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Investigation on the mechanism for the inhibitory effect of the fibrinolytic system on fibrotic process and its therapeutic approach to limit pulmonary fibrosis

Research Project

Project/Area Number 14370200
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Respiratory organ internal medicine
Research InstitutionThe Tazuke Kofukai

Principal Investigator

HATTORI Noburu  Kitano Hospital The Tazuke Kofukai Medical Research Institute, The Fifth Department of Oncology, Chief-researcher, 医学研究所・第5研究部, 主任研究員 (00283169)

Co-Investigator(Kenkyū-buntansha) MIYAKE Masayuki  Kitano Hospital The Tazuke Kofukai Medical Research Institute, The Fifth Department of Thoracic Surgery, Associate-Director, 医学研究所・第5研究部, 部長 (90250076)
Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥14,000,000 (Direct Cost: ¥14,000,000)
Fiscal Year 2003: ¥4,900,000 (Direct Cost: ¥4,900,000)
Fiscal Year 2002: ¥9,100,000 (Direct Cost: ¥9,100,000)
KeywordsPulmonary fibrosis / Fibrinolytic system / HGF / Bleomycin / Urokinase / Aerosol delivery
Research Abstract

We have previously demonstrated that plasminogen activator inhibitor-1 (PAl-1) deficient (PAl-1-/-) mice are protected from developing bleomycin-induced pulmonary fibrosis. We hypothesize that PAl-1 deficiency limits fibrosis through enhanced fibrinolytic activity. Using the tetracycline gene regulatory system, we have generated a transgenic mouse model with the features of inducible, lung specific urokinase. expression. After doxycycline administration, these transgenic mice showed enhanced fibrinolytic activity in the lung and were protected from developing bleomycin-induced pulmonary fibrosis. While searching for an alternative mechanism by which the fibrinolytic system limits pulmonary fibrosis, we have developed an interest in hepatocyte growth factor (HGF). This growth factor, when administered systemically or intratracheally, attenuates bleomycin-induced pulmonary fibrosis, and its activation is in part mediated by the fibrinolytic system. In the current study, we found that HGF … More levels in BAL fluids following bleomycin administration were significantly higher in PAl-1-/-mice compared to PAl-1+/+ mice. Treatment of the bleomycin-injured mice with tranexamic acid, an inhibitor of fibrinolytic system, decreased HGF levels in the bronchoalveolar lavage (BAL) fluids. In addition, neutralization of endogenous HGF in bleomycin-injured PAl-1-/-mice with an anti-HGF antibody markedly increased collagen accumulation in the lungs. Furthermore, we demonstrated that the intratracheal instillation of urokinase into bleomycin-injured PAl-1+/+ mice resulted in a significant increase in the BAL HGF level and less collagen accumulation in the lungs. These results suggest that a mechanism by which the fibrinolytic system limits pulmonary fibrosis is through the mediation of HGF.
Based on these results, we tried aerosol delivery of urokinase to bleomycin-injured mice lungs but found that this approach could not protect the lungs from developing pulmonary fibrosis. This could be due to low efficiency of aerosol delivery to mice lungs. Improvement of aerosol delivery system and alteration of animal models should be considered. Less

Report

(3 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • Research Products

    (34 results)

All Other

All Publications (34 results)

