1999 年度実績報告書

ストレス応答系の人為的修飾と生体防御反応への積極的介入に関する研究 ―分子生物学的ストレス応答における薬理学的調整法の実用化に向けて―

研究課題

研究課題/領域番号	10557120
研究機関	京都大学
研究代表者	山本雄造京都大学, 大学院・医学研究科, 講師 (70281730)
研究分担者	森本泰介京都大学, 大学院・医学研究科, 講師 (60135910) 福本学東北大学, 加齢研究所, 教授 (60156809) 山岡義生京都大学, 大学院・医学研究科, 教授 (90089102) 桶谷清エーザイ株式会社, 薬物評価研究所, 研究員山本成尚京都大学, 大学院・医学研究科, 助手 (30253298)
キーワード	Geranylgeranylacetone / 熱ショック蛋白 / 分子シャペロン / プレコンデショニング / 虚血再潅流障害 / 虚血耐性 / シャペロン誘導剤 / 薬理学的修飾
研究概要	本研究はStress応答を薬剤で修飾しその効率化を図ることが目的でった。その薬剤として期待されるものはDoxorubicinとGeranylgeranylacetoneの2剤であった。その他、Herbimycin A,Futhan,DCIC,Sulindacの効果も検討したが、肝のPreconditioningという面では期待した効果を確認できなかった。 Doxorubicinについては静脈全身投与後48時間で肝内にHSP72,HSP73を誘導することができ、虚血耐性も熱ショックPreconditioningに劣らない効果を確認した。Geranylgeranylacetoneは経口投与が可能であり、それ自身HSP72を肝内に誘導することはなかったが、熱ショックPreconditioningによる負担を軽減するという意味では、HSP72を誘導するために必要な時間を短縮し、熱ショックストレスによる効果を増強することが可能であった。残念ながら、熱ショックストレスの温度閾値をさげることはできなかった。今回の研究の結果から考察すると、薬剤そのものでPreconditioningを行えたDoxorubicinはその抗癌剤としての作用を減弱する方向に発展させることで、また、Geranylgeranylacetoneは熱ショック以外のStressorとでもPreconditioningを増強できるかどうか等を検討してゆくことで、臨床応用可能な薬剤開発に期待できる。肝再生におけるHSPの働きに関しては再生時におけるHSP72,HSP47,3型コラーゲン、デスミンの発現をmRNAレベルで検討をおこなった。この結果、HSP72とデスミンは肝切後18時間で、HSP47は48時間で、3型コラーゲンは96時間で増加し、その後次第に減少することが判明した。これらの動きをさらにどのように修飾すれば肝再生をさらに促進できるかの検討は今後に持ち越された。

研究成果
(33件)

すべてその他

すべて文献書誌 (33件)

