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Exploratory study on drugs for regulation of uterine cervical ripening based on the biochemical analysis of extracellular matrix metabolism in the uterine cervix

Research Project

Project/Area Number 13557139
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Obstetrics and gynecology
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

SAGAWA Norimasa  Kyoto University, Graduate School of Medicine, Associate Professor, 医学研究科, 助教授 (00162321)

Co-Investigator(Kenkyū-buntansha) HIROTA Naoyoshi  Nippon Organon K.K., Res & Develop Division, Head, 医薬研究所, 研究開発管理室長
KARIYA Masatoshi  Kyoto University, Graduate School of Medicine, Lecturer, 医学研究科, 講師 (90243013)
ITOH Hiroaki  Kyoto University, Graduate School of Medicine, Instructor, 医学研究科, 助手 (70263085)
WADA Yukihisa  Nippon Organon K.K., Res & Develop Division, Staff, 医薬研究所, 研究員
Project Period (FY) 2001 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥13,900,000 (Direct Cost: ¥13,900,000)
Fiscal Year 2003: ¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2002: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2001: ¥6,500,000 (Direct Cost: ¥6,500,000)
Keywordscervical softening / uterine cervical fibroblast / chemokine / neutrophil / monocyte / cyclic stretch / matrix metalloproteinase-1 / prostaglandin / 子宮頸部線維維芽細胞 / IL-8 / MCP-3 / 子宮頚部線維芽細胞 / ヒアルロン酸 / ヒアルロン酸合成酵素 / ヒアルロン酸受容体 / interleukin-1 / CD44 / 子宮頸部熱化 / matrix metalloproteinase / prostadlandin / 一酸化窒素 / interleukin-8
Research Abstract

The matrix metalloproteinases (MMPs) mediated degradation of collagen fibril is thought to be one of key events in the complicated process of cervical ripening. In this study, we investigated the expression of MMP-1, 2, 9 as well as inducible and endothelial nitric oxide synthase (iNOS and eNOS) in the human uterine cervix and the possible effect of PGF2α, IL-1αand nitric oxide on MMPs production from cultured human uterine cervical fibroblast (CxF) cells. The present study suggested that PGF2α, IL-1α, and nitric oxide contribute to the process of cervical ripening via enhancement of MMP-1 production.
During active labor, cervical tissue is distended by presenting part of the fetus. In this study, we investigated the effects of cyclic mechanical stretch on the production of MMP-1, 2, 9 from cultured human uterine cervical fibroblast cells. Cyclic mechanical stretch specifically enhanced the mRNA expressions and secretion of MMP-1. The present study suggested that mechanical stretch cont … More ribute to the process of cervical ripening via enhancement of MMP-1 production.
Leukocyte infiltration into the cervix is also a characteristic feature of parturition. In the present study, we examined the effect of cyclic mechanical stretch on secretion of chemokines (IL-8 and MCP-3) from cultured human uterine cervical fibroblast (CxF) cells. IL-8 and MCP-3 proteins and mRNAs were all detected n the human uterine cervices. These substances were positively stained in cervical stromal cells. The IL-8 and MCP-3 mRNA expression in the CxF cells significantly increased to approximately 8 and 3-folds after stimulation with cyclic mechanical stretch for 12 hours, respectively, (both P<0.005). IL-8 and MCP-3 levels in the culture medium of CxF cells after cyclic mechanical stretch for 24 hours were significantl,higher. than those without the stimulation (both P<0.005). Such enhancement of IL-8 and MCP-3 secretion by cyclic mechanical stretch was significantly inhibited by co-treatment with curcumin, an AP-1 inhibitor.
Cyclic mechanical stretch by fetal presenting part during labor may initiate or facilitate cervical ripening through augmentation of production of IL-8 and MCP-3 followed by infiltration of neutrophils and monocyte/macrophage in the uterine cervix. Less

Report

(4 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • Research Products

    (35 results)

All Other

All Publications (35 results)

