1996 Fiscal Year Annual Research Report

炎症・免疫反応分子機構の解析-細胞接着因子とケモカインを中心にして

Research Project

Project/Area Number	08457104
Research Category	Grant-in-Aid for Scientific Research (B)
Research Institution	The University of Tokyo
Principal Investigator	松島綱治東京大学, 医学部, 教授 (50222427)
Co-Investigator(Kenkyū-buntansha)	向田直史金沢大学がん研究所, 薬理部, 助教授 (30182067)
Keywords	エンドトキシン / セレクチン / 腫瘍壊死因子 / インテグリン / インターロイキン8(IL8) / 単球走化活性化因子
Research Abstract	主にエンドトキシンによる全身・局所障害への接着因子ならびにケモカインの関与について検討を加え、本年度は以下の実験結果を得た。1)白血球と血管内皮との初期の接触時に重要な役割を果たすセレクチンのnatural antagonistであるスルファチドの、単回大量リポ多糖類(LPS)投与によって起きるショックへの影響を検討した。その結果、LPS投与によっておきる血圧低下・血清腫瘍壊死因子(TNF)濃度の上昇がスルファチドによって著明に抑制されるとともに、死亡率の著明な改善も認められた。この結果は、エンドトキシン・ショックの発症には、既に我々が報告したインテグリン以外に、セレクチンを介する白血球と血管内皮との相互作用も重要であることを示している。2)P.acnes死菌にてプライミング後のLPS投与によって起きる著明な肝障害が、遺伝子欠損マウスを用いた実験からI型のTNFレセプターを介して、Fas抗原を介する経路とは無関係に起きる肝細胞のアポトーシスによるものであることを明らかにした。3)ウサギの気管内にOK-432を投与36時間後にLPSを静脈投与すると、LPS投与後に著明な好中球浸潤・フィブリン沈着・血漿滲出を伴う肺胞の破壊ならびに低酸素血症が認められ、70%のウサギは死亡した。これらの所見はヒトARDSでの所見と一致していた。この時、肺局所でのIL8産生を示す免疫染色での結果を得たので、OK-432およびLPS投与時に抗IL8抗体を投与したところ、肺での病理変化・低酸素血症の発生は抑制され、死亡率は著明に改善された。以上の結果は、ARDSの発症にIL8が関与しており、抗IL8抗体はARDSの治療薬となりうることを示していた。4)抗体投与実験から、抗基底膜抗体投与によって起きる腎硬化症を伴う腎不全発症への、IL8の近縁分子である単球走化活性化因子の本質的関与を明らかにした。

Research Products

(14 results)

All Other

All Publications (14 results)

[Publications] Wada,T.,Yokoyama,H.and Matsushima,K.et al.: "Intervention of crescentic glomerulonephritis in rats by administering antibodies against monocyte chemotactic and activating factor(MCAF)." FASEB J.10巻. 1418-1425 (1996)
[Publications] Yano,S.,Yanagawa,H.,and Matsushima,K.et al.: "Th2 cytokines differently regulates monocyte chemoattractant protein-1(MCP-1)production by human peripheral blood monocytes and alveolar macrophages." J.Immunol.157巻. 2660-2665 (1996)
[Publications] Shono,T.,Ono,and Matsushima,K.,et al.: "Involvement of the transcription factor NF-κB in tubular morphogenesis of human microvascular endothelial cells by oxidative stress." Mol.Cell.Biol.16巻. 4231-4239 (1996)
[Publications] Mukaida,N.,Ishikawa,Y.,and Matsushima,K.et al.: "Novel insight into molecular mechanism of endotoxin shock." J.Leukocyte Biol.59巻. 145-151 (1996)
[Publications] Harada,A.,Mukaida,N.,and Matsushima,K.: "IL-8 as a novel target for intervention therapy in acute inflammatory diseases." Mol.Med.Today. 2巻. 482-489 (1996)
[Publications] Kuno,K.,Kanada,N.,and Matsushima,K.et al.: "Molecular cloning of a gene encoding a new type of metalloproteinase-disintegrin family protein with thrombospondin motifs as an inflammation associated gene." J.Biol.Chem.272巻. 556-562 (1997)
[Publications] Tan,J.,Moller,B.,and Matsushima,K.,et al.: "Chemotaxis and IL-8 receptor expression in B cells from normal and HIV-infected subjects." J.Immunol.158巻. 475-484 (1997)
[Publications] Fujiki,F.,Mukaida,N.,and Matsushima,K.et al.: "Prevention of adnocarcinoma colon 26-induced cachexia by interleukin-10 gene transfer." Cancer Res.57巻. 94-99 (1997)
[Publications] Higashi,H.,Suzuki,Y.,and Matsushima,K.et al.: "Intervention of endotoxin shock by sulfatide(I^3SO_3-GalCer)with a concomitant reduction in TNF-α production." Infect.Immun.(印刷中).
[Publications] Tsuji,H.,Harada,A.,and Matsushima,K.et al.: "Essential requirement of TNF-TNFR for intrahepatic granuloma formation and hepatocellular apoptosis in a murine bacteria-induced fulminant hepatitis model." Infect.Immun.(印刷中).
[Publications] Kurashima,K.,Mukaida,N.,and Matsushima,K.et al.: "A specific elevation of RANTES in bronchoalveolar lavage fluids with chronic eosinophilic pneumonia." Lab.Invest.(印刷中).
[Publications] Yokoi,K.,Mukaida,N.,and Matsushima,K.et al.: "Prevention of endotoxin-induced acute respiratory distress syndrome(ARDS)-like lung injury in rabbits by a monoclonal antibody to IL-8." Lab.Invest.(印刷中).
[Publications] Harada,A.,Mukaida,N.,and Matsushima,K.: "Use of blocking antibodies as probes for in vivo functions of chemokines.In A Companion to Methods in Enzymology,vol.10.Sozzani,S.(ed.)" Academic Press,New York,NY,U.S.A., pp.166-174 (1996)
[Publications] Harada,A.,Mukaida,N.,and Matsushima,K.: "The role of chemokines in ischemia and reperfusion injury.In Chemokines in Diseases.A.Koch and R.M.Strieter(eds.)." R.G.Landers Company,Austin,Texas,USA,pp.179-193 (1996)

