EVALUATING THE PATHOGENESIS AND DEVELOPMENT OF NOVEL THERAPIES IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE USING GENE-ENGINEERED MICE

2011 Fiscal Year Final Research Report

• Project/Area Number: 21590133
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Environmental pharmacy
• Research Institution: Mie University
• Principal Investigator: TAGUCHI Osamu 三重大学, 大学院・医学系研究科, 准教授 (90197244)
• Co-Investigator(Kenkyū-buntansha): KOBAYASHI Tetsu 三重大学, 医学部附属病院, 講師 (20437114)
• Co-Investigator(Renkei-kenkyūsha): GABAZZA Esteban 三重大学, 大学院・医学系研究科, 教授 (00293770)
• Project Period (FY): 2009 – 2011
• Keywords: 閉塞性肺疾患 / 煙草 / 高齢者 / 炎症性サイトカイン / プロテアーゼ / 肺胞破壊 / 炎症性細胞

Research Abstract

In the present investigation, activated protein C(APC) and thrombomodulin(TM) showed significant suppressive activity on the expression of cytokines and proteases from dendritic cells, alveolar epithelial cells and inflammatory cells. In addition, we succeeded in the design and development of human transforming growth factor-β1(TGFβ1) and human metalloproteinase-2(MMP-2) transgenic mice, and demonstrated the involvement of both TGFβ1 and MMP-2 in the pathogenesis of COPD. Further, we are currently carrying out several in vivo studies to demonstrate the effect of APC and TM on the pulmonary lesions induced in both TGFβ1 and MMP-2 transgenic mice.

Research Products

• [Journal Article] Correlation between circulating fibrocytes and activity and progression of interstitial lung diseases (2012)
  • Author(s): Fujiwara A, Kobayashi H, Masuya M, Maruyama M, Nakamura S, Ibata H, Fujimoto H, Ohnishi M, Urawa M, Naito M, Takagi T, Kobayashi T, Gabazza EC, Takei Y, Taguchi O
  • Journal Title: Respirology Volume: (in press)(掲載決定)
  • Peer Reviewed
• [Journal Article] Role of thrombin-activatable fibrinolysis inhibitor in allergic bronchial asthma (2012)
  • Author(s): Fujiwara A, Taguchi O, Takagi T, D' Alessandro-Gabazza CN, Boveda-Ruiz D, Toda M, Yasukawa A, Matsushima Y, Miyake Y, Kobayashi H, Kobayashi T, Gil-Bernabe P, Naito M, Yoshida M, Morser J, Takei Y, Gabazza EC
  • Journal Title: Lung Volume: 190 Pages: 189-198
  • Peer Reviewed
• [Journal Article] Development and preclinical efficacy of novel transforming growth factor-β1 short interfering RNAs for pulmonary fibrosis (2012)
  • Author(s): D' Alessandro-Gabazza CN, Kobayashi T, Boveda-Ruiz D, Takagi T, Toda M, Gil-Bernabe P, Miyake Y, Yasukawa A, Matsuda Y, Suzuki N, Saito H, Yano Y, Fukuda A, Hasegawa T, Toyobuku H, Rennard SI, Wagner PD, Morser J, Takei Y, Taguchi O, Gabazza EC
  • Journal Title: Am J Respir Cell Mol Biol Volume: 46 Pages: 397-406
  • Peer Reviewed
• [Journal Article] Solitary pulmonary nodule of benign metastasizing leiomyoma associated with primary lung cancer : a case report (2011)
  • Author(s): Naito M, Kobayashi T, Yoshida M, Fujiwara K, Onishi M, Fujiwara A, Takagi T, Kobayashi H, Gabazza EC, Takei Y, Taguchi O
  • Journal Title: J Med Case Reports Volume: 5 Pages: 500
  • Peer Reviewed
• [Journal Article] Inhibition ofallergic bronchial asthma by thrombomodulin is mediated by dendritic cells (2011)
  • Author(s): Takagi T, Taguchi O, Toda M, Ruiz DB, Bernabe PG, D' Alessandro-Gabazza CN, Miyake Y, Kobayashi T, Aoki S, Chiba F, Yano Y, Conway EM, Munesue S, Yamamoto Y, Yamamoto H, Suzuki K, Takei Y, Morser J, Gabazza EC
  • Journal Title: Am J Respir Crit Care Med Volume: 183 Pages: 31-42
