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Mechanism of cell damage and repair in acute lung injury

Research Project

Project/Area Number 16390457
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Anesthesiology/Resuscitation studies
Research InstitutionKyoto Prefectural University of Medicine

Principal Investigator

HASHIMOTO Satoru  Kyoto Prefectural University of Medicine, Department of Anesthesiology, Associate professor (90167578)

Co-Investigator(Kenkyū-buntansha) SHIME Nobuaki  Kyoto Prefectural University of Medicine, Department of Anesthesiology, Associate professor (00260795)
AMAYA Funimasa  Kyoto Prefectural University of Medicine, Department of Anesthesiology, Assistant professor (60347466)
UENO Hiroshi  Kyoto Prefectural University of Medicine, Department of Anesthesiology, Assistant professor (20381965)
ISHIZAKA Akitoshi  Keio University, School of Medicine, Department of Internal Medicine, Professor (90176181)
Project Period (FY) 2004 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥13,330,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥930,000)
Fiscal Year 2007: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2006: ¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2005: ¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2004: ¥3,100,000 (Direct Cost: ¥3,100,000)
KeywordsAcute lung injury / HMGB1 / Microsampling / Ventilator induced lung iniury / Fas / FasL / アポトーシス / ラミニン / ATP / モエシン / ARDS / 急性肺障害
Research Abstract

The first study was performed to examine the putative role of high-mobility group box (HMGB) protein in the pathogenesis of acute lung injury. Observations were made 1) in 21 septic patients with acute lung injury and 15 patients with normal lung function, and 2) in a mouse model, 24 h after intratracheal instillation of lipopolysaccharide. The concentrations of HMGB 1 were increased in plasma and lung epithelial lining fluid of patients with acute lung injury and mice instilled with lipopolysaccharide. Lipopolysaccharide-induced acute lung injury was mitigated by anti-HMGB1 antibody. Although this protein was not detected in the plasma of control humans or mice, the concentrations of HMGB 1 in lung epithelial lining fluid or in bronchoalveolar lavage fluid were unexpectedly high. The nuclear expression of HMGB 1 was apparent in epithelial cells surrounding terminal bronchioles in normal mice, while its nuclear and cytoplasmic expression was observed in alveolar macrophages in lipopoly … More saccharide-instilled mice. Lung instillation of HMGB2 did not cause as much inflammation as HMGB 1. Extracellular HMGB 1 may play a key role in the pathogenesis of clinical and experimental acute lung injury. However, its expression in normal airways is noteworthy, and suggests that it also plays a physiologic role in the lung. And the second study was about Fas/FasL system. Alveolar epithelial cell death plays a crucial role in the progression of acute lung injury. We have demonstrated up-regulation of Fas expression on alveolar epithelial cells, and soluble Fas ligand secretion from inflammatory cells upon acute lung injury. Here we show that the lipopolysaccharide-stimulated human monocyte cell line THP-1 releases Fas ligand, and that conditioned medium from lipopolysaccharide-stimulated THP-1 cells induces apoptosis of the human pulmonary adenocarcinoma cell line A549. Activation of caspase-3 and -8 is associated with the apoptosis. Gene targeting on Fas in A549 cells by specific small interfering RNA impairs apoptosis induced by conditioned medium from activated THP-1, while that on Fas ligand in THP-1 cells impairs the apoptosis-inducing activity of the conditioned medium produced by lipopolysaccharide-stimulated cells. These results suggest that Fas ligand released by monocytes causes alveolar epithelial cell death through a Fas-dependent apoptotic mechanism in the development of acute lung injury. Less

Report

(5 results)
  • 2007 Annual Research Report   Final Research Report Summary
  • 2006 Annual Research Report
  • 2005 Annual Research Report
  • 2004 Annual Research Report
  • Research Products

    (30 results)

All 2008 2007 2006 2005 2004

All Journal Article (19 results) (of which Peer Reviewed: 8 results) Presentation (11 results)

  • [Journal Article] Fas ligand released by activated monocytes causes apoptosis of lung epithelial cells in human acute lung injury model in vitro2008