1996 Fiscal Year Annual Research Report

炎症・免疫反応分子機構の解析-細胞接着因子とケモカインを中心にして

Principal Investigator

松島 綱治 東京大学, 医学部, 教授 (50222427)

Research Products

[Publications] Wada,T.,Yokoyama,H.and Matsushima,K.et al.: "Intervention of crescentic glomerulonephritis in rats by administering antibodies against monocyte chemotactic and activating factor(MCAF)." FASEB J.10巻. 1418-1425 (1996)

[Publications] Yano,S.,Yanagawa,H.,and Matsushima,K.et al.: "Th2 cytokines differently regulates monocyte chemoattractant protein-1(MCP-1)production by human peripheral blood monocytes and alveolar macrophages." J.Immunol.157巻. 2660-2665 (1996)

[Publications] Shono,T.,Ono,and Matsushima,K.,et al.: "Involvement of the transcription factor NF-κB in tubular morphogenesis of human microvascular endothelial cells by oxidative stress." Mol.Cell.Biol.16巻. 4231-4239 (1996)

[Publications] Mukaida,N.,Ishikawa,Y.,and Matsushima,K.et al.: "Novel insight into molecular mechanism of endotoxin shock." J.Leukocyte Biol.59巻. 145-151 (1996)

[Publications] Harada,A.,Mukaida,N.,and Matsushima,K.: "IL-8 as a novel target for intervention therapy in acute inflammatory diseases." Mol.Med.Today. 2巻. 482-489 (1996)

[Publications] Kuno,K.,Kanada,N.,and Matsushima,K.et al.: "Molecular cloning of a gene encoding a new type of metalloproteinase-disintegrin family protein with thrombospondin motifs as an inflammation associated gene." J.Biol.Chem.272巻. 556-562 (1997)

[Publications] Tan,J.,Moller,B.,and Matsushima,K.,et al.: "Chemotaxis and IL-8 receptor expression in B cells from normal and HIV-infected subjects." J.Immunol.158巻. 475-484 (1997)

[Publications] Fujiki,F.,Mukaida,N.,and Matsushima,K.et al.: "Prevention of adnocarcinoma colon 26-induced cachexia by interleukin-10 gene transfer." Cancer Res.57巻. 94-99 (1997)

[Publications] Higashi,H.,Suzuki,Y.,and Matsushima,K.et al.: "Intervention of endotoxin shock by sulfatide(I^3SO_3-GalCer)with a concomitant reduction in TNF-α production." Infect.Immun.(印刷中).

[Publications] Tsuji,H.,Harada,A.,and Matsushima,K.et al.: "Essential requirement of TNF-TNFR for intrahepatic granuloma formation and hepatocellular apoptosis in a murine bacteria-induced fulminant hepatitis model." Infect.Immun.(印刷中).

[Publications] Kurashima,K.,Mukaida,N.,and Matsushima,K.et al.: "A specific elevation of RANTES in bronchoalveolar lavage fluids with chronic eosinophilic pneumonia." Lab.Invest.(印刷中).

[Publications] Yokoi,K.,Mukaida,N.,and Matsushima,K.et al.: "Prevention of endotoxin-induced acute respiratory distress syndrome(ARDS)-like lung injury in rabbits by a monoclonal antibody to IL-8." Lab.Invest.(印刷中).

[Publications] Harada,A.,Mukaida,N.,and Matsushima,K.: "Use of blocking antibodies as probes for in vivo functions of chemokines.In A Companion to Methods in Enzymology,vol.10.Sozzani,S.(ed.)" Academic Press,New York,NY,U.S.A., pp.166-174 (1996)

[Publications] Harada,A.,Mukaida,N.,and Matsushima,K.: "The role of chemokines in ischemia and reperfusion injury.In Chemokines in Diseases.A.Koch and R.M.Strieter(eds.)." R.G.Landers Company,Austin,Texas,USA,pp.179-193 (1996)

松島綱治東京大学, 医学部, 教授 (50222427)