  • [Publications] Ikeda, N. et al.: "Clinical Significance of Aminopeptidase N/CD13 Expression in Human Pancreatic Carcinoma."Clinical Cancer Research. 9. 1503-1508 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hashida, H. et al.: "Clinical Significance of Transmembrane 4 Superfamily in Colon Cancer."British Journal of Cancer. 89. 158-167 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Chin, K. et al.: "Effects of obstructive sleep apnea syndrome on serum aminotransferase levels in obese patients."Am J Med. 114. 370-376 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hattori, Y. et al.: "Vascular expression of matrix metalloproteinase-13(collagenase-3) in basal cell carcinoma."Exp Mol Pathol. 74. 230-237 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Chuang-Tsai S. et al.: "Reduction in fibrotic tissue formation in mice genetically deficient in plasminogen activator inhibitor-1."American Journal of Pathology. 163. 445-452 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hattori, N. et al.: "The plasminogen activation system reduces fibrosis in the lung by a hepatocyte growth factor-dependent mechanism."American Journal of Pathology. 164. 1091-1098 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hattori, N, Miyake, M: "Gene therapy for pulmonary diseases"Frontiers in Immuno-gene Therapy. 18 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 三宅正幸 et al.: "これだけは知っておきたい-遺伝子医学の基礎知識"メデイカル ドゥ. 7 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shimizu, K., Chin, K., Nakamura, T., Masuzaki, H., Ogawa, Y., Hosokawa, R., Niimi, A., Hattori, N., Sasayama, S., Nakao, K., Mishima, M., Nakamura, T., Ohi, M.: "Plasma leptin levels and cardiac sympathetic function in patients with obstructive sleep apnoea-hypopnoea syndrome."THORAX. 57. 429-434 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sisson, TH., Hanson, KE., Subbotina, N., Patwardhan, A., Hattori, N., Simon, RH.: "Inducible lung-specific urokinase expression reduces fibrosis and mortality after lung injury in mice."Am J Physiol Lung Cell Mol Physiol. 283. L1023-L1032 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hashida, H., Takabayashi, A., Tokuhara, T., Taki, T., Kondo, K., Kohno, N., Yamaoka, Y., Miyake M.: "Integrin α3 Expression as a Prognostic Factor in Colon Cancer : Association with MRP-1/CD9 and KAI1/CD82."INT J CANCER. 97. 518-525 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kohno, M., Hasegawa, H., Miyake, M., Yamamoto, T., Fujita, S.: "CD151 Enhances Cell Motility and Metastasis of Cancer Cells in the Presence of Focal Adhesion Kinase."INT J CANCER. 97. 336-343 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hashida, H., Takabayashi, A., Kanai, M., Adachi, M., Kondo, K., Kohno, N., Yamaoka, Y., Miyake, M.: "Aminopeptidase N Is Involved in Cell Motility and Angiogenesis : Its Clinical Significance in Human Colon Cancer."GASTRORNTEROLOGY. 122. 376-386 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kim, KK., Flaherty, KR., Long, Q., Hattori, N., Sisson, TH., Colby, TV., Travis, WD., Martinex, FJ., Murray, S., Simon, RH.: "A plasminogen activator inhibitor-1 promoter polymorphism and Idiopathic interstitial pneumonia."Mol Med. 9. 52-56 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ikeda, N., Nakajima, Y., Tokuhara, T., Hattori, N., Sho, M., Kanehiro, H., Miyake, M.: "Clinical Significance of Aminopeptidase N/CD13 Expression in Human Pancreatic Carcinoma."CLIN CANCER RES. 9. 1503-1508 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Chin, K., Nakamura, T., Takahashi, K., Sumi, K., Ogawa, Y., Masuzaki, H., Muro, S., Hattori, N., Matsumoto, H., Niimi, A., Chiba, T., Nakao, K., Mishima, M., Ohi, M., Nakamura, T.: "Effects of obstructive sleep apnea syndrome on serum aminotransferase Levels in obese patients."Am J Med. 114. 370-376 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hashida, H., Takabayashi, A., Tokuhara, T., Hattori, N., Taki, T., Hasegawa, H., Satoh, S., Kobayashi, N., Yamaoka, Y., Miyake, M.: "Clinical Significance of Transmenbrane 4 Superfamily in Colon Cancer."BRIT J CANCER. 89. 158-167 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hattori Y., Nerusu, KC., Bhagavathula, N., Brennan, M., Hattori, N., Murphy, HS., Su, LD., Wang, TS., Johnson, TM., Varani, J.: "Vascular expression of matrix metalloproteinase-13 (collagenase-3) In basal cell carcinoma."Exp Mol Pathol.. 74. 230-237 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Chuang-Tsai, S., Sisson, TH., Hattori, N., Tsai, CG., Subbotina, NM., Hanson, KB., Simon, RH.: "Reduction in fibrotic tissue formation in mice genetically deficient in Plasminogen avtivator inhibitor-1."AM J PATHOL. 163. 445-452 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ding, Y., Shimada, Y., Maeda, M., Kawabe, A., Kaganoi, J., Komoto, I., Hashimoto Y., Miyake M., Hashida, H., Imamura, M: "Association of CC cChemokine Receptor 7 with Lymph Node Metastasis of Esophageal Squamous Cell Carcinoma."CLIN CANCER RES. 9. 3406-3412 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hattori, N., Mizuno, S., Yoshida, Y, Chin, K., Mishima, M., Sisson, TH., Simon, RH., Nakamura, T., Miyake, M.: "The Plasminogen activation system reduces fibrosis in the lung by a Hepatocyte growth factor-dependent mechanism."AM J PATHOL. 164. 1091-1098 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hattori, N., Miyake M.: "Gene therapy for pulmonary diseases."Frontiers in Immuno-gene Therapy. 209-225 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ikeda, N. et al.: "Clinical significance of aminopeptidase N/CD13 expression in human pancreatic carcinoma"Clinical Cancer Research. 9. 1503-1508 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Hattori Y, et al.: "Vascular expression of matrix metalloproteinase-13 (collagenase-3) in basal cell carcinoma"Experimental and Molecular Pathology. 74. 230-237 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Hashida H, et al.: "Clinical significance of transmembrane 4 superfamily in colon cancer"British Journal of Cancer. 89. 158-167 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Chin K, et al.: "Effects of obstructive sleep apnea syndrome on serum aminotransferase levels in obese patients"American Journal of Medicine. 114. 370-376 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Chuang-Tsai S, et al.: "Reduction in fibrotic tissue formation in mice genetically deficient in plasminogen activator inhibitor-1"American Journal of Pathology. 163. 445-452 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Hattori N, et al.: "The plasminogen activation system reduces fibrosis in the lung by a hepatocyte growth factor-dependent mechanism"American Journal of Pathology. 164. 1091-1098 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Shimizu, K. et al.: "Plasma leptm levels and cardiac sympathetic function in patients with obstructive sleep apnoea-hypopnoea syndrome"Thorax. 47. 429-434 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Sisson, TH. et al.: "Inducible lung-specific urokinase expression reduces fibrosis and mortality after lung injury in mice"Amencan Journal of Physiology-Lung cellular and molecular physiology. 283. L1023-L1032 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kim, KK. et al.: "A plasminogen activator inhibitor-1 promoter polymorphism and idiopathic interstitial pneumonia"Molecular Medicine. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] Ikeda, N. et al.: "Clinical significance of aminopeptidase N/CD13 expression in human pancreatic carcinoma"Clinical Cancer Research. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] Hattori Y, et al.: "Vascular expression of matrix metalloprotemase-13 (collagenase-3) in basal cell carcinoma"Experimental and Molecular Pathology. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] 服部 登: "線溶系-呼吸器疾患とのかかわり"分子呼吸器病. 6. 58-60 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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