[文献書誌] Yamamoto Y.: "Implication of heat shock proteins in liver surgery and liver perfusion"Recent Res Can Res. 147. 157-172 (1998)
[文献書誌] Yamamoto Y.: "Induction of heat shock response: Effect on the rat liver with carbon tetrachloride-induced fibrosis from ischemia-reperfusion injury"World J. Surg. 22. 464-469 (1998)
[文献書誌] Yamamoto Y.: "Heat shock preconditioning ameliorates liver injury following normothermic ischemia-reperfusion in stratotic rat livers"J Surg Res. 79. 47-53 (1998)
[文献書誌] Yamamoto Y.: "Pharmacological stimulation of adenosine A2 receptor supplants ischemic preconditioning in providing ischemic tolerance in rat livers"Surgery. 126. 945-954 (1999)
[文献書誌] Yamamoto Y.: "New simple technique for hepatic parenchymal resection using a cavitron ultrasonic surgical aspirator and bipolar cautery equipped with a channel for water dripping"World J Surg. 23. 1032-1037 (1999)
[文献書誌] Yamamoto Y.: "Heat shock preconditioning on mitochondria during warm ischemia in rat livers"J Surg Res. 87. 178-184 (1999)
[文献書誌] Yamamoto Y.: "The augumentative effects of repeated heat shock preconditioning on the production of heat shock protein 72 and on ischemic tolerance in rat liver tissue"Int J Hyperthermia. (in press).
[文献書誌] Yamamoto Y.: "Heat shock preconditioning reduces oxidative protein denaturation and ameliorates liver injury by carbon tetrachloride in rats"Res Exq Med. (in press).
[文献書誌] Yamamoto Y.: "Adenosine (A2) receptor stimulation protects the predamaged livers from cold preservation through activation of cAMP-protein kinase A pathway"Liver Transplant Surg. (in press).
[文献書誌] Yamamoto Y.: "The effects of geranyl-geranyl-acetone administration prior to heat shock preconditioning for conferring tolerance against ischemia-reperfusion injury in rat livers"J Labo Clin Med. (in press).
[文献書誌] Yamamoto Y.: "Formation of 8-hydroxy-2ユ-deoxyguanosine and 4-hydroxy-2-nonenal-modified proteins in rat liver after ischemia-reperfusion: Distinct localization of the two oxidatively modified products"Antiox Redox Signal. (in press).
[文献書誌] Yamamoto Y.: "Different response of tissue adenosine metabolism upon reperfusion period after short and long term ischemia in rat liver"Eur Surg Res. 30 suppl 1. 120-121 (1998)
[文献書誌] Yamamoto Y.: "Modified adenosine kinetics by ischemic preconditioning affects energy metabolism upon ischemia-reperfusion injury of the rat liver"Eur Surg Res. 30 suppl 1. 121-122 (1998)
[文献書誌] Yamamoto Y.: "Adenosine and Adenine nucleotide metabolisms in rat liver tissue after ischemia and reperfusion"Degestion. 59. 62 (1998)
[文献書誌] Yamamoto Y.: "Role of reduced Glutathione pool in acquiring ischemic tolerance of the liver"Digestion. 59. 65 (1998)
[文献書誌] Yamamoto Y.: "Geranyl-geranyl-acetone enhances HSP72 induction by heat shock pretreatment to increase tolerance against ischemia-reperfusion injury in rat livers"Digestion. 59. 62 (1998)
[文献書誌] Yamamoto Y.: "Augumentation of ischemic tolerance of rat liver by the repetition of heat shock preconditioning"Digestion. 59. 61 (1998)
[文献書誌] Yamamoto Y.: "Tissue response in Adenosine metabolism under hepatic ischemia and reperfusion, in relation to the effect of ischemic preconditioning of rat liver"Dig Surg. 15. 563 (1998)
[文献書誌] Yamamoto Y.: "Reduced Glutathione pool plays no major role in the ischemic tolerance of the rat liver induced by heat shock treatment"Dig Surg. 15. 565 (1998)
[文献書誌] Yamamoto Y.: "Geranyl-geranyl-acetone decreased thermal stress necessary to induce HSP72 by heat shock pretreatrment in rat livers"Dig Surg. 15. 502 (1998)
[文献書誌] Yamamoto Y.: "Impact of repetitive heat shock pretreatment of rats on the histomorphological distribution of HSP72 and ischemic tolerance of the liver"Dig Surg. 15. 548 (1998)
[文献書誌] Yamamoto Y.: "The effect of ischemic preconditioning on the liver is mediated by Adenosine A2 receptor"Dig Surg. 15. 563 (1998)
[文献書誌] Yamamoto Y.: "Stress preconditioning of the intestine ameliorates liver injury induced by Pringle's mneuver"Dig Surg. 15. 543 (1998)
[文献書誌] Yamamoto Y.: "Geranyl-geranyl-acetone abates time requirment of thermal preconditioning for triggering heat shock response and ischemic tolerance in rat-liver"Hepatology. 28. 627A (1998)
[文献書誌] Yamamoto Y.: "Tissue expression of heat shock protein (HSP) 72 and hemeoxygenase-1 (HSP32) after heat xhock and ischemic preconditionings of rat livers"Eur Surg Res. 31 suppl. 182 (1999)
[文献書誌] Yamamoto Y.: "Heat xhock pretreatment suppressed TNF-α production in the liver during reperfusion after ischemia"Eur Surg Res. 31 suppl 1. 65-66 (1999)
[文献書誌] Yamamoto Y.: "Heat shock preconditioning suppresses the translocation of NF-kB to the nucleus during ischemia-reperfusion injury of the rat livers by protecting I-kB degradation"Hepatology. 30. 227A (1999)
[文献書誌] Yamamoto Y.: "Suppression of Tumor Necrosis Factor Alpha induced by heat shock preconditioning ameliorated hepatic ischemia reperfusion injury"Hepatology. 30. 227A (1999)
[文献書誌] Yamamoto Y.: "Stimulation of adenosine A2 receptor reproduces ischemic tolerance after preconditioning in rat liver"Hepatology. 30. 311A (1999)
[文献書誌] 山本雄造: "肝切除術における体外血流シャントの必要性とその適応"日本肝胆膵外科関連会議・徳島合同プログラム. 85 (1999)
[文献書誌] 山本雄造: "消化器外科と Heat Shock Protein: 肝組織の Preconditioning"日本ハイパーサーミア学会誌. 15. 34-35 (1999)
[文献書誌] 山本雄造: "ストレス応答誘発による肝の虚血耐性獲得"生化学学会誌. 71. 683 (1999)
[文献書誌] 山本雄造: "臨床侵襲学 ◇臨床に生かす侵襲学のすべて◇"小川道雄、斎藤英昭. 680 (1998)

