A molecular target for preventing airway remodeling

• Project/Area Number: 19590891
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Nagoya University
• Principal Investigator: KUME Hiroaki Nagoya University, 大学院・医学系研究科, 講師 (50303631)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2008: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2007: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
• Keywords: 気道平滑筋 / 気道過敏性 / β耐性化 / 酸化ストレス / Rho-kinase / 気管支喘息 / Ca^<2+>感受性 / 細胞遊走 / 細胞骨格 / 好酸球性気道炎症 / βアドレナリン受容体 / 化学メディエーター

Research Abstract

気管支喘息の難治化の主因である気道リモデリングにおける気道構成細胞の役割について、炎症細胞や上皮細胞と、平滑筋細胞との関連性に焦点を当て検討した。
肥満細胞、好酸球、気道上皮から産生、放出される種々の化学物質により、気道平滑筋細胞は直接に影響を受けることで気道平滑筋収縮(気流制限)、ムスカリン受容体刺激に対する反応性増強(気道過敏性の亢進)、βアドレナリン受容体の反応性の低下(β耐性化)、気道平滑筋細胞の増殖、遊走能の増強(気道リモデリング)を生じる。これらの現象のすべてにRhoA/Rho-kinase由来のCa^<2+>感受性亢進は密接に関わっていた。
以上の結果から、気道平滑筋細胞におけるRhoA/Rho-kinase系はこの疾患に対する病態解明、治療法の開発のためのあらたな標的分子と考えられる。

Research Products

• [Journal Article] Regulation of endothelin-1-induced interleukin-6 production by Ca2+influx in human airway smooth muscle cells (2009)
  • Author(s): Iwata S, Ito S, Iwaki M, Kondo M, Sashio T, Takeda N, Sokabe M, Hasegawa Y, Kume H
  • Journal Title: Eur J Pharmacol 605 Pages: 15-22
  • Peer Reviewed
• [Journal Article] Role of Ca2+mobilization and Ca2+ sensitization in 8-iso-PGF 2 alpha-induced contraction in airway smooth muscle (2009)
  • Author(s): Shiraki A, Kume H, Oguma T, Makino Y, Ito S, Shimokata K, Honjo H, Kamiya K
  • Journal Title: Clin Exp Allergy 39 Pages: 236-245
  • Peer Reviewed
• [Journal Article] Regulation of endothelin-1-induced interleukin-6 production by Ca^<2+> influx in human airway smooth muscle (2009)
  • Author(s): Iwata S, et al
  • Journal Title: Eur J Pharmacol 605 Pages: 15-22
  • Peer Reviewed
• [Journal Article] Role of Ca^<2+> mobilization and Ca^<2+> sensitization in 8-iso-PGF_<2α>-induced contraction in airway smooth muscle (2009)
  • Author(s): Shiraki A, et al
  • Journal Title: Clin Exp Allergy 39 Pages: 236-245
  • Peer Reviewed
• [Journal Article] RhoA/Rho-kinase as a therapeutic target in asthma (2008)
  • Author(s): Kume H
  • Journal Title: Curr Med Chem 15 Pages: 2876-2885
  • Peer Reviewed
• [Journal Article] Inhibition by the cold receptor agonists menthol and icilin of airway smooth muscle contraction (2008)
  • Author(s): Ito S, Kume H, Shiraki A, Kondo M, Makino Y, Kamiya K, Hasegawa Y
  • Journal Title: Pulm Pharmacol Ther 21 Pages: 812-817
  • Peer Reviewed
• [Journal Article] Role of Ca2+mobilization in desensitization of beta-adrenoceptors by platelet-derived growth factor in airway smooth muscle (2008)
  • Author(s): Ikenouchi T, Kume H, Oguma T, Makino Y, Shiraki A, Ito Y, Shimokata K
  • Journal Title: Eur J Pharmacol 591 Pages: 259-265
  • Peer Reviewed
• [Journal Article] Mast cell tryptase causes homologous desensitization of beta-adrenoceptors by Ca2+sensitization in tracheal smooth muscle (2008)
  • Author(s): Kobayashi M, Kume H, Oguma T, Makino Y, Ito Y, Shimokata K
  • Journal Title: Clin Exp Allergy 38 Pages: 135-144
  • Peer Reviewed
• [Journal Article] A novel Ca2+influx pathway activated by mechanical stretch in human airway smooth muscle cells (2008)