  • Peer Reviewed
• [Journal Article] Efficacy of 23-valent pneumococcal vaccine in preventing pneumonia and improving survival in nursing home residents : double blind, randomised and placebo controlled trial (2010)
  • Author(s): Maruyama T, Taguchi O, Niederman MS, Morser J, Kobayashi H, Kobayashi T, D' Alessandro-Gabazza C, Nakayama S, Nishikubo K, Noguchi T, Takei Y, Gabazza EC
  • Journal Title: BMJ Volume: 340 Pages: 1004
  • Peer Reviewed
• [Journal Article] Pulmonary hypertension is ameliorated in mice deficient in thrombin-activatable fibrinolysis inhibitor (2010)
  • Author(s): Qin L, D' Alessandro-Gabazza CN, Aoki S, Gil-Bernabe P, Yano Y, Takagi T, Boveda-Ruiz D, Ramirez Marmol AY, San Martin Montenegro VT, Toda M, Miyake Y, Taguchi O, Takei Y, Morser J, Gabazza EC
  • Journal Title: J Thromb Haemost Volume: 8 Pages: 808-816
  • Peer Reviewed
• [Journal Article] Community-acquired pneumonia and nursing home-acquired pneumonia in the very elderly patients (2010)
  • Author(s): Maruyama T, Gabazza EC, Morser J, Takagi T, D' Alessandro-Gabazza C, Hirohata S, Nakayama S, Ramirez AY, Fujiwara A, Naito M, Nishikubo K, Yuda H, Yoshida M, Takei Y, Taguchi O
  • Journal Title: Respir Med. Volume: 104 Pages: 584-92
  • Peer Reviewed
• [Journal Article] Direct effects of protein S in ameliorating acute lung injury (2009)
  • Author(s): Takagi T, Taguchi O, Aoki S, Toda M, Yamaguchi A, Fujimoto H, Boveda-Ruiz D, Gil-Bernabe P, Ramirez AY, Naito M, Yano Y, D' Alessandro-Gabazza CN, Fujiwara A, Takei Y, Morser J, Gabazza EC
  • Journal Title: J Thromb Haemost Volume: 7 Pages: 2053-2063
  • Peer Reviewed
• [Journal Article] The coagulation and protein C pathways in patients with sleep apnea (2009)
  • Author(s): Takagi T, Morser J, Gabazza EC, Qin L, Fujiwara A, Naito M, Yamaguchi A, Kobayashi T, D' Alessandro-Gabazza CN, Boveda Ruiz D, Gil Bernabe P, Iwasaki Y, Takei Y, Taguchi O
  • Journal Title: Lung Volume: 187 Pages: 209-213
  • Peer Reviewed
• [Journal Article] Presence of thrombin-activatable fibrinolysis inhibitor in Helicobacter pylori-associated gastro-duodenal disease (2009)
  • Author(s): Ikeda A, Gabazza EC, Morser J, Imoto I, Kuroda M, D' Alessandro-Gabazza CN, Hara K, Ruiz DB, Bernabe PG, Katsurahara M, Toda M, Kobayashi Y, Yano Y, Sumida Y, Suzuki K, Taguchi O, Takei Y
  • Journal Title: Helicobacter Volume: 14 Pages: 147-155
  • Peer Reviewed
• [Presentation] 気管支喘息患者におけるthrombomodulin陽性樹状細胞の役割について/Inverse correlation of thrombomodulin-positive dendritic cells with airflow limitation in patients with allergic bronchial asthma (2011)
  • Author(s): 高木健裕,田口修,内藤雅大,戸田雅昭,小林哲,三宅泰士, Boveda-Ruiz D, D' Alessandro-Gabazza, Morser J, Gabazza EC
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 千葉幕張メッセ
  • Year and Date: 20111127-29
• [Presentation] Role of the complement system in exacerbation of acute lung injury in Thrombin-Activatable fibrinolysis inhibitor-deficient mice (2011)
  • Author(s): 内藤雅大,田口修,高木健裕,戸田雅昭,小林哲,三宅泰士, Boveda-Ruiz D, D' Alessandro-Gabazza, C, Gabazza EC
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 千葉幕張メッセ
  • Year and Date: 20111127-29
• [Presentation] Role of thrombin-activatable fibrinolysis inhibitor in lipopolysaccharide-induced acute lung injury (2011)
  • Author(s): Naito M, Taguchi O, Takagi T, Kobayashi T, D' Alessandro-Gabazza CN, Gabazza EC.
