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急性膵炎における一酸化窒素(NO)産生とその分子機構に関する研究

Research Project

Project/Area Number 07670556
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionTohoku University

Principal Investigator

下瀬川 徹  東北大学, 医学部・附属病院, 助手 (90226275)

Co-Investigator(Kenkyū-buntansha) 小泉 勝  東北大学, 医学部・附属病院, 講師 (40111281)
Project Period (FY) 1995 – 1996
Project Status Completed (Fiscal Year 1996)
Budget Amount *help
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1996: ¥200,000 (Direct Cost: ¥200,000)
Fiscal Year 1995: ¥1,900,000 (Direct Cost: ¥1,900,000)
Keywords重症急性膵炎 / 誘導型NO合成酵素 / 分子機序 / NF-KB / IRF-1 / 卓球・マクロファージ / 治療 / 急性膵炎 / 重症化機序 / Nitric Oxide / NF-κB / 転写調節因子 / サイトカイン / 重症化 / NO
Research Abstract

膵炎の進展過程における一酸化窒素(Nitric Oxide:NO)産生とNO合成酵素(NO synthase:NOS)誘導の分子機序をを検討した。重症壊死性膵炎モデルであるラットラウロコール酸(taurocholate:TCA)膵炎と、軽症浮腫性膵炎モデルであるラットセルレイン(caerulein:CAE)膵炎を用いてNO産生を比較した。NO産生の指標として血清NO代謝産物(NOx)濃度を測定し、誘導型NO合成酵素(inducible NOS:iNOS)の免疫活性とmRNA発現、転写調節因子nuclear factor-μB(NF-μB)、interferon-γ responsive factor-1(IRF-1)の活性化につして検討した。TCA膵炎モデルではNOxの血清濃度ga上昇し、iNOSmRNAとiNOS活性が発現していた。一方、CAE膵炎モデルでは血清NOx濃度の上昇は認められず、腹腔マクロファージ(Mφ)にもiNOS活性は発現しなかった。しかし、TCT膵炎とCAE膵炎両者の腹腔MφにおいてNF-μB、IRF-1活性化とiNOSmRNAの増加が観察され、CAE膵炎ラットから分離した腹腔MφのLPSに対するNO産生応答は、膵炎非誘導ラットのMφに比べ亢進していた。NOS阻害剤、IFNγ中和抗体、NF-μB活性化阻害剤の投与はいずれもTCA膵炎におけるNO産生亢進を抑制し、IFN-γ中和抗体ならびにNF-μB活性化阻害剤は生存率を著名に改善した。また、PLA2阻害剤IS-741はTCA膵炎ラット腹腔MφのNF-μB活性化を抑制し、この致死性膵炎を軽減した。ヒト膵静脈培養細胞系HUVECを用いたin vitroの検討ではTCA膵炎腹水と血清、ならびに重症急性膵炎患者血清が、HUVECに接着分子ICAM-1とVCAM-1を同様の機序で誘導する結果を得た。以上より、重症急性膵炎では腹腔Mφを中心とする炎症細胞が強い活性化を受け、これらがNOを始めとするmediatorやeffectorを産生し、全身を循環することによって多臓器障害を惹起する機序が想定された。このような活性化機序を阻止することにより重症膵炎時の全身合併症を予防し死亡率を低下させる治療法の可能性が示された。

Report

(3 results)
  • 1996 Annual Research Report   Final Research Report Summary
  • 1995 Annual Research Report
  • Research Products

    (23 results)

All Other

All Publications (23 results)

  • [Publications] 下瀬川徹: "Transgenic copper/zinc-superoxrde dismutase analiorates caerulein-induced paucreutitis in mice"Biochem.Biophys.Res.Commun. 233. 177-181 (1997)

    • Related Report
      1996 Final Research Report Summary
  • [Publications] 下瀬川徹: "Gallbladcler emptymg,cholecystokinin and pancreatic polypeptide responses to a liquid meal in diabetic patients"J.Gastroenterology. 32. 628-634 (1997)

    • Related Report
      1996 Final Research Report Summary
  • [Publications] 下瀬川徹: "The role of pituitary-adrenal counterrezulation of inflammation in cerulein-induced pancreatitis"Pancreas. 12. 280-285 (1996)