  • Author(s): Ito S, Kume H, Naruse K, Kondo M, Takeda N, Iwata S, Hasegawa Y, Sokabe M
  • Journal Title: Am J Respir Cell Mol Biol 38 Pages: 407-413
  • Peer Reviewed
• [Journal Article] ホルモテロールの薬理学的特性-長時間作用性、かつ、即効性に基づく臨床的有効性 (2008)
  • Author(s): 久米裕昭
  • Journal Title: アレルギー・免疫 15 Pages: 12-130
• [Journal Article] Inhibition by cold receptor agonists menthol and icilin of airway smooth muscle (2008)
  • Author(s): Ito S, et al
  • Journal Title: Curr Med Chem 15 Pages: 2876-2885
  • Peer Reviewed
• [Journal Article] Role of Ca^<2+> mobilization in desensitization of β-adrenoceptors by platelet derived growth factor in airway smooth muscle (2008)
  • Author(s): Ikenouchi T, et al
  • Journal Title: Eur J Pharmacol 591 Pages: 259-265
  • Peer Reviewed
• [Journal Article] A novel Ca^<2+> influx pathway activated by mechanical stretch in human airway smooth muscle cells (2008)
  • Author(s): Ito S, et al
  • Journal Title: Am J Respir Cell Mol Biol 38 Pages: 407-413
  • Peer Reviewed
• [Journal Article] ホルモテロールの薬理学的特性-長時間作用性、かつ、即効性に基づく臨床的有効性. (2008)
  • Author(s): 久米裕昭
  • Journal Title: アレルギー・免疫 15 Pages: 120-130
• [Journal Article] Mast cell tryptase causes homologous desensitization of β-adrenoceptors by Ca^<2+> sensitization in tracheal smooth muscle (2008)
  • Author(s): Kobayashi M, et. al.
  • Journal Title: Clin Exp Allergy 38 Pages: 135-144
  • Peer Reviewed
• [Journal Article] Roles of P2X receptors and Ca2+sensitization in extracellular adenosine triphosphate-induced hyperresponsiveness in airway smooth muscle (2007)
  • Author(s): Oguma T, Ito S, Kondo M, Makino Y, Shimokata K, Honjo H, Kamiya K, Kume H
  • Journal Title: Clin Exp Allergy 37 Pages: 893-900
  • Peer Reviewed
• [Journal Article] Effects of Rho-kinase inactivation on eosinophilia and hyper-reactivity in murine airways by allergen challenges (2007)
  • Author(s): Taki F, Kume H, Kobayashi T, Ohta H, Aratake H, Shimokata K
  • Journal Title: Clin Exp Allergy 37 Pages: 599-607
  • Peer Reviewed
• [Journal Article] 喘息と気道平滑筋 (2007)
  • Author(s): 久米裕昭
  • Journal Title: 日胸 66 Pages: 51-60
• [Journal Article] Sphingosine 1-phosphate causes airway hyper-reactivity by rho-mediated myosin phosphatase inactivation (2007)
  • Author(s): Kume H, Takeda N, Oguma T, Ito S, Kondo M, Ito Y, Shimokata K
  • Journal Title: J Pharmacol Exp Ther 320 Pages: 766-73
  • Peer Reviewed
• [Journal Article] Direct effects of hydrogen peroxide on airway smooth muscle tone : roles of Ca2+influx and Rho-kinase (2007)
  • Author(s): Kojima K, Kume H, Ito S, Oguma T, Shiraki A, Kondo M, Ito Y, Shimokata K
  • Journal Title: Eur J Pharmacol 556 Pages: 151-6
  • Peer Reviewed
• [Journal Article] 喘息における気道平滑筋の役割 (2007)
  • Author(s): 久米裕昭、伊藤理
  • Journal Title: 呼吸と循環 55 Pages: 57-64
• [Journal Article] 症状が安定している気管支喘息患者に潜む好酸球性気道炎症-気道炎症と肺機能との乖離 (2007)
  • Author(s): 久米裕昭
  • Journal Title: 呼吸 26 Pages: 481-486
  • Peer Reviewed
• [Journal Article] Roles of P2X receptors and Ca^<2+> sensitization in extracellular adenosine triphosphate-induced hyperresponsiveness in airway smooth muscle (2007)
  • Author(s): Oguma T, et. al.
