肝壊死-再生の病態連繋機構に関する研究

1994 Fiscal Year Annual Research Report

• Project/Area Number: 04304038
• Research Institution: GIFU UNIVERSITY
• Principal Investigator: 武藤 泰敏 岐阜大学, 医学部, 教授 (20010069)
• Co-Investigator(Kenkyū-buntansha): 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)
• Keywords: 細胞障害性T細胞 / NK細胞 / 胸腺外分化T細胞 / 細胞外マトリックス / TGF-β / 肝微小循環 / apoptpsis / インターフェロン-γ

Research Abstract

1.肝細胞死の機構:(1)HCVコア抗原刺激により増殖するHLA class I抗原B44拘束性のCTL活性の存在が確認された。(2)HCV感染肝細胞では核DNAの断裂像は観察されず、Fas‐ligandならびにFas抗原系に抑制的に作用するbc1‐2遺伝子産物の発現も観察されなかったとの報告がなされた。またクッパー細胞がapoptosisに陥った肝細胞の処理によりさらに活性化される可能性が示された。さらにIFN‐γが肝細胞のapoptosisを誘導し、HGFがそれに拮抗的に作用することが示された。2.細胞外マトリックス(ECM):肝細胞膜に存在するfigroglycanがHGFと結合することが示され、ECMはHGFとその受容体との結合を抑制している可能性が報告された。3.肝細胞増殖因子の細胞内情報伝達機構:肝細胞増殖のcomitogenであるinsulinの受容体のチロシンキナーゼ内因性物質であるinsulin receptor substrate 1(IRS‐1)のPtdlns 3‐kinaseとの結合ならびにチロシン燐酸化が、HGFの場合と同様に肝部分切除後の再生過程で認められることが示された。4.肝細胞増殖抑制因子:(1)急性肝不全剖検肝におけるTGF‐β_1mRNA発現は著明に亢進していたが、PCNA labeling indexとは相関がなかったことが示された。またTGF‐β_1の免疫染色にて劇症肝炎における肝細胞から連続的に胆管に移行する部位に陽性所見がみられ、同部に核DNA断裂がみられることが報告された。(2)劇症肝炎患者血中に存在する新たな肝細胞増殖抑制因子の存在が報告された。5.肝微小循環動態:肝類洞血流を調節する伊東細胞の炎症部位への集積は、局所での増殖とともに他の部位からの遊走も関与していること、クッパー細胞が異物貧食による胞体容積の増大により局所血流に影響を与えていることが報告された。6.肝再生と神経系:核酸代謝が抑制されている自然発症糖尿病ラットでの肝膵同時支配神経細胞の変化が検討された。7.肝再生と免疫系:再生肝細胞に対しNK細胞ならびに胸腺外分化T細胞が障害活性を有する可能性が報告された。

