1993 年度実績報告書

肝壊死-再生の病態連繋機構に関する研究

研究課題

研究課題/領域番号	04304038
研究機関	岐阜大学
研究代表者	武藤泰敏岐阜大学, 医学部, 教授 (20010069)
研究分担者	沖田極山口大学, 医学部, 教授 (70107738) 鎌田武信大阪大学, 医学部, 教授 (80028399) 和気健二郎東京医科歯科大学, 医学部, 教授 (00046963) 黒川清東京大学, 医学部, 教授 (30167390) 水戸廸郎旭川医科大学, 教授 (60000981)
キーワード	細胞障害性T細胞 / 細胞外マトリックス / HGF / TGF-β / 肝細胞膜 / 肝微小循環 / 接着分子 / IFN-γ
研究概要	1.肝壊死の免疫学的機構:(1)C型肝炎ウイルス(HCV)コア抗原刺激で増殖するTh_1細胞の存在が示されたが、C型慢性肝炎の多くで増殖反応が認められず、免疫応答が抑制されていることが推定された。HCV感染肝細胞のapoptosisの関与を否定する報告がみられた。(2)B型肝炎ウイルス(HBV)transgenic mouseにHBV特異的細胞障害性T細胞(CTL)を静注することによる広範肝壊死はCTLによる肝細胞のapoptosisとその貧食、CTLから産生されるIFN-γによるマクロファージの2段階の活性化によることが明らかにされた。(3)分離肝細胞にIL-1α,TNFα,IFN-γを添加することでICAM-1の発現とT細胞との接着性の増加がみられた。(4)Kupffer細胞と異なるIa陽性細胞は、肝壊死とその終焉過程でDisse腔からグリゾン鞘へ移動し、炎症に関与する細胞の肝内移動経路の存在が示された。2.細胞外マトリックス(ECM):部分切除後の肝再生の極めて早期に、ECM分子の発現増強が起こり、これは肝細胞と伊東細胞の両者が関与している可能性が示された。3.肝細胞増殖因子(HGF)と阻害因子:HGF受容体をコードするc-Met mRNAは肝部分切除後では肝小葉内に散在性に、肝障害ラットでは障害領域周囲の肝細胞に認められた。TGF-β_1 mRNAは、P.acnesとLPS投与マウスではHGF mRNAに先行して発現し、肝切除後と肝壊死後では両者の発現様式が異なることが示された。肝障害により肝細胞膜(PM)に存在する増殖促進活性は低下するが、PMの抑制因子活性は変動しないことが示された。また劇症肝炎剖検肝でのTGF-β_1の局在が検討された。4.肝微小循環動態:肝類洞血流を調節する伊東細胞の収縮、Kupffer細胞の貧食は細胞内Ca^<2+>が関与し、肝再生過程では細胞内Ca^<2+>のoscillationが増殖のシグナルとして重要であることが示された。5.延髄迷走神経背側核、疑核、頚神経節内に多数の肝膵同時支配神経細胞が存在し、正常肝の類洞、肝細胞にはこれと同じ神経ペプチド含有線維の分布がみられた。

研究成果
(44件)

すべてその他

すべて文献書誌 (44件)