  • Journal Title: Clin Exp Allergy 37 Pages: 893-900
  • Peer Reviewed
• [Journal Article] Effects of Rho-kinase inactivation on eosinophilia and hyper-reactivity in murine airways by allergen challenges (2007)
  • Author(s): Taki F, et. al.
  • Journal Title: Clin Exp Allergy 37 Pages: 559-607
  • Peer Reviewed
• [Journal Article] 喘息における気道平滑筋の役割 (2007)
  • Author(s): 久米裕昭、伊藤 理
  • Journal Title: 呼吸と循環 55 Pages: 57-64
• [Journal Article] 症状が安定している気管支喘息患者に潜む好酸球性気道炎症-気道炎症と肺機能との乖離 (2007)
  • Author(s): 久米裕昭, 他
  • Journal Title: 呼吸 26 Pages: 481-486
  • Peer Reviewed
• [Presentation] 気道平滑筋とアレルギー (2008)
  • Author(s): 久米裕昭
  • Organizer: 第58回日本アレルギー学会秋季学術大会
  • Place of Presentation: 東京
  • Year and Date: 2008-11-28
• [Presentation] ヒト肺微小血管内皮細胞におけるstretch-activated Ca2+ influxの制御 (2008)
  • Author(s): 伊藤理、久米裕昭、岩木舞、岩田晋、指尾豊和、近藤征史、今泉和良、橋本直純、長谷川好規
  • Organizer: 第48回日本呼吸器学会学術講演会
  • Place of Presentation: 神戸市
  • Year and Date: 2008-06-17
• [Presentation] COPDの気道炎症に対するLABAの抑制効果 (2008)
  • Author(s): 久米裕昭、辻清太、岩木舞、浅野俊明、牧野靖、指尾豊和、白木晶、長谷川好規、下方薫
  • Organizer: 第48回日本呼吸器学会学術講演会
  • Place of Presentation: 神戸市
  • Year and Date: 2008-06-16
• [Presentation] 気道平滑筋のβアドレナリン受容体機能に対する酸化ストレスの影響 (2008)
  • Author(s): 牧野靖、久米裕昭、白木晶、伊藤理、長谷川好規
  • Organizer: 第48回日本呼吸器学会学術講演会
  • Place of Presentation: 神戸市
  • Year and Date: 2008-06-16
• [Presentation] 最適な喘息治療戦略-LABAの立場から (2008)
  • Author(s): 久米裕昭
  • Organizer: 第48回日本呼吸器学会学術講演会
  • Place of Presentation: 神戸市
  • Year and Date: 2008-06-15
• [Presentation] 酸化ストレスに対するβ2刺激薬の抑制効果 (2008)
  • Author(s): 久米裕昭、白木晶、牧野靖、伊藤理、長谷川好規、下方薫
  • Organizer: 第48回日本呼吸器学会学術講演会
  • Place of Presentation: 神戸市
  • Year and Date: 2008-06-15
• [Presentation] 酸化ストレスに対するβ_2刺激薬の抑制効果 (2008)
  • Author(s): 久米裕昭
  • Organizer: 第48回日本呼吸器学会学術講演会
  • Place of Presentation: 神戸市
  • Year and Date: 2008-06-15
• [Presentation] Rho/Rho-kinase in airway smooth muscle as a therapeutic target for asthma (2008)
  • Author(s): Kume H
  • Organizer: Seminar in Center for Cardiovascular Sciences, Albany Medical College
  • Place of Presentation: Albany NY, U.S.A
  • Year and Date: 2008-05-22
• [Presentation] Rho/Rho-kinase in airway smooth muscle as a therapeutic target for asthma (2008)
  • Author(s): Kume H
  • Organizer: Seminar in the Center for Cardiovascular Sciences, Albany Medical College
  • Place of Presentation: Albany, NY, U.S.A.
