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

• 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
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2011: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2010: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2009: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• 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 / 肺気腫 / 樹状細胞 / マトリックスメタロプロテーゼ / サイトカイン / 活性かプロテインC / 気管支炎 / 慢性閉塞性肺疾患 / タバコ / 血管内皮細胞傷害 / 凝固系因子 / 肺胞上皮細胞傷害 / 活性化プロテインC / 肺傷害 / 凝固系 / トロンビン受容体 / T細胞 / 慢性気管支炎 / トロンビン

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] Role of Thrombin-Activatable Fibrinolysis Inhibitor in Allergic Bronchial Asthma (2011)
  • Author(s): Atsushi Fujiwara
  • Journal Title: Lung Volume: (掲載確定) Issue: 2 Pages: 189-198
  • DOI: 10.1007/s00408-011-9337-9
  • Year and Date: 2011-10-25
  • Peer Reviewed
• [Journal Article] Lung Radiofrequency Ablation for the Treatment of Unresectable Recurrent Non-Small-Cell Lung Cancer After Surgical Intervention (2011)
  • Author(s): Hiroshi Kodama
  • Journal Title: CardioVascular and Interventional Radiology Volume: (掲載確定) Issue: 3 Pages: 563-569
  • DOI: 10.1007/s00270-011-0220-0
  • Year and Date: 2011-07-06
  • 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: 500-500
  • 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] Solitary pulmonary nodule of benign metastasizing leiomyoma associated with primary lung cancer : a case report (2011)
  • Author(s): Masahiro Naito
  • Journal Title: Journal of Medical Case Reports Volume: 5 Issue: 1
  • DOI: 10.1186/1752-1947-5-500
  • Peer Reviewed
• [Journal Article] Community-acquired macrolide-resistant Mycoplasma pneumoniae pneumonia in patients more than 18 years of age (2011)
  • Author(s): Naoyuki Miyashita
  • Journal Title: Journal of Infection and Chemotherapy Volume: 1 Issue: 1 Pages: 114-8
  • DOI: 10.1007/s10156-010-0093-1
  • Peer Reviewed
• [Journal Article] Inhibition of allergic bronchial asthma by thrombomodulin is mediated by dendritic cells. (2011)
  • Author(s): Takagi T, Taguchi O, 他
  • Journal Title: American Journal of Respiratory and Critical Care Medicine 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: 1004-1004
  • 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] Development and Preclinical Efficacy of Novel Transforming Growth Factor-β1 siRNAs for Pulmonary Fibrosis (2010)
  • Author(s): Corina N D'Alessandro-Gabazza
  • Journal Title: American Journal of Respiratory Cell and Molecular Biology Volume: (掲載確定) Issue: 3 Pages: 397-406
  • DOI: 10.1165/rcmb.2011-0158oc
  • Peer Reviewed
• [Journal Article] Pulmonary hypertension is ameliorated in mice deficient in thrombin-activatable fibrinolysis inhibitor. (2010)
  • Author(s): Qin L, Taguchi O, 他
  • Journal Title: Journal of Thrombosis and Haemostasis Volume: 8 Pages: 808-816
  • 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, 他
  • Journal Title: British Medical Journal Volume: 340 Pages: 1004-1004
  • Peer Reviewed
• [Journal Article] Community-acquired pneumonia and nursing home-acquired pneumonia in the very elderly patients. (2010)
  • Author(s): Maruyama T, Taguchi O, 他
  • Journal Title: Respiratory Medicine Volume: 104 Pages: 584-592
  • Peer Reviewed
• [Journal Article] Resection of mucinous lung adenocarcinoma presenting with intractable bronchorrhea. (2010)
  • Author(s): Takao M, Taguchi O, 他
  • Journal Title: Journal of Thoracic Oncology Volume: 5 Pages: 576-578
  • Peer Reviewed
• [Journal Article] Pulmonary hypertension is ameliorated in mice deficient in thrombin-activatable fibrinolysis inhibitor (2010)
  • Author(s): Qin Liqiang
  • Journal Title: J.Thromb Haemost. (印刷中)
  • Peer Reviewed
• [Journal Article] Community-acquired pneumonia and nursing home-acquired pneumonia in the very elderly patients (2010)
  • Author(s): Maruyama Takaya
  • Journal Title: Respir Med (印刷中)
  • 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
• [Journal Article] Direct effects of protein S in ameliorating acute lung injury (2009)
  • Author(s): Takagi Takehiro
  • Journal Title: J Thromb Haemost 7 Pages: 2053-2063
  • Peer Reviewed
• [Presentation] Nasal obstruction and bronchial asthma (2011)
  • Author(s): Hiroyasu Kobayashi
  • Organizer: American Thoracic Society
  • Place of Presentation: Convention Center, Denver, Colorado
  • Year and Date: 2011-05-15
• [Presentation] New therapeutic strategy based on severity and multidrug resistance risk factors in healthcare associated pneumonia (2011)
  • Author(s): Takaya Maruyama
  • Organizer: American Thoracic Society
  • Place of Presentation: Convention Center, Denver, Colorado
  • Year and Date: 2011-05-04
• [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
• [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
• [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
• [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
• [Presentation] Deficiency of thrombion-activatable fibrinolysis inhibitor worsens bronchial asthma (2010)
  • Author(s): Takagi T, Taguchi O, 他
  • Organizer: 2010 American Thoraci Society International Conference
  • Place of Presentation: New Orleans(米国)
  • Year and Date: 2010-05-19
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [Presentation] Role of thrombin-activatable fibrinolysis inhibitor in bronchial asthma (2009)
  • Author(s): Takagi Takehiro
  • Organizer: European Respiratory Society
  • Place of Presentation: Vienna
  • Year and Date: 2009-09-14
• [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
• [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
• [Remarks]
  • URL: http://www.mie-u.ac.jp/
• [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: 2011-237166
  • Filing Date: 2011-10-28