[文献書誌] Masahito Nagaki: "Hepatic Injury and Lethal Shock in Galactosamine Sensitized Mice Induces by the Superrantigen Staphylococal Enterotoxin B" Gastroenterology. (in press).
[文献書誌] Fumihiro Asano: "Enhanced Production of Leukotriene B4 by Peripheral Blood Mononuclear Cells in Patients with Fulminant Hepatitis" J Gastroenterol Hepatol. 8. 228-231 (1993)
[文献書誌] Kazuki Ando: "Mechanisms of Class I-Restricted Immunopathology A Transgenic Mouse Model of Fulminant Hepatitis" J Exp Med. 178. 1541-1554 (1993)
[文献書誌] 友田隆: "急性肝不全における血清ジギタリス様物質の動態とその臨床的意義に関する研究" 肝臓. 34. 8-17 (1993)
[文献書誌] 杉山宏: "重症肝炎患者における血清ヒト肝細胞増殖因子(hHGF)の測定とその臨床的意義に関する研究" 肝臓. 34. 493-503 (1993)
[文献書誌] Hiroo Ohnishi: "Natural Killer Cell May Impair Liver Regeneration in Furuminant Hepatic Failure" Gastroenterol Jpn. 28(Suppl4). 40-44 (1993)
[文献書誌] Toshihiro Akaike: "Design of Hepatocyte-specific Extracellular Matrices for Hybrid Artificial Liver" Gastroenterol Jpn. 28(Suppl4). 45-52 (1993)
[文献書誌] 竹下和良: "ホローファイバー型モジュールを用いたコラーゲンゲル内肝細胞高密度潅流培養" 人工肝臓. 22(1). 153-158 (1993)
[文献書誌] Ryuichi Takezawa: "Determination of Mouse Major Asialoglycoprotein Receptor cDNA Sequence" Biochimica et Biophysica Acta. 1172. 220-222 (1993)
[文献書誌] Masahiko Morita: "Enhancement by Inflammatory Cytokines of ICAM-1 Expression on Hepatocytes and T Cell Adhesion" Lymphokine and Cytokines Res. 12. 373 (1993)
[文献書誌] Masahiko Morita: "Infammatory Cytokines Upregulate the ICAM-1 Expression on Primary Cultured Mouse Hepatocytes and T Cell Adhesion" Hepatology. 19 (in press). (1994)
[文献書誌] Kouei Shinzawa: "Mechanisms of Apoptopsis in Primary Cultured Hepatocytes" Cell Structure and Function. (in press).
[文献書誌] Kita H: "HLA B44-Restricted Cytotoxic T Lymphocytes Recognizing an Epitope on Hepatitis C Virus Nucleocapsid Protein" Hepatology. 18. 1039-1044 (1993)
[文献書誌] Kenji Fujiwara: "Stimulation of Liver Growth by Exogenous Human Hepatocyte Growth Factor in Normal and Partially Hepatectomized Rats" Hepatology. 18. 1443-1449 (1993)
[文献書誌] Haruki Yamada: "Humoral Inhibitor of Rat Hepatocyte DNA Synthesis from Patients with Fulminant Hepatic Failure" Hepatology. (in press).
[文献書誌] Masahiro Arai: "Coagulability in the Sinusoid of Orthotopically Transplanted Liver in Rats" Transplantation Proceedings. (in press).
[文献書誌] Miyoko Hirose: "Pertussis Toxin-induced Redistribution of Cortical Actomyosin and Inhibition of Phagocytosis in Rat Kupffer Cells" J.Gastroenterol.Hepatol.8. 348-352 (1993)
[文献書誌] Takashi Ueno: "Partial Characterization of a Rabbit Liver Ca^<2+>-calmodulin" Biochem.Molecul.Biol.Int.29. 1145-1152 (1993)
[文献書誌] Osamu Segawa: "Actin and Myosin Deposition Around Bile Canaliculi" J.Pediatr.Surg.28. 851-856 (1993)
[文献書誌] Nobuhiro Sato: "Gastric Flood Flow in Ulcer Diseases" Scand.J.Gastroent. (in press).
[文献書誌] M.Oshita: "Ethanol-induced Vasoconstriction Causes Focal Hepatocellular Injury in the Isolated Perfused Rat Livers" Hepatology. 16. 1007-1013 (1992)