Research Products

• [Publications] Masahito Nagaki: "Hepatic injury and lethal shock in galactosamine-sensitized mice induced by the superantigen staphylococcal enterotoxin B" Gastroenterology. 106. 450-458 (1994)
• [Publications] Hiroo Ohnishi: "Hepatitis C virus infection involved in fulminant hepatitis in Japan" Int Hepatol Commun. 2. 347-351 (1994)
• [Publications] 名倉一夫: "劇症肝炎における網内系機能に関する臨床的ならびに実験的研究とくに貧食能を中心に" 岐阜大医紀. 42. 415-425 (1994)
• [Publications] 永木正仁: "広範性肝細胞壊死と肝類洞壁細胞との関連に関する実験的検討" 肝臓. 35. 270-271 (1994)
• [Publications] 大西弘生: "肝再生と免疫" 肝胆膵. 28. 853-860 (1994)
• [Publications] 永木正仁: "ハイブリッド型人工肝研究の動向" 日本臨床. 52. 2205-2213 (1994)
• [Publications] 永木正仁: "ハイブリッド型人工肝" 医学と薬学. 31. 305-312 (1994)
• [Publications] 内藤智雄: "亜急性の経過をたどる重症肝炎に対するシクロスポリンAの使用経験" 肝臓. 35. 274 (1994)
• [Publications] Yamada H: "Humoral inhibitor of rat hepatocyte DNA synthesis from patients with fulminant liver failure" Hepatology. 19. 1133-1140 (1994)
• [Publications] W Ekataksin: "Hepatic Microcirculatory subunits(HMS):A new look at functional units in mammalian liver" FASEB J8:Abstracts(Part II). (1994)
• [Publications] K Wake: "Intralobular gradients of vitamin A-storage in the porcine liver" FASEB J8:3174 Abstracts(Part II). (1994)
• [Publications] Nagochi S: "Putrescine as a comitogen of epidermal growth factor in rat liver growth" Hepatology. 20. 725-730 (1994)
• [Publications] Ohno A: "Fat-storing cell abnormalities with endothelial cell damage after cold ischemic storage of rat liver in UW solution" Dig Dis Sci. 39. 861-865 (1994)
• [Publications] Sasaki Y: "Ethanol impairs insulin receptor substrate-1 mediated signal transduction during rat liver regeneration" Biochem Biophys Res Commun. 199. 403-409 (1994)
• [Publications] Suzuki K: "Expression of the c-met protooncogene in human hepatocellular carcinoma" Hepatology. 20. 1231-1236 (1994)
• [Publications] Tanaka Y: "Characterization of signaling pathways to Na^+/H^+ exchenger activation with epidermal growth factor in hepatocytes" Hepatology. 20. 966-974 (1994)
• [Publications] Kono T: "Individual neurons on the lower brainstem innervate both liver and pancreas in the rat" J Comp Meurol. in press
• [Publications] 河野 透: "自律神経系における複数臓器同時支配神経細胞による肝再生機序への関与" 肝臓. 35 suppl(1). 287 (1994)
• [Publications] H Yamamoto: "Morphometric analysis of infiltrating cells that adhere to the sinusoidal wall and migrate into the space of Disse in the orthotopically transplanted rat liver" Transplantation. 58. 8-13 (1994)
• [Publications] Watanabe S: "Role of actin and calmodulin in migration and proliferation of rabbit gastric mucosal cell in culture" J Gastroenterol Hepatol. (in press).
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• [Publications] Watanabe S: "Hepatocyte growth factor accelerats the wound repair of cultured gastric mucosal cells" Biochem Biophys Res Commun. 199. 1453-1460 (1994)
• [Publications] Sato N: "Effect of nicotine in migration and proliferation of rabbit mucosal cells in a culture cell model" J Gastroenterol Hepatol. 9. S66-S71 (1994)
• [Publications] Mikami H: "Role of extracellular matrix in wound repair by cultured gastric mucosal cells" Biochem Biophys Res Commun. 202. 285-292 (1994)
• [Publications] Okumura S: "Vassoactive effect of endothelin‐1 on rat liver in vivo" Hepatology. 19. 155-161 (1994)
• [Publications] Kitami N: "Immunoreactivity to M2 proteins in antimitochondrial antibody‐negative patients with primary biliary cirrhosis" J Gastroenterol Hepatol. 9. 7-12 (1994)
• [Publications] Endo K: "Restoration of junctions in the regenerative process of ethanol‐induced gastric mucosal injury" J Gastroenterol Hepatol. (in press).
• [Publications] Kitamura T: "Different feagures of Ca^<2+> oscillations in differentiated and undifferentiated hepatocyte doublets" Hepatology. (in press).
• [Publications] Ohkura T: "Increase of fucosylated serum cholinesterase in relation to higt risk group for hepatocellular carcinoma" Can Res. 54. 55-61 (1994)