  • [Publications] Masahiro Yoshida, Norimasa Sagawa, et al.: "Nitric oxide increases matrix metalloproteinase-1 production in human uterine cervical fibroblast cells-Nitric oxide as a possible mediator of uterine cervical ripening-"Molecular Human Reproduction. 7. 979-985 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Masahiro Yoshida, Norimasa Sagawa, et al.: "Prostaglandin F_<2α>, cytokines, and cyclic mechanical stretch augment matrix metalloproteinase-1 secretion from cultured human uterine cervical fibroblast cells."Molecular Human Reproduction. 8. 681-687 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Daizo Korita, Norimasa Sagawa, et al.: "Cyclic Mechanical Stretch Augments Prostacyclin Production in Cultured Human Uterine Myometrial Cells from Pregnant Women : Possible Involvement of Up-regulation of Prostacyclin Synthase Expression"The Journal of Clinical Endocrinology & Metabolism. 87. 5209-5219 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shigeo Yura, Norimasa Sagawa, et al.: "Rsistin Is Expressed in the Human Placenta."The Journal of Clinical Endocrinology & Metabolism. 88. 1394-1397 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kazuyo Kakui, Hiroaki Itoh, et al.: "Augmented endothelial nitric oxide synthase (eNOS) protein expression in human pregnant myometrium : Possdible involvement of eNOS promoter activation by estrogen via both ERα and ERβ."Molecular Human Reproduction. 10. 115-122 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Maki Takemura, Hiroaki Itoh, et al.: "Cyclic mechanical stretch augment both interleukin-8 and monocyte chemotactic protein-3 production from cultured human uterine cervical fibroblast cells."Molecular Human Reproduction. (in press). (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Norimasa Sagawa, Shigeo Yura, et al.: "Role of Leptin in Pregnancy-A Review. Trophoblast Research"Eds.K.Shiverick, I.Cetin, A.M.Marconi, C.Sibley, WB saunders. 164(80-86) (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Masahiro Yoshida, Norimasa Sagawa, et al.: "Nitric oxide increases matrix metalloproteinase-1 production in human uterine cervical fibroblast cells -Nitric oxide as a possible mediator of uterine cervical ripening-"Molecular Human Reproduction. Vol.7. 979-985 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Masahiro Yoshida, Norimasa Sagawa, et al.: "Prostaglandin F_<2α>, cytokines, and cyclic mechanical stretch augment matrix metalloproteinase-1 secretion from cultured human uterine cervical fibroblast cells."Molecular Human Reproduction. Vol.8. 681-687 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Daizo Korita, Norimasa Sagawa, et al.: "Cyclic Mechanical Stretch Augments Prostacyclin Production in Cultured Human Uterine Myometrial Cells from Pregnant Women : Possible Involvement of Up-regulation of Prostacyclin Synthase Expression"The Journal of Clinical Endocrinology & Metabolism. Vol.87. 5209-5219 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shigeo Yura, Norimasa Sagawa, et al.: "Rsistin Is Expressed in the Human Placenta."The Journal of Clinical Endocrinology & Metabolism. Vol.88. 1394-1397 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kazuyo Kakui, Hiroaki Itoh, et al.: "Augmented endothelial nitric oxide synthase (eNOS) protein expression in human pregnant myometrium : Possdible involvement of eNOS promoter activation by estrogen via both ERα and ERβ."Molecular Human Reproduction. Vol.10. 115-122 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Maki Takemura, Hiroaki Itoh, et al.: "Cyclic mechanical stretch augment both interleukin-8 and monocyte chemotactic protein-3 production from cultured human uterine cervical fibroblast cells."Molecular Human Reproduction. (in press). (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Norimasa Sagawa, Shigeo Yura, et al.: "Role of Leptin in Pregnancy-A Review"Trophoblast Research (Eds.K.Shiverick, I.Cetin, A.M.Marconi, C.Sibley) (WB Saunders). 80-86 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] K Kakui, H Itoh, N Sagawa 他6名: "Augmented eNOS protein expression in human pregnant myometrium : Possible involvement of eNOS promoter activation by estrogen via both ERα and ERβ"Mol Hum Reprod. 10. 