| Project/Area Number |
16590745
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Respiratory organ internal medicine
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| Research Institution | Mie University |
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Principal Investigator |
TAGUCHI Osamu Mie University, School of Medicine, Research Associate, 医学部附属病院, 講師 (90197244)
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| Co-Investigator(Kenkyū-buntansha) |
GABAZZA Esteban Mie University, School of Medicine, Research Associate, 大学院・医学系研究科, 助手 (00293770)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2004: ¥2,600,000 (Direct Cost: ¥2,600,000)
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| Keywords | Coagulation system / Inflammatory cytokines / Lung fibrosis / Thrombin receptors / Hypofibrinolysis / Thrombin / Lung inflammatory disease / Animal models / 線溶系 / 気道リモデリング / 成長因子 / 実験動物モデル / 気管支喘息 / 肺線維症モデル / Th2サイトカイン / 気道過敏性 / 気管支喘息モデル / トロンビンレセプター / 肺障害 / 間質性肺疾患 / 喘息の発症 |
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| Research Abstract |
Background : The coagulation and fibrinolysis systems play a critical role in the pathogenesis of chronic inflammatory lung diseases including bronchial asthma, pulmonary artery hypertension and lung fibrosis. The authors have previously demonstrated that patients with chronic inflammatory diseases of the lung show increased activation of the coagulation system with dysfunction of the anticoagulant protein C pathway. It has been also recently demonstrated that the protease-activated receptor-1 (PAR-1) is involved in cell activation and that the protective action of activated protein C is mediated by PAR-1.
Objective : In the present study, we hypothesized that PAR-1 and TAFI are involved in the mechanistic pathway of lung injury and fibrosis.
Method : To demonstrate our hypothesis, we induced and compared the degree of lung fibrosis in wild type mice and in mice with PAR-1 and thrombin-activatable fibrinolysis inhibitor (TAFI) deficiency. Lung fibrosis was induced by treating the animals with bleomycin using subcutaneous osmotic minipumps ; the animals were sacrificed on the 3^<rd> week of bleomycin treatment.
Results : The results of this investigation showed that mice deficient in PAR-1 and TAFI have less collagen deposition as measured by the total lung content of collagen and hydroxyproline and less lung fibrotic changes as compared to their wild type counterparts. Measurement of inflammatory cytokines and growth factors was also performed in each group of mice. PAR-1 and TAFI knockout mice showed significantly decreased bronchoalveolar lavage fluid concentrations of TNF-α, IL-1β, TGF-β1 and thrombin-antithrombin complex as compared to wild type mice.
Conclusion : Overall, the results of this study showed that both PAR-1 and TAFI are involved in the pathogenesis of lung injury and fibrosis.
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