• [Publications] Usumoto R: "Effect of proton pump inhibitor,Omeprazole,on expression of rat parietal cell specific carbohydrate antigen,type 2 chain N‐acetyllactosamine" Dig Dis Sci. 39. 169-176 (1994)
• [Publications] Sunayama T: "Elevated plasma levels of a carbohydrate antigen,sialyl Lewis X,in liver diseases" J Hepatol. 19. 451-458 (1994)
• [Publications] Yimoto Y: "Estimation of remnant liver function before hepatectomy by means of technetium‐99m‐diethylene‐trianibe‐pentaacetic and galactosyl human albumin" Can Chemther Pharmacol. 33. S1-6 (1994)
• [Publications] Okada Y: "Changes in expression of sialy‐Lewis^×,a hepatic necroinflammation‐associated carbohydrate neoantigen,in human hepatocellular carcinomas" Cancer. 73. 1811-1816 (1994)
• [Publications] Tomita M: "Immunohistochemical analysis on the exprssion of maturation associated Fc γ receptors and CD1_4 in normal and diseased human liver macrophages" Int Natl Hepatol Commun. 2. 245-249 (1994)
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• [Publications] Kobayashi H: "Nonsuppurative cholangitis is induced in neonatally thymectomized mice:a possible animal model for primary biliary cirrhosis" Hepatplogy. 19. 1424-1430 (1994)
• [Publications] Tsuji T: "Liver disease" Clinical Science Regional Focus Series. 87. 125-127 (1994)
• [Publications] 沖田 極: "肝細胞壊死と再生のメカニズム" 病態生理. 13. 248-255 (1994)
• [Publications] Masuhara M: "Expression of the hepatocyte growth factor and transforming growth factor β1 mRNA in P.acnes and lipopolysaccaride‐treated rats" J Gastroenterol. 30. 48-54 (1994)
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• [Publications] Yoshifumi Watanabe: "Highly efficient transfection into primary cultured hepatocytes by use of cation‐liposomes:An application for immunization" J Biochem. 116. 1220-1226 (1994)
• [Publications] Mitsuaki Goto: "Lactose‐carrying polystyrene as drug carriers:Investigation of body distributions to parenchymal liver cells using ^<125>I‐labeled lactose‐carrying polystyrene" J Controlled Release. 28. 223-233 (1994)
• [Publications] Masahiko Morita: "Inflammatory cytokines upregulate the ICAM‐1 expression on primary cultured mouse hepatocytes and T cell adhesion" Hepatology. 19. 426-431 (1994)
• [Publications] Natsuki Matsushita: "Induction of cytochrome P‐450s and expression of liver‐specific genes in rat primary hepatocytes cultured on different extracellular matrices" Biosci Biotech Biochem. 58. 1514-1516
• [Publications] Akira Kobayashi: "Receptor mediated regulation of differentiation and proliferation of hepatocyte by synthetic polymer model of asialoglycoprotein" J Biomater Sci Polymer Ed. 6. 325-342 (1994)
• [Publications] 赤池敏宏: "糖鎖と細胞「糖鎖工学と人工臓器」" 日経サイエンス. 114-129 (1994)
• [Publications] 小林 明: "細胞接着システムの新展開" 化学と生物. 32. 260-268 (1994)
• [Publications] 小林 明: "細胞特異性材料による表面修飾と細胞機能抑制" 表面技術. 45. 152-159 (1994)
• [Publications] Yasutoshi Muto: "Springer‐Verlag,Tokyo" Pathobiology of fulminant hepatitis.In "Viral Hepatitis and Liver Disease"eds by Nishioka K,Suzuki H,Mishiro S,Oda T, 200-203 (1994)
• [Publications] K Wake: "Marcel Dekker Inc,New York,Basel,Hong Kong" Role of perisinusoidal stellate cells in vitamin A storage.In"Vitamin A in Health and Disease"ed R Blomhoff, 73-86 (1994)
• [Publications] K Wake: "Kluwer Academic Publ,Dordrecht,Boston,London" Perisinusoidal fat‐storing cells of the liver.In"Fat‐storing cells and liver fibrosis"eds C Surrenti et al, 1-10 (1994)
• [Publications] Sakaguchi K: "Elsevier Science" Autoimmunity in hepatitis virus infection In"Autoimmune Hepatitis"eds by Nishioka M,Toda G,Zeniya M, 69-81 (1994)
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• [Publications] Kita H: "Springer‐Verlag,Tokyo" Recognition of hepatitis C virus nucleocapsid protein‐derived peptides by cytotoxic T lymphocytes In"Viral Hepatitis and Liver Diseases"eds by Nishioka K,Suzuki H,Mishiro S,Oda T, 186-189 (1994)
• [Publications] 後藤光昭: "中山書店" Gene targetingへの細胞特異性材料の応用「人工臓器」, 1994-1995 (1994)