  • Organizer: European Respiratory Society International Congress
  • Place of Presentation: Amsterdam, Netherlands
  • Year and Date: 20110924-28
• [Presentation] Effect of thrombin inhalation in a murine model of bronchial asthma (2011)
  • Author(s): Takagi T, Onishi M, Naito M, Fujiwara A, Kobayashi T, Kobayashi H, D' Alessandro-Gabazza CN, Gabazza EC, Taguchi O.
  • Organizer: European Respiratory Society International Congress
  • Place of Presentation: Amsterdam, Netherlands
  • Year and Date: 20110924-28
• [Presentation] Protective effect of thrombomodulin-positive dendritic cells against murine asthma (2010)
  • Author(s): Fujiwara A, Urawa M, Naito M, Takagi T, Ebihara A, Kobayashi T, Kobayashi H, D' Alessandro-Gabazza CN, Takei Y, Gabazza EC, Taguchi O.
  • Organizer: European Respiratory Society International Congress
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 20100918-23
• [Presentation] Protective effect of thrombomodulin-positive dendritic cells against murine asthma (2010)
  • Author(s): Naito M, Takagi T, Taguchi O, Toda M, Kobayashi H, Kobayashi T, Fujiwara A, D' Alessandro-Gabazza CN, Boveda-Ruiz D, Morser J and Gabazza EC.
  • Organizer: The 14^<th> International Congress of Immunology
  • Place of Presentation: Kobe, Japan
  • Year and Date: 20100822-27
• [Presentation] Thrombin regulates the immune response (2010)
  • Author(s): Miyake Y, Toda M, Yasukawa A, D' Alessandro-Gabazza CN, Takagi T, Naito M, Boveda-Ruiz D, Morser J, Taguchi O, Gabazza EC.
  • Organizer: The 14^<th> International Congress of Immunology
  • Place of Presentation: Kobe, Japan
  • Year and Date: 20100822-27
• [Presentation] The role of regulatory T cells in lung fibrosis (2010)
  • Author(s): Boveda-Ruiz D, Toda M, D' Alessandro-Gabazza CN, Gil-Bernabe P, Miyake Y, Yasukawa A, Naito M, Takagi T, Morser J, Taguchi O, Gabazza EC.
  • Organizer: The 14^<th> International Congress of Immunology
  • Place of Presentation: Kobe, Japan
  • Year and Date: 20100822-27
• [Presentation] Exogenous activated protein C ameliorates diabetic nephropathy (2010)
  • Author(s): Gil-Bernabe P, Yano Y, D' Alessandro-Gabazza CN, Boveda-Ruiz D, Toda M, Miyake Y, Yasukawa A, Takagi T, Morser J, Taguchi O, Gabazza EC.
  • Organizer: The 14^<th> International Congress of Immunology
  • Place of Presentation: Kobe, Japan
  • Year and Date: 20100822-27
• [Presentation] Protective effect of thrombomodulin in a murine model of allergen-induced asthma (2010)
  • Author(s): Takagi T, Taguchi O, Toda M, Kobayashi H, Kobayashi T, Fujiwara A, Naito M, D' Alessandro-Gabazza CN, Boveda-Ruiz D, Gil-Bernabe P, Morser J, Gabazza EC.
  • Organizer: The 14^<th> International Congress of Immunology
  • Place of Presentation: Kobe, Japan
  • Year and Date: 20100822-27
• [Presentation] Allergen-induced bronchial asthma in the factor V Leiden mouse (2010)
  • Author(s): Yasukawa A, Toda M, Miyake Y, D' Alessandro-Gabazza CN, Boveda-Ruiz D, Takagi T, Naito M, Taguchi O, Morser J, Gabazza EC.
  • Organizer: The 14^<th> International Congress of Immunology
  • Place of Presentation: Kobe, Japan
  • Year and Date: 20100822-27
• [Presentation] Role of thrombin-activatable fibrinolysis inhibitor in lipopolysaccharide-induced acute lung injury (2010)
  • Author(s): Naito M, Taguchi O, Takagi T, Toda M, Kobayashi T, Miyake Y, Boveda-Ruiz D, D' Alessandro-Gabazza CN, Morser J, Takei Y, Gabazza EC.