    • Author(s)
      Mizuta M, Nakajima H, Mizuta N, Kitamura Y, Nkakajima Y, Hashimoto S, Matsuyama H, Shime N, Amaya F, Koh H, Ishizaka A, Magae J, Tanuma S, Hashimoto S
    • Journal Title

      Biol Pharm Bull 31

      Pages: 386-390

    • NAID

      110006623061

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Vascular endothelial growth factor in epithelial lining fluid of patients with acute respiratory distress syndrome2008

    • Author(s)
      Koh H, Tasaka S, Hasegawa N, Asano K, Kotani T, Morisaki H, Takeda J, Fujishima S, Matsuda T, Hashimoto S, Ishizaka A
    • Journal Title

      Respirology 13

      Pages: 281-284

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Pharmacokinetics of clarithromycin in bronchial epithelial lining fluid2008

    • Author(s)
      Kikuchi E, Yamazaki K, Kikuchi J, Hasegawa N, Hashimoto S, Ishizaka A, Nishimura M
    • Journal Title

      Respirology 13

      Pages: 221-226

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Fas ligand released by activated monocytes causes apoptosis of lung epithelial cells in human acute lung injury model in vitro2008

    • Author(s)
      Mizuta, M., Nakajima, H., Mizuta, N., Kitamura, Y., Nkakajima, Y., Hashimoto, S., Matsuyama, H., Shime, N., Amaya, F., Koh, H., Ishizaka, A., Magae, J., Tanuma, S., Hashimoto, S
    • Journal Title

      Biol Pharm Bull 31(3)

      Pages: 386-390

    • NAID

      110006623061

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Pharmacokinetics of clarithromycin in bronchial epithelial lining fluid2008

    • Author(s)
      Kikuchi, E., Yamazaki, K., Kikuchi, J., Hasegawa, N., Hashimoto, S., Ishizaka, A., Nishimura, M
    • Journal Title

      Respirology 13

      Pages: 221-6

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Vascular endothelial growth factor in epithelial lining fluid of patients with acute respiratory distress syndrome2008

    • Author(s)
      Koh, H., Tasaka, S., Hasegawa, N., Asano, K., Kotani, T., Morisaki, H., Takeda, J., Fujishima, S., Matsuda, T., Hashimoto, S., Ishizaka, A
    • Journal Title

      Respirology 13

      Pages: 281-4

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Fas ligand released by activated monocytes causes apoptosis of lung epithelial cells in human acute lung injury model in vitro.2008

    • Author(s)
      Mizuta M, Nakajima H, Mizuta N, Kitamura Y, . Nkakajima Y, Hashimoto S, Matsuyama H, Shime N, Amaya F, Koh H, Ishizaka A, Maga J, Tanuma S, Hashimoto S
    • Journal Title

      Biol Pharm Bull 31

      Pages: 386-390

    • NAID

      110006623061

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Vascular endothelial growth factor in epithelial lining fluid of patients with acute respiratory distress syndrome.2008

    • Author(s)
      Koh H, Tasaka S, Hasegawa N, Asano K, Kotani T, Morisaki H, Takeda J, Fujishima S, Matsuda T, Hashimoto S, Ishizaka A
    • Journal Title

      Respirology 13

      Pages: 281-284

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Pharmacokinetics of clarithromycin in bronchial epithelial lining fluid.2008

    • Author(s)
      Kikuchi E, Yamazaki K, Kikuchi J, Hasegawa N, Hashimoto S, Ishizaka A, Nishimura M
    • Journal Title

      Respirology 13

      Pages: 221-226

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Neutrophil elastase inhibitor improves postoperative clinical courses after thoracic esophagectomy2007

    • Author(s)
      Suda K, Kitagawa Y, Ozawa S, Miyasho T, Okamoto M, Saikawa Y, Ueda M, Yamada S, Tasaka S, Funakoshi Y, Hashimoto S, Yokota H, Maruyama I, Ishizaka A, Kitajima M
    • Journal Title

      Dis Esophagus 20

      Pages: 478-486

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Effects of controlled perioperative antimicrobial prophylaxis on infectious outcomes in pediatric cardiac surgery2007