[文献書誌] K.Ikejima: "Marked Retention of Indocyanine Green and Sulfobromophthalein with Chronic Persistent hepatitis" J.Gastroentel.Hepatology. 8. 489-494 (1993)
[文献書誌] Hoshino: "Expression of the Hepatocyte Growth Factor Receptor in the Regenerating Rat Liver" Cancer Lett. 71. 119-123 (1993)
[文献書誌] Kishiye T: "Cinematographic analysis of in Vitro Movements of Liver-associated Large Granular Lymphocytes of the Rat" Biomedical Research. 14(1). 81-92 (1993)
[文献書誌] Wake K: "Intralobular Heterogeneity of Perisinusoidal Stellate Cells in Porcine Liver" Cell & Tissue Research. 273. 227-237 (1993)
[文献書誌] Lukita-Atmadja: "Granuloma formation in the Liver of Balb/c Mice Intoxicated with Carbon Tetrachloride" Virchows Archiv B Cell Pathology. 64. 247-257 (1993)
[文献書誌] Bhunchet E: "Capillarization and Venularization of Hepatic Sinusoids in Porcine Serum-induced Rat Liver Fibrosis:A Mechanism to Maintain Liver Blood Flow" Hepatology. 18. 1450-1458 (1993)
[文献書誌] 和気健二郎: "肝臓の支配神経" BRAIN and NERVE. 45. 695-702 (1993)
[文献書誌] Shinichi Kakumu: "Effect of Recombinant Human Transforming Growth Factor Beta 1 on Immune Responses in Patients with Chronic Hepatitis B" Liver. 13. 62-68 (1993)
[文献書誌] Shinichi Kakumu: "Interleukin 6 Production by Peripheral Blood Mononuclear Cells in Patients with Chronic Hepatitis B Virus Infection and Primary Biliary,Cirrhosis" Gastroenterol Jpn. 28. 18-24 (1993)
[文献書誌] Eiji Miyoshi: "N-Acetylglucosaminyltransferase III and V Messenger RNA Levels in LEC Rats During Hepatocarcinogenesis" Cancer Research. 53. 3899-3902 (1993)
[文献書誌] Toshifumi Ito: "Expression of the C-met/Hepatocyte Growth Factor Receptor Gene During Rat Liver Regeneration Induced by Carbon Tetrachloride" BBRC. 190. 870-874 (1993)
[文献書誌] Eiji Miyoshi: "Expression of DNA Methyltransferase in LEC Rats During Hepatocarcinogenesis" Carcinogenesis. 14. 603-605 (1993)
[文献書誌] Hideki Hagiwara: "Quantitation Analysis of Hepatitis C Virus RNA in Serum During Interferon Alfa Therapy" Gastroenterology. 104. 877-883 (1993)
[文献書誌] Hideki Hagiwara: "Quantitation of Hepatitis C Virus RNA in Serum of Asymptomatic Blood Donors and Patients with Type C Chronic Liver Disease" Hepatology. 17. 545-550 (1993)
[文献書誌] 小出典男: "肝細胞接着と分化機能発現の関連" 肝臓病の進歩. 19. 1-10 (1993)
[文献書誌] 矢田俊量: "プロテオグリカンと三次元培養" 組織培養. 19. 312-316 (1993)
[文献書誌] Koide N: "Small Dermatan Sulfate/Chondrotin Sulfate Proteoglycans and hepatocyte Spheroids" Tiss Cult Res Commun. 11. 339-344 (1992)
[文献書誌] Kawaguchi M: "Combination of Epidermal Growth Factor and Insulin is Required for Multicellular Spheroid Formation of Rat Hepatocytes in Primary Culture" Acta Medica Okayama. 46. 195-201 (1992)
[文献書誌] 広瀬美代子: "21世紀を目指し羽ばたく消化器病学" 日本医学館, 516 (1993)
[文献書誌] 佐藤信紘: "医学のあゆみ(エンドテリン、NOと消化器疾患…編)" 医歯薬出版 (in press),
[文献書誌] 和気健二郎: "肝障害の診断的アプローチ大久保昭行編" 文光堂(東京), 192 (1993)
[文献書誌] Wake Kenjirou: "Cells of the Hepatic Sinusoid Vol 4" Kupffer Cell Foundation, XXII 612 (1993)
[文献書誌] 小出典男: "人工肝臓「糖鎖工学と医薬品開発」" 薬業時報社, 350 (1993)