  • Organizer: Congress of the International Society on Thrombosis and Haemostasis
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 20100723-28
• [Presentation] Protective role of protein S in liver fibrosis (2010)
  • Author(s): Moroka R, Gil-Bernabe P, D' Alessandro-Gabazza CN, Boveda-Ruiz D, Toda M, Miyake Y, Yasukawa A, Naito M, Takagi T, Iwasa M, Taguchi O, Morser J, Takei Y, Gabazza EC.
  • Organizer: Congress of the International Society on Thrombosis and Haemostasis
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 20100723-28
• [Presentation] Protective effect of thrombomodulin in a murine model of allergen-induced asthma (2010)
  • Author(s): Takagi T, Taguchi O, Naito M, Toda M, Kobayashi T, Miyake Y, Boveda-Ruiz D, D' Alessandro-Gabazza CN, Morser J, Gabazza EC.
  • Organizer: Congress of the International Society on Thrombosis and Haemostasis
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 20100723-28
• [Presentation] Thrombomodulin modulates maturation and antigen presentation of murine dendritic cells in vitro (2010)
  • Author(s): Toda M, Takagi T, Taguchi O, Boveda-Ruiz D, Gil-Bernabe P, D' Alessandro-Gabazza CN, Miyake Y, Yasukawa A, Morser J, Gabazza EC.
  • Organizer: Congress of the International Society on Thrombosis and Haemostasis
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 20100723-28
• [Presentation] Allergen-induced bronchial asthma in the factor V Leiden mouse (2010)
  • Author(s): Miyake Y, Matsushima Y, D' Alessandro-Gabazza CN, Takagi T, Naito M, Boveda-Ruiz D, Gil-Bernabe P, Morser J, Taguchi O, Gabazza EC.
  • Organizer: Congress of the International Society on Thrombosis and Haemostasis
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 20100723-28
• [Presentation] The role of thrombin in allergic bronchial bronchial asthma is mediated by dendritic cells (2010)
  • Author(s): Miyake Y, Matsushima Y, D' Alessandro-Gabazza CN, Takagi T, Naito M, Boveda-Ruiz D, Gil-Bernabe P, Morser J, Taguchi O, Gabazza EC.
  • Organizer: Congress of the International Society on Thrombosis and Haemostasis
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 20100723-28
• [Presentation] Protective role of thrombin-activatable fibrinolysis inhibitor in allergic bronchial asthma (2010)
  • Author(s): Boveda-Ruiz D, D' Alessandro-Gabazza CN, Toda M, Gil-Bernabe P, Miyake Y, Yasukawa A, Matsushima Y, Naito M, Takagi T, Morser J, Taguchi O, Gabazza EC.
  • Organizer: Congress of the International Society on Thrombosis and Haemostasis
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 20100723-28
• [Presentation] Protein Salters differentiation, maturation and antigen presentation of murine dendritic cells in vitro (2010)
  • Author(s): Matsushima Y, Corina N. D' Alessandro-Gabazza, Takagi T, Naito M, Boveda-Ruiz D, Gil-Bernabe P, Taguchi O, Morser J, Gabazza EC.
  • Organizer: Congress of the International Society on Thrombosis and Haemostasis
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 20100723-28
• [Presentation] Role of thrombin-activatable fibrinolysis inhibitor in bronchial asthma (2009)
  • Author(s): Takagi T, Naito M, Fujiwara A, Fujimoto H, Ebihara A, Yasui H, Kobayashi T, Kobayashi H, D' Alessandro-Gabazza CN, Gabazza EC, Takei Y, Taguchi O.
  • Organizer: European Respiratory Society International Congress
  • Place of Presentation: Vienna, Austria
  • Year and Date: 20090912-15
• [Presentation] Effect of a thrombin inhibitor on murine bronchial asthma (2009)
  • Author(s): Fujiwara A, Naito M, Takagi T, Ebihara A, Kobayashi T, Kobayashi H, D' Alessandro-Gabazza CN, Gabazza EC, Takei Y, Taguchi O.
  • Organizer: European Respiratory Society International Congress
  • Place of Presentation: Vienna, Austria
  • Year and Date: 20090912-15
• [Patent(Industrial Property Rights)] ヒトTGFβ1を発現するトランスジェニックマウス (2011)
  • Inventor(s): 小林哲、Gabazza Esteban
  • Industrial Property Rights Holder: 小林哲、Gabazza Esteban
  • Industrial Property Number: 特許、特願2011-237166
  • Filing Date: 2011-10-28