    • Author(s)
      Kato, Y., Shime, N., Hashimoto, S., Nomura, M., Okayama, Y., Yamagishi, M., Fujita, N
    • Journal Title

      Crit Care Med 35

      Pages: 1763-1768

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Neutrophil elastase inhibitor improves postoperative clinical courses after thoracic esophagectomy2007

    • Author(s)
      Suda, K., Kitagawa, Y., Ozawa, S., Miyasho, T., Okamoto, M., Saikawa, Y., Ueda, M., Yamada, S., Tasaka, S., Funakoshi, Y., Hashimoto, S., Yokota, H., Maruyama, I., Ishizaka, A., Kitajima, M
    • Journal Title

      Dis Esophagus 20(6)

      Pages: 478-486

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Neutrophil elastase inhibitor improves postoperative clinical courses after thoracic esophagectomy.2007

    • Author(s)
      Suda K, Kitagawa Y, Ozawa S, Miyasho T, Okamoto M, Saikawa Y, Ueda M, Yamada S, Tasaka S, Funakoshi Y, Hashimoto S, Yokota H, Maruyama I, Ishizaka A, Kitajima M
    • Journal Title

      Dis Esophagus 20

      Pages: 478-486

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Contribution of High Mobility Group Box-1 to the Development of Ventilator-induced Lung Injury2006

    • Author(s)
      Ogawa, EN., Ishizaka, A., Tasaka, S., Koh, H., Ueno, H., Amaya, F., Ebina, M., Yamada, S., Funakoshi, Y., Soejima, J., Moriyama, K., Kotani, T., Hashimoto, S., Morisaki, H., Abraham, E., Takeda, J
    • Journal Title

      Am J Respir Crit Care Med 174

      Pages: 400-407

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Anti-High-Mobility Group Box Chromosomal Protein 1 Antibodies Improve Survival of Rats with Sepsis2006

    • Author(s)
      Suda, K., Kitagawa, Y., Ozawa, S., Saikawa, Y., Ueda, M., Ebina, M., Yamada, S., Hashimoto, S., Fukata, S., Abraham, E., Maruyama, I., Kitajima, M., Ishizaka, A
    • Journal Title

      World J Surg 30

      Pages: 1755-62

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Contribution of High Mobility Group Box-1 to the Development of Ventilator-induced Lung Injury.2006

    • Author(s)
      Ogawa N, Ishizaka A, Hashimoto S, et al.
    • Journal Title

      Am J Respir Crit Care Med 174:12

      Pages: 400-407

    • Related Report
      2006 Annual Research Report
  • [Journal Article] ARDSnetworkの現状と最新の成果2005

    • Author(s)
      橋本悟, 小林敦子
    • Journal Title

      臨床医学 31(4)

      Pages: 484-490

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Clinical Outcome in Acute Lung Injury is Predicted by KL-6, a Lung Epithelial Cell Marker2004

    • Author(s)
      Ishizaka, A., Matsuda, T., Albertine, KH., Koh, H., Tasaka, S., Hasegawa, N., Kohno, N., Kotani, T., Morisaki, H., Takeda, J., Nakamura, M., Fang, X., Martin, TR., Matthay, MA., Hashimoto, S
    • Journal Title

      Am J Physiol 286

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Contributions of High Mobility Group Box Protein in Experimental and Clinical Acute Lung Injury2004

    • Author(s)
      Ueno, H., Matsuda, T., Hashimoto, S., Amaya, F., Kitamura, Y., Tanaka, M., Kobayashi, A., Maruyama, I., Yamada, S., Hasegawa, N., Soejima, J., Koh, H., Ishizaka, A
    • Journal Title

      Am J Respir Crit Care Med 170

      Pages: 1310-6

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Adenosine triphosphate instillation induces lung inflammation in mouse2007

    • Author(s)
      Matsuyama H, Hashimoto S, Amaya F, Mizuta M, Ueno H, Hashimoto S
    • Organizer
      American Thoracic Society annual meeting
    • Place of Presentation
      San Diego,USA
    • Year and Date
      2007-05-21
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Substantial role of Moesin, a class of ERM protein, for maintenance of alveoral structure and function2007

