Therapeutic effect of combined protein C pathway factors on acutelung injury

• Project/Area Number: 18590846
• 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: Mie University
• Principal Investigator: TAGUCHI Osamu Mie University, Hospital, Lecturer (90197244)
• Co-Investigator(Kenkyū-buntansha): GABAZZA Esteban Mie University, Graduate School of Medicine, Professor (00293770)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥4,010,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥510,000); Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
• Keywords: Acute lung iniury / Combined therapy / Protein S / Protein C pathway / Cytokines / Sepsis / Activated protein C / Coagulation system / 併用治療 / プロテインC制御機構 / 敗血症状 / 炎症性サイトカイン / 血液凝固系 / 肺胞マクロファージ / 血液凝固制御機構 / 急性肺傷害 / 感染症

Research Abstract

Background: Protein S (PS) and activated protein C (APC) have anticoagulant and anti-inflammatory activities. PS may exert anticoagulant activity by favoring the anticoagulant activity of APC and/or by directly inhibiting the prothrombinase complex. The role of PS and the combination of PS and APC on acute lung injury have not been as yet appraised.
Objective : The aim of this present study was to evaluate the effect of PS and APC plus PS on acute lung injury in the mouse.
Methods : Acute lung injury was induced in C57/BL6 mice by intratracheal instillation of lipopolysaccharide(LPS)(5mg/kg). Mice treated with saline served as controls. To evaluate the therapeutic effect of PS and APC plus PS, the animals were treated with PS alone, a combination of PS and APC or saline by intraperitoneal injection one hour before LPS instillation. These animals were sacrificed 24 hours after LPS injection and sampling of bronchoalveolar lavage fluid and lung tissue were performed. The in vitro effect of PS on secretion of inflammatory cytokines from alveolar epithelial cells was also assessed.
Results : The total cell count and the bronchoalveolar lavage fluid level of total protein, interleukin-6 and monocyte chemoattractant protein-1 were significantly increased in LPS-treated mice compared with controls. Mice with acute lung injury treated with PS and combined therapy of PS plus APC had significantly decreased concentration of interleukin-6 and monocyte chemoattractant protein-1 in bronchoalveolar lavage fluid as compared to untreated animals. Treatment with protein C pathway factors also improved lung pathological changes. PS alone significantly abated the expression of inflammatory cytokines from alveolar epithelial cells.
Conclusions : These results suggest that combined administration of protein C pathway factors may be a potential therapeutic strategy for the therapy of acute lung injury.

