Mechanism of cell damage and repair in acute lung injury

• Project/Area Number: 16390457
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Anesthesiology/Resuscitation studies
• Research Institution: Kyoto 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: ¥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)
• Keywords: Acute 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 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.

Research Products

• [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, 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
  • 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
  • Description: 「研究成果報告書概要(和文)」より
  • 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
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [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., 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
• [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: 221-6
  • Description: 「研究成果報告書概要(欧文)」より
• [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: 281-4
  • Description: 「研究成果報告書概要(欧文)」より
• [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
  • 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
  • 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
  • Peer Reviewed
• [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
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Effects of controlled perioperative antimicrobial prophylaxis on infectious outcomes in pediatric cardiac surgery (2007)
  • 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
• [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(6) Pages: 478-486
  • Description: 「研究成果報告書概要(欧文)」より
• [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
  • Peer Reviewed
• [Journal Article] Contribution of High Mobility Group Box-1 to the Development of Ventilator-induced Lung Injury (2006)
  • 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
• [Journal Article] Anti-High-Mobility Group Box Chromosomal Protein 1 Antibodies Improve Survival of Rats with Sepsis (2006)
  • 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
• [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
• [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
• [Journal Article] Clinical Outcome in Acute Lung Injury is Predicted by KL-6, a Lung Epithelial Cell Marker (2004)
  • 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
• [Journal Article] Contributions of High Mobility Group Box Protein in Experimental and Clinical Acute Lung Injury (2004)
  • 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
• [Presentation] Adenosine triphosphate instillation induces lung inflammation in mouse (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
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Substantial role of Moesin, a class of ERM protein, for maintenance of alveoral structure and function (2007)
  • 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
• [Presentation] Adenosine triphosphate instillation induces lung inflammation in mouse (2007)
  • 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
• [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
• [Presentation] Lung protective ventilation Versus hyperventilation in pediatric patients with pulmonary hypertension after heart surgery (2006)
  • 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
• [Presentation] Lipopolysaccharide-Stimulated Human Macrophages Induce Apoptosis of Human Lung Epithelial Cells (A549) via Release of Soluble Fas Ligand (2006)
  • 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
• [Presentation] Endothelin-1 levels of serum and epithelial lining fluid in ALI/ARDS (2006)
  • 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
• [Presentation] Measurement of neutrophil elastase activity in ARDS patients treated with neutrophil elastase inhibitor (2005)
  • 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
• [Presentation] High mobility group protein (HMGB1) as a possible mediator of acute exacerbation in idiopathic pulmonary fibrosis (2005)
  • 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
• [Presentation] Large tidal volume ventilation increases high mobility group box-1 in bronchoalveolar lavage fluid in rabbit lung (2005)
  • 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
• [Presentation] Alveolar Epithelial Cell Repair Process Assessed by Laminin 5 gamma 2-chain Measurements in Patients with Acute Lung Injury (2004)
  • 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