1993 年度 実績報告書

肝壊死-再生の病態連繋機構に関する研究

研究代表者

武藤 泰敏 岐阜大学, 医学部, 教授 (20010069)

研究成果

[文献書誌] Masahito Nagaki: "Hepatic Injury and Lethal Shock in Galactosamine Sensitized Mice Induces by the Superrantigen Staphylococal Enterotoxin B" Gastroenterology. (in press).

[文献書誌] Fumihiro Asano: "Enhanced Production of Leukotriene B4 by Peripheral Blood Mononuclear Cells in Patients with Fulminant Hepatitis" J Gastroenterol Hepatol. 8. 228-231 (1993)

[文献書誌] Kazuki Ando: "Mechanisms of Class I-Restricted Immunopathology A Transgenic Mouse Model of Fulminant Hepatitis" J Exp Med. 178. 1541-1554 (1993)

[文献書誌] 友田 隆: "急性肝不全における血清ジギタリス様物質の動態とその臨床的意義に関する研究" 肝臓. 34. 8-17 (1993)

[文献書誌] 杉山 宏: "重症肝炎患者における血清ヒト肝細胞増殖因子(hHGF)の測定とその臨床的意義に関する研究" 肝臓. 34. 493-503 (1993)

[文献書誌] Hiroo Ohnishi: "Natural Killer Cell May Impair Liver Regeneration in Furuminant Hepatic Failure" Gastroenterol Jpn. 28(Suppl4). 40-44 (1993)

[文献書誌] Toshihiro Akaike: "Design of Hepatocyte-specific Extracellular Matrices for Hybrid Artificial Liver" Gastroenterol Jpn. 28(Suppl4). 45-52 (1993)

[文献書誌] 竹下 和良: "ホローファイバー型モジュールを用いたコラーゲンゲル内肝細胞高密度潅流培養" 人工肝臓. 22(1). 153-158 (1993)

[文献書誌] Ryuichi Takezawa: "Determination of Mouse Major Asialoglycoprotein Receptor cDNA Sequence" Biochimica et Biophysica Acta. 1172. 220-222 (1993)

[文献書誌] Masahiko Morita: "Enhancement by Inflammatory Cytokines of ICAM-1 Expression on Hepatocytes and T Cell Adhesion" Lymphokine and Cytokines Res. 12. 373 (1993)

[文献書誌] Masahiko Morita: "Infammatory Cytokines Upregulate the ICAM-1 Expression on Primary Cultured Mouse Hepatocytes and T Cell Adhesion" Hepatology. 19 (in press). (1994)

[文献書誌] Kouei Shinzawa: "Mechanisms of Apoptopsis in Primary Cultured Hepatocytes" Cell Structure and Function. (in press).

[文献書誌] Kita H: "HLA B44-Restricted Cytotoxic T Lymphocytes Recognizing an Epitope on Hepatitis C Virus Nucleocapsid Protein" Hepatology. 18. 1039-1044 (1993)

[文献書誌] Kenji Fujiwara: "Stimulation of Liver Growth by Exogenous Human Hepatocyte Growth Factor in Normal and Partially Hepatectomized Rats" Hepatology. 18. 1443-1449 (1993)

[文献書誌] Haruki Yamada: "Humoral Inhibitor of Rat Hepatocyte DNA Synthesis from Patients with Fulminant Hepatic Failure" Hepatology. (in press).

[文献書誌] Masahiro Arai: "Coagulability in the Sinusoid of Orthotopically Transplanted Liver in Rats" Transplantation Proceedings. (in press).

[文献書誌] Miyoko Hirose: "Pertussis Toxin-induced Redistribution of Cortical Actomyosin and Inhibition of Phagocytosis in Rat Kupffer Cells" J.Gastroenterol.Hepatol.8. 348-352 (1993)

[文献書誌] Takashi Ueno: "Partial Characterization of a Rabbit Liver Ca^<2+>-calmodulin" Biochem.Molecul.Biol.Int.29. 1145-1152 (1993)

[文献書誌] Osamu Segawa: "Actin and Myosin Deposition Around Bile Canaliculi" J.Pediatr.Surg.28. 851-856 (1993)

[文献書誌] Nobuhiro Sato: "Gastric Flood Flow in Ulcer Diseases" Scand.J.Gastroent. (in press).

[文献書誌] M.Oshita: "Ethanol-induced Vasoconstriction Causes Focal Hepatocellular Injury in the Isolated Perfused Rat Livers" Hepatology. 16. 1007-1013 (1992)

[文献書誌] K.Ikejima: "Marked Retention of Indocyanine Green and Sulfobromophthalein with Chronic Persistent hepatitis" J.Gastroentel.Hepatology. 8. 489-494 (1993)

[文献書誌] Hoshino: "Expression of the Hepatocyte Growth Factor Receptor in the Regenerating Rat Liver" Cancer Lett. 71. 119-123 (1993)

[文献書誌] Kishiye T: "Cinematographic analysis of in Vitro Movements of Liver-associated Large Granular Lymphocytes of the Rat" Biomedical Research. 14(1). 81-92 (1993)

[文献書誌] Wake K: "Intralobular Heterogeneity of Perisinusoidal Stellate Cells in Porcine Liver" Cell & Tissue Research. 273. 227-237 (1993)

[文献書誌] Lukita-Atmadja: "Granuloma formation in the Liver of Balb/c Mice Intoxicated with Carbon Tetrachloride" Virchows Archiv B Cell Pathology. 64. 247-257 (1993)

[文献書誌] Bhunchet E: "Capillarization and Venularization of Hepatic Sinusoids in Porcine Serum-induced Rat Liver Fibrosis:A Mechanism to Maintain Liver Blood Flow" Hepatology. 18. 1450-1458 (1993)