    • Author(s)
      Hashimoto, S., Matsuyama, H., Amaya, F., Mizuta, M., Ueno, H., Kikuchi, S., Ishizaka, A., Hashimoto, S
    • Organizer
      ATS Meeting
    • Place of Presentation
      San Francisco
    • Year and Date
      2007-05-21
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Adenosine triphosphate instillation induces lung inflammation in mouse2007

    • Author(s)
      Matsuyama, H., Hashimoto, So., Amaya, F., Mizuta, M., Ueno, H., Hashimoto, S
    • Organizer
      ATS Meeting
    • Place of Presentation
      San Francisco
    • Year and Date
      2007-05-21
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Adenosine triphosphate instillation induces lung inflammation inmouse.2007

    • Author(s)
      Matsuyama H, Hashimoto S, Amaya F, Mizuta M, Ueno H, Hashimoto S
    • Organizer
      American Thoracic Society annual meeting
    • Place of Presentation
      San Diego, USA
    • Year and Date
      2007-05-21
    • Related Report
      2007 Annual Research Report
  • [Presentation] Lung protective ventilation Versus hyperventilation in pediatric patients with pulmonary hypertension after heart surgery2006

    • Author(s)
      Umenai, T., Shime, N., Kato, Y., Hashimoto, S
    • Organizer
      ATS Meeting
    • Place of Presentation
      San Diego
    • Year and Date
      2006-05-23
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Lipopolysaccharide-Stimulated Human Macrophages Induce Apoptosis of Human Lung Epithelial Cells (A549) via Release of Soluble Fas Ligand2006

    • Author(s)
      Mizuta, M., Mizuta, N., Kitamura, Y., Nakajima, Y., Hashimoto, S., Matsuyama, H., Koh, H., Ishizaka, A., Nakajima, H., Hashimoto, S
    • Organizer
      ATS Meeting
    • Place of Presentation
      San Diego
    • Year and Date
      2006-05-21
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Endothelin-1 levels of serum and epithelial lining fluid in ALI/ARDS2006

    • Author(s)
      Nakano, Y., S., Tasaka, Hashimoto, S., Ogawa, Y., Kurihara, A., Saito, F., Yamada, W., Shimizu, M., Koh, H., Nakamura, M., Hasegawa, N., Fujishima, S., Ishizaka, A
    • Organizer
      ATS Meeting
    • Place of Presentation
      San Diego
    • Year and Date
      2006-05-21
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Measurement of neutrophil elastase activity in ARDS patients treated with neutrophil elastase inhibitor2005

    • Author(s)
      Hashimoto, S., Okayama, Y., Shime, N., Amaya, F., Ishizaka, A
    • Organizer
      ATS Meeting
    • Place of Presentation
      San Diego
    • Year and Date
      2005-05-22
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] High mobility group protein (HMGB1) as a possible mediator of acute exacerbation in idiopathic pulmonary fibrosis2005

    • Author(s)
      Ebina, M., Kimura, Y., Shibata, N., Konishi, K., Ishizaka, A., Hashimoto, S., MaruyamaI, Nukiwa, T
    • Organizer
      ATS Meeting
    • Place of Presentation
      San Diego
    • Year and Date
      2005-05-22
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Large tidal volume ventilation increases high mobility group box-1 in bronchoalveolar lavage fluid in rabbit lung2005

    • Author(s)
      Ogawa, EN., Ishizaka, A., Hashimoto, S., Morisaki, H., Takeda, J
    • Organizer
      ATS Meeting
    • Place of Presentation
      San Diego
    • Year and Date
      2005-05-22
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Alveolar Epithelial Cell Repair Process Assessed by Laminin 5 gamma 2-chain Measurements in Patients with Acute Lung Injury2004

    • Author(s)
      Ishizaka, A., Katayama, M., Sakamoto, M., Sekiguchi, K., Hashimoto, S
    • Organizer
      Orlando
    • Year and Date
      2004-05-24
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary

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Published: 2004-04-01   Modified: 2016-04-21  

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