Research Products

• [Journal Article] Role of thrombin in interleukin-5 expression from basophils. (2008)
  • Author(s): Yamaguchi A
  • Journal Title: Biochem Biophys Res Commun 368 Pages: 116-120
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Protective role of thrombin activatable fibrinolysis inhibitor in obstructive nephropathy-associated tubulointerstitial fibrosis. (2008)
  • Author(s): Bruno N
  • Journal Title: J Thromb Haemost 6 Pages: 139-146
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Role of thrombin in interleukin-5 expression from basophils (2008)
  • Author(s): Yamaguchi, A, Gabazza, EC, Takei, Y, Yano, Y, Fujimoto, H, D'Alessandro-Gabazza, CN, Murakami, E, Kobayashi, T, Takagi, T, Maruyama, J, Suzuki, K, Taguchi, O
  • Journal Title: Biochem Biophys Res Commun 368 Pages: 116-20
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Protective role of thrombin activatable fibrinolysis inhibitor in obstructive nephropathy-associated tubulointerstitial fibrosis (2008)
  • Author(s): Bruno, NE, Yano, Y, Takei, Y, Gabazza, EC, Qin, L, Nagashima, M, Morser, J, D'Alessandro-Gabazza, CN, Taguchi, O, Sumida, Y
  • Journal Title: J Thromb Haemost 6 Pages: 139-46
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Inhibition of nuclear factor-kappa B in T cells suppresses lung fibrosis. (2007)
  • Author(s): Fujimoto H
  • Journal Title: Am J Respir Crit Care Med 176 Pages: 1251-1260
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Inhibition of nuclear factor-kappa B in T cells suppresses lung fibrosis (2007)
  • Author(s): Fujimoto, H, D'Alessandro-Gabazza, CN, Palanki, MS, Erdman, PE, Takagi, T, Gabazza, EC, Bruno, NE, Yano, Y, Hayashi, T, Tamaki, S, Sumida, Y, Adachi, Y, Suzuki, K, Taguchi, O
  • Journal Title: Am J Respir Crit Care Med 176 Pages: 1251-60
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Inhibition of nuclear factor-kappaB in T cells suppresses lung fibrosis. (2007)
  • Author(s): Fujimoto H
  • Journal Title: Am J Respir Crit Care Med 176 Pages: 1251-1260
  • Peer Reviewed
• [Journal Article] Deficiency of tenascin C attenuates allergen-induced bronchial asthma in the mouse. (2006)
  • Author(s): Nakahara H
  • Journal Title: Eur J Immunol 36 Pages: 3334-33345
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Protective role of protein C inhibitor in monocrotaline-induced pulmonary hypertension (2006)
  • Author(s): Nishii Y
  • Journal Title: J Thromb Haemost 4 Pages: 2331-2339
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Deficiency of tenascin C attenuates allergen-induced bronchial asthma in the mouse (2006)
  • Author(s): Nakahara, H, Gabazza, EC, Fujimoto, H, Nishii, Y, D'Alessandro-Gabazza, CN, Bruno, NE, Takagi, T, Hayashi, T, Maruyama, J, Maruyama, K, Imanaka-Yoshida, K, Suzuki, K, Yoshida, T, Adachi, Y, Taguchi, O
  • Journal Title: Eur J Immunol 36 Pages: 3334-45
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Protective role of protein C inhibitor in monocrotaline-induced pulmonary hypertension (2006)
  • Author(s): Nishii, Y, Gabazza, EC, Fujimoto, H, Nakahara, H, Takagi T, Bruno, N, D'Alessandro-Gabazza, CN, Maruyama, Maruyama, K, Hayashi, T, Adachi, Y, Suzuki, K, Taguchi, O
  • Journal Title: J Thromb Haemost 4 Pages: 2331-9
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Protective role of protein C inhibitor in monocrotaline-induced pulmonary hypertension (2006)
  • Author(s): Yoichi Nishii
  • Journal Title: Journal of Thrombosis and Haemostasis 4・11 Pages: 2331-2339
• [Journal Article] Decreased protein C activation in patients with fulminant hepatic failure (2006)
  • Author(s): Michihiko Yamaguchi
  • Journal Title: Scandinavian Journal of Gastroenterology 41・3 Pages: 331-337
• [Journal Article] Lipopolysaccharide-induced decreased protein S expression in liver cells is mediated by MEK/ERK signaling and NFkappaB activation : involvement of membrane-bound CD14 and toll-like receptor-4 (2006)
  • Author(s): Tatsuya Hayashi
  • Journal Title: Journal of Thrombosis and Haemostasis 4・8 Pages: 1763-1773
• [Journal Article] Deficiency of tenascin C attenuates allergen-induced bronchial asthma in the mouse (2006)
  • Author(s): Hiroki Nakahara
  • Journal Title: European Journal of Immunology 36・12 Pages: 3334-3345
• [Presentation] Allergen-induced bronchial asthma in the factor v leiden mouse (2007)
  • Author(s): Takagi T
  • Organizer: European Respiratory Society International Congress
  • Place of Presentation: Stockholm, Sweden
  • Year and Date: 2007-09-17
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Role of NF-kappa-B p50 in bleomycin-induced pulmonary fibrosis (2007)
  • Author(s): Takagi T
  • Organizer: European Respiratory Society International Congress
  • Place of Presentation: Stockholm, Sweden
  • Year and Date: 2007-09-17
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Role of NF-kappaB p50 in bleomycin-induced pulmonary fibrosis (2007)
  • Author(s): Takagi, T, Gabazza, EC, Fujimoto, H, Maruyama, T, Nishii, Nakahara, H, D'Alessandro-Gabazza, CN, Kobayashi, H, Taguchi, O
  • Organizer: European Respiratory Society International Congress
  • Place of Presentation: Stockholm, Sweden
  • Year and Date: 2007-09-17
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Effect of protein S on lipopolysaccharide-induced acute lung injury (2007)
  • Author(s): Takagi T
  • Organizer: American Thoracic Society International Congress
  • Place of Presentation: San Francisco, California, USA
  • Year and Date: 2007-05-22
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Role of Thrombin in interleukin-5 secretion from basophils (2007)
  • Author(s): Yamaguchi A
  • Organizer: American Thoracic Society International Congress
  • Place of Presentation: San Francisco, California, USA
  • Year and Date: 2007-05-22
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Role of Thrombin in Interleukin-5 Secretion from Basophils (2007)
  • Author(s): Yamaguchi, A, Gabazza, EC, Takagi, T, Nakahara, H, H., Fujimoto, H, Kobayashi, T, Kobayashi, H, D'Alessandro-Gabazza, CN, Taguchi, O
  • Organizer: American Thoracic Society International Congress
  • Place of Presentation: San Francisco, California, USA
  • Year and Date: 2007-05-22
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Effect of protein S on lipopolysaccharide-induced acute lung injury (2007)
  • Author(s): Takagi T
  • Organizer: American Thoracic Society International Congress
  • Place of Presentation: San Francisco,California,USA
  • Year and Date: 2007-05-22
• [Book] Encyclopedia of Respiratory Medicine (2006)
  • Author(s): Esteban C Gabazza
  • Total Pages: 2576
  • Publisher: Elsevier