  • Year and Date: 2008-05-22
• [Presentation] Role of sphingosine-1-phosphate for adhesion molecules expression in human pulmonary microvascular endothelial cells (2008)
  • Author(s): Sashio T, Kume H, Takeda N, Ito S, Kondo M, Hasegawa Y
  • Organizer: ATS 2008 International Conference
  • Place of Presentation: Toronto, Canada
  • Year and Date: 2008-05-21
• [Presentation] Mechanical stretch activates Ca^<2+> influx in human lung microvascular endothelial cells (2008)
  • Author(s): Ito S, Kume H, Iwaki M, Sashio T, Iwata S, Kondo M, Imaizumi K, Naruse K, Sokabe M, Hasegawa Y
  • Organizer: ATS 2008 International Conference
  • Place of Presentation: Toronto, Canada
  • Year and Date: 2008-05-21
• [Presentation] Involvement of endothelin-1 in migration of human airway smooth muscle cells (2008)
  • Author(s): Kume H, Tsuji S, Sasio T, Takeda N, Ito S, Kondo M, Hasegawa Y, Shimokata K
  • Organizer: ATS 2008 International Conference
  • Place of Presentation: Toronto, Canada
  • Year and Date: 2008-05-19
• [Presentation] Role of hydrogen peroxide in β-adrenergic receptor desensitization of tracheal smooth muscle (2008)
  • Author(s): Makino Y, Kume H, Shiraki A, Ito S, Hasegawa Y, Honjo H, Kamiya K
  • Organizer: ATS 2008 International Conference
  • Place of Presentation: Toronto, Canada
  • Year and Date: 2008-05-19
• [Presentation] Role of intracellular Ca2+for endothelin-1-induced IL-6 production in human airway smooth muscle cells (2008)
  • Author(s): Iwata S, Ito S, Iwaki M, Sashio T, Kondo M, Sokabe M, Hasegawa Y, Kume H
  • Organizer: ATS 2008 International Conference
  • Place of Presentation: Toronto, Canada
  • Year and Date: 2008-05-19
• [Presentation] Role of hydrogen peroxide in β-adren-adrenergic receptor desensitization of tracheal smooth muscle (2008)
  • Author(s): Makino Y
  • Organizer: ATS 2008 International Conference
  • Place of Presentation: Toronto, Canada
  • Year and Date: 2008-05-19
• [Presentation] Role of intracellular Ca^<2+> for endothelin-1-induced IL-6 production in human airway smooth muscle cells (2008)
  • Author(s): Iwata S
  • Organizer: ATS 2008 International Conference
  • Place of Presentation: Toronto, Canada
  • Year and Date: 2008-05-19
• [Presentation] Losartanはイソプロスタンによる気道収縮を抑制する (2007)
  • Author(s): 白木晶、久米裕昭、伊藤理、辻清太、長谷川好規
  • Organizer: 第57回日本アレルギー学会秋季学術大会
  • Place of Presentation: 横浜市
  • Year and Date: 2007-11-12
• [Presentation] 好酸球性気道炎症に対する吸入ステロイド薬と長時間作用性β_2刺激薬との併用療法の有用性 (2007)
  • Author(s): 久米裕昭、辻清太、岩木舞、中島治典、浅野俊明、白木晶、指尾豊和、下方薫
  • Organizer: 第57回日本アレルギー学会秋季学術大会
  • Place of Presentation: 横浜市
  • Year and Date: 2007-11-03
• [Presentation] エンドセリンが及ぼす気管支平滑筋細胞の遊走能への影響 (2007)
  • Author(s): 辻清太、久米裕昭、武田直也、伊藤理、近藤征史、今泉和良、長谷川好規、下方薫
  • Organizer: 第57回日本アレルギー学会秋季学術大会
  • Place of Presentation: 横浜市
  • Year and Date: 2007-11-02
• [Presentation] L-メンソールによる細胞内Ca2+流入抑制を介した気道平滑筋弛緩効果 (2007)
  • Author(s): 伊藤理、久米裕昭、白木晶、近藤征史、岩田晋、長谷川好規、下方薫
  • Organizer: 第19回日本アレルギー学会春季臨床大会
  • Place of Presentation: 横浜市
  • Year and Date: 2007-06-09
• [Presentation] The effects of β^2-agonists intrinsic efficacy on oxidative stress-induced contraction in airway smooth muscle (2007)
  • Author(s): Kume H, Shiraki A, Ikenouchi T, Makino Y, Ito S, Kondo M, Shimokata K
  • Organizer: ATS 2007 International Conference
  • Place of Presentation: San Francisco, U.S.A
  • Year and Date: 2007-05-21
• [Presentation] Intracellular mechanisms of isoprostane-induved contraction in tracheal smooth muscle (2007)
  • Author(s): Shiraki A, Kume H, Ito S, Kondo M, Honjo H, Kamiya K, Shimokata K
  • Organizer: ATS 2007 International Conference
  • Place of Presentation: San Francisco, U.S.A
  • Year and Date: 2007-05-21
• [Presentation] The role of voltage-dependent Ca2+channels on β-adrenergic desensitization by platelet-derived growth factor in tracheal smooth muscle (2007)
  • Author(s): Ikenouchi T, Kume H, Oguma T, Shiraki A, Ito S, Kondo M, Shimokata K
  • Organizer: ATS 2007 International Conference
  • Place of Presentation: San Francisco, U.S.A
  • Year and Date: 2007-05-21
• [Presentation] The effects of β_2-agonist intrinsic efficacy on oxidative stress-induced contraction in airway smooth muscle (2007)
  • Author(s): Kume H, et. al.