    • Related Report
      1996 Final Research Report Summary
  • [Publications] 下瀬川徹: "The role of nitric oxide in mouse cerulein-induced pancreatitis with and without lipopolysaccharyle pretreatment"Pancreas. 12. 68-75 (1996)

    • Related Report
      1996 Final Research Report Summary
  • [Publications] 下瀬川徹: "Effects of ethanol on meal-stimulated secretion of pancreatic polyoeptide and cholecystokinin"J.Gastroenterology. 31. 86-93 (1996)

    • Related Report
      1996 Final Research Report Summary
  • [Publications] 下瀬川徹: "The role of endogenous glucocrticsids in rat experimentel models of acute pancreatitis"Gastroenterology. 109. 933-943 (1995)

    • Related Report
      1996 Final Research Report Summary
  • [Publications] 下瀬川徹: "消化器疾患とNO-石井裕正 編集"医歯薬出版. 5 (1997)

    • Related Report
      1996 Final Research Report Summary
  • [Publications] 下瀬川徹: "NOのすべて-平田結喜緒 編集"医歯薬出版. 6 (1996)

    • Related Report
      1996 Final Research Report Summary
  • [Publications] 下瀬川 徹: "The role of nitric oxide in mouse cerulein-induced pancreatitis with and without lipopolysaccharide pretreatuient." Paucreas. 12. 68-75 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] 下瀬川 徹: "Transgenic copper/zinc-superoxide dismufuse ameliorates caerulein-induced paucreatitis in mice." Biochem. Biophys. Res. Commun.(in press). (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] 下瀬川 徹: "The role of pituitary-adrenal counterregulation of inflamnation in cerulein-induced paucreatitis: A comparison between Fischer and Lewis rats." Paucreas. 12. 280-285 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] 下瀬川 徹: "Lipopolysaccharide induces manganese superoxide dismufase in the rat paucreas: Its role in caerulein paucreatitis." Biochem. Biophys. Res. Commun.217. 1216-1222 (1995)

    • Related Report
      1996 Annual Research Report
  • [Publications] 下瀬川 徹: "The role of endogenous glucocorticoids in rat expan mental models of acute pancreatitis." Gastroenterology. 109. 933-943 (1995)

    • Related Report
      1996 Annual Research Report
  • [Publications] 下瀬川 徹: "Nitric Oxide modulates paucreatic edema formation in rat caeruleiu-induced poucreatitis." J. Gastroenterol.30. 636-642 (1995)

    • Related Report
      1996 Annual Research Report
  • [Publications] 下瀬川 徹: "消化器疾患とNO.-石井裕正 編集" 医歯薬出版, 5 (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] 下瀬川 徹: "NOのすべて-平田 結喜緒 編集" 医歯薬出版, 6 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] 下瀬川徹: "The role of nitric oxide in mouse caerulein-induced pancreatitis with and without lipopolysaccharide-pretreatment." Pancreas. 12. 68-75 (1996)

    • Related Report
      1995 Annual Research Report
  • [Publications] 下瀬川徹: "Nitric oxide modulates pancreatic Edema formation in the rat caerulein-induced pancreatitis." J. Gastroenterol. 30. 636-642 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] 下瀬川徹: "NADPH-diaphorase activity, a marker for NO synthase, in neurons of the guinea-pig respiratory tract." Am Rev Respir Dis. 150. 1402-1410 (1994)

    • Related Report
      1995 Annual Research Report
  • [Publications] 下瀬川徹: "NADPH-diaphorase activity in neurons of the mammalian pancreas :coexpression with VIP." Gastroenterology. 105. 999-1008 (1993)

    • Related Report
      1995 Annual Research Report
  • [Publications] 下瀬川徹: "Neurons containing gastrin releasing peptide-like immunoreactivity in the human pancreas." Pancreas. 8. 403-412 (1993)

    • Related Report
      1995 Annual Research Report
  • [Publications] 下瀬川徹: "Role of nitric oxide in the pancreatic blood flow : Response to caerulein." Pancreas. 9. 574-579 (1994)

    • Related Report
      1995 Annual Research Report
  • [Publications] 下瀬川徹: "NOと病態・治療:糖尿病とNO" メジカルビュー社, 96-107 (1995)

    • Related Report
      1995 Annual Research Report

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Published: 1995-04-01   Modified: 2016-04-21  

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