[文献書誌] 和気 健二郎: "肝臓の支配神経" BRAIN and NERVE. 45. 695-702 (1993)

[文献書誌] Shinichi Kakumu: "Effect of Recombinant Human Transforming Growth Factor Beta 1 on Immune Responses in Patients with Chronic Hepatitis B" Liver. 13. 62-68 (1993)

[文献書誌] Shinichi Kakumu: "Interleukin 6 Production by Peripheral Blood Mononuclear Cells in Patients with Chronic Hepatitis B Virus Infection and Primary Biliary,Cirrhosis" Gastroenterol Jpn. 28. 18-24 (1993)

[文献書誌] Eiji Miyoshi: "N-Acetylglucosaminyltransferase III and V Messenger RNA Levels in LEC Rats During Hepatocarcinogenesis" Cancer Research. 53. 3899-3902 (1993)

[文献書誌] Toshifumi Ito: "Expression of the C-met/Hepatocyte Growth Factor Receptor Gene During Rat Liver Regeneration Induced by Carbon Tetrachloride" BBRC. 190. 870-874 (1993)

[文献書誌] Eiji Miyoshi: "Expression of DNA Methyltransferase in LEC Rats During Hepatocarcinogenesis" Carcinogenesis. 14. 603-605 (1993)

[文献書誌] Hideki Hagiwara: "Quantitation Analysis of Hepatitis C Virus RNA in Serum During Interferon Alfa Therapy" Gastroenterology. 104. 877-883 (1993)

[文献書誌] Hideki Hagiwara: "Quantitation of Hepatitis C Virus RNA in Serum of Asymptomatic Blood Donors and Patients with Type C Chronic Liver Disease" Hepatology. 17. 545-550 (1993)

[文献書誌] 小出典男: "肝細胞接着と分化機能発現の関連" 肝臓病の進歩. 19. 1-10 (1993)

[文献書誌] 矢田俊量: "プロテオグリカンと三次元培養" 組織培養. 19. 312-316 (1993)

[文献書誌] Koide N: "Small Dermatan Sulfate/Chondrotin Sulfate Proteoglycans and hepatocyte Spheroids" Tiss Cult Res Commun. 11. 339-344 (1992)

[文献書誌] Kawaguchi M: "Combination of Epidermal Growth Factor and Insulin is Required for Multicellular Spheroid Formation of Rat Hepatocytes in Primary Culture" Acta Medica Okayama. 46. 195-201 (1992)

[文献書誌] 広瀬 美代子: "21世紀を目指し羽ばたく消化器病学" 日本医学館, 516 (1993)

[文献書誌] 佐藤 信紘: "医学のあゆみ(エンドテリン、NOと消化器疾患…編)" 医歯薬出版 (in press),

[文献書誌] 和気健二郎: "肝障害の診断的アプローチ 大久保昭行 編" 文光堂(東京), 192 (1993)

[文献書誌] Wake Kenjirou: "Cells of the Hepatic Sinusoid Vol 4" Kupffer Cell Foundation, XXII 612 (1993)

[文献書誌] 小出典男: "人工肝臓「糖鎖工学と医薬品開発」" 薬業時報社, 350 (1993)

1993 年度実績報告書

武藤泰敏岐阜大学, 医学部, 教授 (20010069)

[文献書誌] 友田隆: "急性肝不全における血清ジギタリス様物質の動態とその臨床的意義に関する研究" 肝臓. 34. 8-17 (1993)

[文献書誌] 杉山宏: "重症肝炎患者における血清ヒト肝細胞増殖因子(hHGF)の測定とその臨床的意義に関する研究" 肝臓. 34. 493-503 (1993)

[文献書誌] 竹下和良: "ホローファイバー型モジュールを用いたコラーゲンゲル内肝細胞高密度潅流培養" 人工肝臓. 22(1). 153-158 (1993)

[文献書誌] 和気健二郎: "肝臓の支配神経" BRAIN and NERVE. 45. 695-702 (1993)

[文献書誌] 広瀬美代子: "21世紀を目指し羽ばたく消化器病学" 日本医学館, 516 (1993)

[文献書誌] 佐藤信紘: "医学のあゆみ(エンドテリン、NOと消化器疾患…編)" 医歯薬出版 (in press),

[文献書誌] 和気健二郎: "肝障害の診断的アプローチ大久保昭行編" 文光堂(東京), 192 (1993)