1999 年度 実績報告書

ストレス応答系の人為的修飾と生体防御反応への積極的介入に関する研究 ―分子生物学的ストレス応答における薬理学的調整法の実用化に向けて―

研究代表者

山本 雄造 京都大学, 大学院・医学研究科, 講師 (70281730)

研究成果

[文献書誌] Yamamoto Y.: "Implication of heat shock proteins in liver surgery and liver perfusion"Recent Res Can Res. 147. 157-172 (1998)

[文献書誌] Yamamoto Y.: "Induction of heat shock response: Effect on the rat liver with carbon tetrachloride-induced fibrosis from ischemia-reperfusion injury"World J. Surg. 22. 464-469 (1998)

[文献書誌] Yamamoto Y.: "Heat shock preconditioning ameliorates liver injury following normothermic ischemia-reperfusion in stratotic rat livers"J Surg Res. 79. 47-53 (1998)

[文献書誌] Yamamoto Y.: "Pharmacological stimulation of adenosine A2 receptor supplants ischemic preconditioning in providing ischemic tolerance in rat livers"Surgery. 126. 945-954 (1999)

[文献書誌] Yamamoto Y.: "New simple technique for hepatic parenchymal resection using a cavitron ultrasonic surgical aspirator and bipolar cautery equipped with a channel for water dripping"World J Surg. 23. 1032-1037 (1999)

[文献書誌] Yamamoto Y.: "Heat shock preconditioning on mitochondria during warm ischemia in rat livers"J Surg Res. 87. 178-184 (1999)

[文献書誌] Yamamoto Y.: "The augumentative effects of repeated heat shock preconditioning on the production of heat shock protein 72 and on ischemic tolerance in rat liver tissue"Int J Hyperthermia. (in press).

[文献書誌] Yamamoto Y.: "Heat shock preconditioning reduces oxidative protein denaturation and ameliorates liver injury by carbon tetrachloride in rats"Res Exq Med. (in press).

[文献書誌] Yamamoto Y.: "Adenosine (A2) receptor stimulation protects the predamaged livers from cold preservation through activation of cAMP-protein kinase A pathway"Liver Transplant Surg. (in press).

[文献書誌] Yamamoto Y.: "The effects of geranyl-geranyl-acetone administration prior to heat shock preconditioning for conferring tolerance against ischemia-reperfusion injury in rat livers"J Labo Clin Med. (in press).

[文献書誌] Yamamoto Y.: "Formation of 8-hydroxy-2ユ-deoxyguanosine and 4-hydroxy-2-nonenal-modified proteins in rat liver after ischemia-reperfusion: Distinct localization of the two oxidatively modified products"Antiox Redox Signal. (in press).

