Exploration of therapeutic targets for refractory inflammatory lung diseases and development of novel therapeutic strategies

2006 Fiscal Year Final Research Report Summary

• Project/Area Number: 15209029
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: The University of Tokyo
• Principal Investigator: NAGASE Takahide The University of Tokyo, Faculty of Medicine, Professor, 医学部附属病院, 教授 (40208004)
• Co-Investigator(Kenkyū-buntansha): KURIHARA Hiroki The University of Tokyo, Graduate School of Medicine, Professor, 大学院医学系研究科, 教授 (20221947)
• Project Period (FY): 2003 – 2006
• Keywords: Lipid mediators / Antimicrobial peptides / Transgenic mouse / Knockout mouse

Research Abstract

Inflammatory lung diseases including acute lung injury and pulmonary fibrosis are of significant importance in terms of both motality and difficulty in management. Acute respiratory distress syndrome (ARDS) is an acute lung injury and the mortality rate for ARDS ranges from 40-70% despite of intensive care. Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disorder of the lung parenchyma, while no useful drugs are currently available to treat IPF. However, molecular mechanisms underlying these lung diseases are little known and the development of a novel therapeutic strategy is of urgent necessity. The purpose of this project is to investigate molecular mechanisms underlying inflammatory lung diseases and develop novel therapeutic strategies. We studied the pathophysiological roles of 1) lipid mediators including platelet-activating factor (PAF) and metabolites of arachidonic acid, i.e., eicosanoids, 2) CGRP family peptides, and 3) antimicrobial peptides. We have shown that these substances might be involved in the pathogenesis of inflammatory lung diseases including ARDS and IPF, suggesting that bioactive mediators, e.g., lipid mediators, might be potential targets to develop a novel therapeutic strategy to refractory lung diseases.

