita et al.: "The role of nitric oxide in paraquat-induced cytotoxicity in the human A549 lung carcinoma cell line."Free Rad.Res. (印刷中).

    • Related Report
      2000 Annual Research Report
  • [Publications] K.Hidaka,Y.Watanabe,M.Tomita et al.: "Gene analysis of genomic DNA from stored serum by polymerase chain reaction : identification of three missense mutations in patients with cholinesterasemia and ABO genotyping."Clinica Chimica Acta. (印刷中).

    • Related Report
      2000 Annual Research Report
  • [Publications] M.TOMITA et al.: "Changes in mRNAs of inducible nitric oxide synthase and interleukin-1b in the liver,kidney and lung tissues of rats acutely exposed to paraquat"Legal Medicine. 1・3. 127-134 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] M.TOMITA et al.: "Enhancement of DNA fragmentation in PC12 cells by methamphetamine under serumfree conditions"Res.Pract.Forens.Med.. 42. 75-79 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] J.ADACHI,M.TOMITA et al.: "7-Hydroxycholesterol as a marker of oxidative stress in rat kidney induced by paraquat"Free Rad.Res. (印刷中). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Masafumi TOMITA: "Effect of paraquat on the glutathione metabolism in lungs"Proceedings of Int.Assoc.Forensic Sci.(UCLA,CA). 258-259 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 富田正文: "ラットでのパラコートによる酸化ストレスとグルタチオン代謝"日本法医学雑誌. 53・1. 99-99 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 富田正文,奥山敏子: "パラコート毒性と細胞内グルタチオンレベル"過酸化脂質研究. 23・1. 59-59 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Masafumi TOMITA: "Amplification of nitric oxide(NO)biosynthesis by paraquat in cytokine-stimulated A549 cells." Proceeding of 14th Meeting Int.Assoc.Forensic Sci.183-185 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] 富田正文: "急性パラコート中毒とグルタチオン代謝" 過酸化脂質研究. 22. 41-41 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 富田正文: "ラットiNOSmRNA発現にたいするパラコートの影響について" 日本法医学雑誌. 52. 113-114 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 富田正文: "パラコートによるNO合成酵素およびサイトカインのmRNA発現に及ぼす影響について(1)" 日本法医学雑誌. 52・suppl. 81-81 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Masafumi TOMITA: "Does paraquat affect the mRNA expression for nitric oxide synthase and cytokines?" Proceeding of 6th Indo Pacific Congress on Legal Medicine and Forensic Sciences. 812-815 (1999)

    • Related Report
      1998 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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