115-122 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] D Korita, H Itoh, N Sagawa 他6名: "Cyclic mechanical stretch and interleukin-1α synergistically up-regulate prostacyclin secretion in cultured human uterine myometrial cells"Gynecol Endocrinol. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] MA Nuamah, N Sagawa 他6名: "Significant increase in maternal plasma leptin concentration in induced delivery : A possible contribution of pro-inflammatory cytokines to placental leptin secretion"Endocr J. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] MA Nuamah, N Sagawa 他6名: "Free-to-total leptin ratio in maternal plasma is constant throughout human pregnancy"Endocr J. 50. 421-428 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] K Kakui, N Sagawa 他6名: "Expression of nitric oxide synthase isoforms in the human placenta is not altered by labor"Endocr J. 50. 412-415 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] N Sagawa, S Yura, 他8名: "Possible role of placental leptin in pregnancy -A review-"Endocrine. 19. 65-71 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 佐川 典正: "Annual Review内分泌,代謝"金澤康徳、武谷雄二、関原久彦、山田信博 編集、中外医学社. 304 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Terakawa, H Itoh他5名: "Site-specific Augmentation of Amnion Cyclooxygenase-2 and Decidua Vera Phospholipase-A_2 Expression in Labor : Possible Contribution of Mechanical Stretch and Interleukin-1 to Amnion Prostaglandin Synthesis"J Soc Gynecol Invest. 9. 68-74 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] M Yoshida, N Sagawa他8名: "Cytokines, prostaglandin F_<2a> and mechanical stretch augment matrix metalloproteinase-1 secretion from cultured human uterine cervical fibroblast cells"Mol Hum Reprod. 8. 681-687 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] D Korita, N Sagawa他8名: "Cyclic Mechanical Stretch Augments Prostacyclin Production in Cultured Human Uterine Myometrial Cells from Pregnant Women: Possible Involvement of Up-regulation of Prostacyclin Synthase Expression"J Clin Endocrinol Metab. 87. 5209-5219 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] N Sagawa, S Yura他8名: "Possible Role of Placental Leptin in Pregnancy -A Review-"Endocrine. 19. 65-71 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] N Sagawa, H Itoh他10名: "Role of leptin in pregnancy-a review"Placenta. 23. S80-S86 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] S Yura, N Sagawa他6名: "Resistin Is Expressed in the Human Placenta"J Clin Endocrinol Metab. 88(In press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] 由良茂夫, 佐川典正: "胎児の成長・発達(新女性医学大系29巻):「胎児発育の分子機構」"中山書店(編集:中野仁雄). 154-156 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Takuya Inoue, et al.: "Severe congenital cytomegalovirus infection with fetal hydrops in a cytomegalovirus-seropositive healthy woman"European Journal of Obstetrics & Gynecology and Reproductive Biology. 195. 184-186 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Masahiro Yoshida, et al.: "Nitric oxide increases matrix metalloproteinase-1 production in human uterine cervical fibroblast cells -Nitric oxide as a possible mediator of uterine cervical ripening-"Molecular Human Reproduction. 7. 979-985 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Koichi Terakawa, et al.: "Site-specific Augmentation of Amnion Cyclooxygenase-2 and Decidua Vera Phospholipase-A_2 Expression in Labor : Possible Contribution of Mechanical Stretch and Interleukin-1 to Amnion Prostaglandin Synthesis"Journal of the Society for Gynecologic Investigation. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Norimasa Sagawa, et al.: "Role of Leptin in Pregnancy-A Review-"Trophoblast Research. 23(in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] 佐川 典正: "産婦人科領域におけるレプチンの意義"日本産婦人科学会雑誌. 53・8. 1686-1692 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 佐川 典正: "羊膜の生物学"周産期医学. 31・5. 1007-1014 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Norimasa Sagawa, et al.: "Placental Protein and Fetal Growth In : Proceedings of 12^<th> Fukuoka International Symposium on Perinatal Medicine, (pp. 59-65)"Maternity and Perinatal Care Unit Kyushu University Hospital. 7 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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