Research Products

• [Journal Article] Beta-defensin overexpression induces progressive muscle degeneration in mice. (2007)
  • Author(s): Yamaguchi Y, Nagase T, Tomita T, Nakamura K, Fukuhara S, Amano T, Yamamoto H, Ide Y, Suzuki M, Teramoto S, Asano T, Kangawa K, Nakagata N, Ouchi Y, Kurihara H
  • Journal Title: Am J Physiol Cell Physiol (in press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Impaired innate adrenomedullin function deteriorates airway hyperresponsiveness in mice : possible roles of allergen-induced airway wall remodeling. (2007)
  • Author(s): Yamamoto H, Nagase T, Shindo T, Teramoto S, Aoki-Nagase T, Yamaguchi Y, Yokomizo T, Nagai R, Kurihara H, Ouchi Y
  • Journal Title: J Appl Physiol (in press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Calcitonin gene-related peptide mediates acid-induced lung injury in mice. (2007)
  • Author(s): Aoki-Nagase T, Nagase T, Oh-hashi Y, Kurihara Y, Yamaguchi Y, Yamamoto H, Nagata T, Kurihara H, Ouchi Y
  • Journal Title: Respirology (in press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Beta-defensin overexpression induces progressive muscle degeneration in mice. (2007)
  • Author(s): Yamaguchi Y, Nagase T, Tomita T, Nakamura K, Fukuhara S, Amano T, Yamamoto H, Ide Y, Suzuki M, Teramoto S, Asano T, Kangawa K, Nakagata N, Ouchi Y, Kurihara H.
  • Journal Title: Am J Physiol Cell Physiol (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Impaired innate adrenomedullin function deteriorates airway hyperresponsiveness in mice : possible roles of allergen-induced airway wall remodeling. (2007)
  • Author(s): Yamamoto H, Nagase T, Shindo T, Teramoto S, Aoki-Nagase T, Yamaguchi Y, Yokomizo T, Nagai R, Kurihara H, Ouchi Y.
  • Journal Title: J Appl Physiol (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Calcitonin gene-related peptide mediates acid-induced lung injury in mice. (2007)
  • Author(s): Aoki-Nagase T, Nagase T, Oh-hashi Y, Kurihara Y, Yamaguchi Y, Yamamoto H, Nagata T, Kurihara H, Ouchi Y.
  • Journal Title: Respirology (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Betaine improved restriction digestion. (2005)
  • Author(s): Sugimoto K, Makihara T, Saito A, Ohishi N, Nagase T, Takai D
  • Journal Title: Biochem Biophys Res Commun 337 Pages: 1027-1029
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Absence of leukotriene B4 receptor 1 confers resistance to airway hyperresponsiveness and Th2-type immune responses. (2005)
  • Author(s): Terawaki K, Yokomizo T, Nagase T, Toda A, Taniguchi M, Hashizume K, Yagi T, Shimizu T
  • Journal Title: J Immunol 175 Pages: 4217-4225
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Acute and chronic effects of eicosapentaenoic acid on voltage-gated sodium channel expressed in cultured human bronchial smooth muscle cells. (2005)
  • Author(s): Jo T, Iida H, Kishida S, Imuta H, Oonuma H, Nagata T, Hara H, Iwasawa K, Soma M, Sato Y, Nagase T, Nagai R, Nakajima T
  • Journal Title: Biochem Biophys Res Commun 331 Pages: 1452-1459
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Leukotriene D_4 potentiates fibronectin-induced migration of human lung fibroblasts. (2005)
  • Author(s): Kato J, Kohyama T, Okazaki H, Desaki M, Rennard SI, Takizawa H, Nagase T
  • Journal Title: Clinical Immunol 117 Pages: 177-181
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Molecular mechanisms underlying inflammatory lung diseases in the elderly : development of a novel therapeutic strategy for acute lung injury and pulmonary fibrosis. (2005)
  • Author(s): Nagase T, Aoki-Nagase T, Yamaguchi Y, Yamamoto H, Ouchi Y
  • Journal Title: Griatrics Gerontology International 5 Pages: 139-145
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Betaine improved restriction digestion. (2005)
  • Author(s): Sugimoto K, Makihara T, Saito A, Ohishi N, Nagase T, Takai D.
  • Journal Title: Biochem Biophys Res Commun 337 Pages: 1027-9
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Absence of leukotriene B4 receptor 1 confers resistance to airway hyperresponsiveness and Th2-type immune responses. (2005)
  • Author(s): Terawaki K, Yokomizo T, Nagase T, Toda A, Taniguchi M, Hashizume K, Yagi T, Shimizu T.
  • Journal Title: J Immunol 175 Pages: 4217-25
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Acute and chronic effects of eicosapentaenoic acid on voltage-gated sodium channel expressed in cultured human bronchial smooth muscle cells. (2005)
  • Author(s): Jo T, Iida H, Kishida S, Imuta H, Oonuma H, Nagata T, Hara H, Iwasawa K, Soma M, Sato Y, Nagase T, Nagai R, Nakajima T.
  • Journal Title: Biochem Biophys Res Commun 331 Pages: 1452-9
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Leukotriene D_4 potentiates fibronectin-induced migration of human lung fibroblasts. (2005)
  • Author(s): Kato J, Kohyama T, Okazaki H, Desaki M, Rennard SI, Takizawa H, Nagase T.
  • Journal Title: Clinical Immunol 117 Pages: 177-181
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Molecular mechanisms underlying inflammatory lung diseases in the elderly : development of a novel therapeutic strategy for acute lung injury and pulmonary fibrosis. (2005)
  • Author(s): Nagase T, Aoki-Nagase T, Yamaguchi Y, Yamamoto H, Ouchi Y.
  • Journal Title: Griatrics Gerontology International 5 Pages: 139-145
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Platelet-activating factor receptor develops airway hyperresponsiveness independently of airway inflammation in a murine asthma model. (2004)
  • Author(s): Ishii S, NagaseT, Shindou H, Takizawa H, Ouchi Y, Shimizu T
  • Journal Title: J Immunol 172 Pages: 7095-7102
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] New therapeutic key for cystic fibrosis : a role for lipoxins. News and Views(論文解説) (2004)
  • Author(s): Takai D, Nagase T, Shimizu T
  • Journal Title: Nature Immunol 5 Pages: 2004; 5
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Voltage-gated sodium channel expressed in cultured human smooth muscle cells : Involvement of SCN9A. (2004)
  • Author(s): Jo T, Nagata T, Iida H, Imuta H, Iwasawa K, Ma J, Hara K, Omata M, Nagai R, Takizawa H, Nagase T, Nakajima T
  • Journal Title: FEBS Lett 567 Pages: 339-343
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Platelet-activating factor receptor develops airway hyperresponsiveness independently of airway inflammation in a murine asthma model. (2004)
  • Author(s): Ishii S, Nagase T, Shindou H, Takizawa H, Ouchi Y, Shimizu T.
  • Journal Title: J Immunol 172 Pages: 7095-7102
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] New therapeutic key for cystic fibrosis : a role for lipoxins. (2004)
  • Author(s): Takai D, Nagase T, Shimizu T.
  • Journal Title: Nature Immunol 5(News and Views) Pages: 357-8
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Voltage-gated sodium channel expressed in cultured human smooth muscle cells : Involvement of SCN9A. (2004)
  • Author(s): Jo T, Nagata T, Iida H, Imuta H, Iwasawa K, Ma J, Hara K, Omata M, Nagai R, Takizawa H, Nagase T, Nakajima T.
  • Journal Title: FEBS Lett 567 Pages: 339-43
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A potent inhibitor of cytosolic phospholipase A_2, arachidonyl trifluoromethyl ketone, attenuates LPS-induced lung injury in mice. (2003)
  • Author(s): Nagase T, Uozumi N, Aoki-Nagase T, Terawaki K, Ishii S, Tomita T, Yamamoto H, Hashizume K, Ouchi Y, Shimizu T
  • Journal Title: Am J Physiol Lung Cell Mol Physiol 284 Pages: L720-L726
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The effects of obstructive sleep apnea on circulating ICAM-1, IL-8 and MCP-1. (2003)
  • Author(s): Ohga E, Tomita T, Wada H, Yamamoto H, Nagase T, Ouchi Y
  • Journal Title: J Appl Physiol 94 Pages: 179-184
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A potent inhibitor of cytosolic phospholipase A_2, arachidonyl trifluoromethyl ketone, attenuates LPS-induced lung injury in mice. (2003)
  • Author(s): Nagase T, Uozumi N, Aoki-Nagase T, Terawaki K, Ishii S, Tomita T, Yamamoto H, Hashizume K, Ouchi Y, Shimizu T.
  • Journal Title: Am J Physiol Lung Cell Mol Physiol 284 Pages: L720-L726
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The effects of obstructive sleep apnea on circulating ICAM-1, IL-8 and MCP-1. (2003)
  • Author(s): Ohga E, Tomita T, Wada H, Yamamoto H, Nagase T, Ouchi Y.
  • Journal Title: J Appl Physiol 94 Pages: 179-184
  • Description: 「研究成果報告書概要(欧文)」より