[文献書誌] Yamamoto Y.: "Different response of tissue adenosine metabolism upon reperfusion period after short and long term ischemia in rat liver"Eur Surg Res. 30 suppl 1. 120-121 (1998)

[文献書誌] Yamamoto Y.: "Modified adenosine kinetics by ischemic preconditioning affects energy metabolism upon ischemia-reperfusion injury of the rat liver"Eur Surg Res. 30 suppl 1. 121-122 (1998)

[文献書誌] Yamamoto Y.: "Adenosine and Adenine nucleotide metabolisms in rat liver tissue after ischemia and reperfusion"Degestion. 59. 62 (1998)

[文献書誌] Yamamoto Y.: "Role of reduced Glutathione pool in acquiring ischemic tolerance of the liver"Digestion. 59. 65 (1998)

[文献書誌] Yamamoto Y.: "Geranyl-geranyl-acetone enhances HSP72 induction by heat shock pretreatment to increase tolerance against ischemia-reperfusion injury in rat livers"Digestion. 59. 62 (1998)

[文献書誌] Yamamoto Y.: "Augumentation of ischemic tolerance of rat liver by the repetition of heat shock preconditioning"Digestion. 59. 61 (1998)

[文献書誌] Yamamoto Y.: "Tissue response in Adenosine metabolism under hepatic ischemia and reperfusion, in relation to the effect of ischemic preconditioning of rat liver"Dig Surg. 15. 563 (1998)

[文献書誌] Yamamoto Y.: "Reduced Glutathione pool plays no major role in the ischemic tolerance of the rat liver induced by heat shock treatment"Dig Surg. 15. 565 (1998)

[文献書誌] Yamamoto Y.: "Geranyl-geranyl-acetone decreased thermal stress necessary to induce HSP72 by heat shock pretreatrment in rat livers"Dig Surg. 15. 502 (1998)

[文献書誌] Yamamoto Y.: "Impact of repetitive heat shock pretreatment of rats on the histomorphological distribution of HSP72 and ischemic tolerance of the liver"Dig Surg. 15. 548 (1998)

[文献書誌] Yamamoto Y.: "The effect of ischemic preconditioning on the liver is mediated by Adenosine A2 receptor"Dig Surg. 15. 563 (1998)

[文献書誌] Yamamoto Y.: "Stress preconditioning of the intestine ameliorates liver injury induced by Pringle's mneuver"Dig Surg. 15. 543 (1998)

[文献書誌] Yamamoto Y.: "Geranyl-geranyl-acetone abates time requirment of thermal preconditioning for triggering heat shock response and ischemic tolerance in rat-liver"Hepatology. 28. 627A (1998)

[文献書誌] Yamamoto Y.: "Tissue expression of heat shock protein (HSP) 72 and hemeoxygenase-1 (HSP32) after heat xhock and ischemic preconditionings of rat livers"Eur Surg Res. 31 suppl. 182 (1999)

[文献書誌] Yamamoto Y.: "Heat xhock pretreatment suppressed TNF-α production in the liver during reperfusion after ischemia"Eur Surg Res. 31 suppl 1. 65-66 (1999)

[文献書誌] Yamamoto Y.: "Heat shock preconditioning suppresses the translocation of NF-kB to the nucleus during ischemia-reperfusion injury of the rat livers by protecting I-kB degradation"Hepatology. 30. 227A (1999)

[文献書誌] Yamamoto Y.: "Suppression of Tumor Necrosis Factor Alpha induced by heat shock preconditioning ameliorated hepatic ischemia reperfusion injury"Hepatology. 30. 227A (1999)

[文献書誌] Yamamoto Y.: "Stimulation of adenosine A2 receptor reproduces ischemic tolerance after preconditioning in rat liver"Hepatology. 30. 311A (1999)

[文献書誌] 山本雄造: "肝切除術における体外血流シャントの必要性とその適応"日本肝胆膵外科関連会議・徳島合同プログラム. 85 (1999)

[文献書誌] 山本雄造: "消化器外科と Heat Shock Protein: 肝組織の Preconditioning"日本ハイパーサーミア学会誌. 15. 34-35 (1999)

[文献書誌] 山本雄造: "ストレス応答誘発による肝の虚血耐性獲得"生化学学会誌. 71. 683 (1999)

[文献書誌] 山本雄造: "臨床侵襲学 ◇臨床に生かす侵襲学のすべて◇"小川道雄、斎藤英昭. 680 (1998)

1999 年度実績報告書

山本雄造京都大学, 大学院・医学研究科, 講師 (70281730)