  • Organizer: ATS 2007 International Conference
  • Place of Presentation: San Francisco, U.S.A.
  • Year and Date: 2007-05-21
• [Presentation] Endothelin-1刺激による培養ヒト気道平滑筋細胞のIL-6産生能に対する影響 (2007)
  • Author(s): 岩田晋、伊藤理、武田直也、指尾豊和、岩木舞、近藤征史、長谷川好規、下方薫、久米裕昭
  • Organizer: 第47回日本呼吸器学会学術講演会
  • Place of Presentation: 東京
  • Year and Date: 2007-05-12
• [Presentation] ヒト気道平滑筋細胞のメカノバイオロジー : ストレッチによるMAP-kinase系活性化 (2007)
  • Author(s): 岩田晋、伊藤理、武田直也、指尾豊和、岩木舞、近藤征史、長谷川好規、下方薫、久米裕昭
  • Organizer: 第47回日本呼吸器学会学術講演会
  • Place of Presentation: 東京
  • Year and Date: 2007-05-12
• [Presentation] イソプロスタン(8-iso-PGF2α)による気道平滑筋収縮におけるCa2+動態とCa2+感受性の関与 (2007)
  • Author(s): 白木晶、久米裕昭、伊藤理、牧野靖、近藤征史、下方薫
  • Organizer: 第47回日本呼吸器学会学術講演会
  • Place of Presentation: 東京
  • Year and Date: 2007-05-12
• [Presentation] Mentholは寒冷受容体を介して気導平滑筋を弛緩させる (2007)
  • Author(s): 伊藤理、久米裕昭、近藤征史、池ノ内紀祐、白木晶、岩田晋、長谷川好規、下方薫
  • Organizer: 第47回日本呼吸器学会学術講演会
  • Place of Presentation: 東京
  • Year and Date: 2007-05-12
• [Presentation] 気道平滑筋のβアドレナリン受容体機能に対するアンギオテンシンIIの影響 (2007)
  • Author(s): 牧野靖、久米裕昭、白木晶、池ノ内紀祐、武田直也、伊藤理、近藤征史、今泉和良、長谷川好規、下方薫
  • Organizer: 第47回日本呼吸器学会学術講演会
  • Place of Presentation: 東京
  • Year and Date: 2007-05-12
• [Presentation] Mechanobiology of airway smooth muscle cells : Effects of mechanical stretch (2007)
  • Author(s): Ito S, Kume H, Naruse K, Iwata S, Takeda N, Kondo M, Hasegawa Y, Shikata K
  • Organizer: 第47回日本呼吸器学会学術講演会
  • Place of Presentation: 東京
  • Year and Date: 2007-05-10
• [Presentation] モニタリングからみた誘発喀痰検査と肺機能 (2007)
  • Author(s): 久米裕昭
  • Organizer: 第47回日本呼吸器学会学術講演会
  • Place of Presentation: 東京
  • Year and Date: 2007-05-10
• [Book] β_2刺激薬気管支拡張薬の吸入療法"21世紀の吸入療法"薬物吸入療法研究会編 (2008)
  • Author(s): 久米裕昭
  • Publisher: 仙台気道研究所 仙台市
• [Book] β_2刺激薬 気管支拡張薬の吸入療法“21世紀の吸入療法"薬物吸入療法研究科会編 (2008)
  • Author(s): 久米裕昭
  • Publisher: 仙台気道研究所、仙台市