Pulmonary collectin regulates drug-induced lung injury.

• Project/Area Number: 20590930
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Sapporo Medical University
• Principal Investigator: TAKAHASHI Hiroki Sapporo Medical University, 医学部, 教授 (60231396)
• Co-Investigator(Kenkyū-buntansha): KUROKI Yoshio 札幌医科大学, 医学部, 教授 (70161784)
• Co-Investigator(Renkei-kenkyūsha): SHIRATORI Masanori 札幌医科大学, 医学部, 講師 (40295366) ; CHIBA Hirofumi 札幌医科大学, 医学部, 助教 (40347175) ; KUDO Kazumi 札幌医科大学, 医学部, 助教 (90438002) ; KURONUMA Koji 札幌医科大学, 医学部, 助教 (40563250)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2010: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2009: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2008: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 薬剤性肺障害 / ブレオマイシン / 肺コレクチン / 肺サーファクタント蛋白質A / トル様受容体 / SP-A / TLR2 / ノックアウトマウス / 肺線維化

Research Abstract

The purposes of this project were to investigate the mechanisms of regulation by which lung collectins, surfactant proteins A and D (SP-A and SP-D), and Toll-like receptor (TLR) function against inflammation on the development of drug induced lung injury, and to establish the molecular basis for the clinical application of these proteins. First, the mouse model of lung injury was established using drugs, and SP-A^<-/-> mice had significantly higher mortality rates than WT mice. SP-A inhibited drug-induced inflammatory cytokine production from rat alveolar macrophages. SP-A blocked sTLR2-bleomycin binding in the dose dependent manner. These results suggest that bleomycin signals are transmitted through TLR2 dependent pathway and regulated by the molecular interaction of SP-A.

Research Products

• [Journal Article] Pulmonary Collectins Protect Macrophages against Pore-forming Activity of Legionella pneumophila and Suppress Its Intracellular Growth. (2010)
  • Author(s): Sawada K, Ariki S, Kojima T, Saito A, Yamazoe M, Nishitani C, Shimizu T, Takahashi M, Mitsuzawa H, Yokota S, Sawada N, Fujii N, Takahashi H, Kuroki Y.
  • Journal Title: J Biol Chem 285 Pages: 8434-8443
  • Peer Reviewed
• [Journal Article] Development of an enzyme-linked immunosorbent assay for measurement of rat pulmonary surfactant protein D using monoclonal antibodies. (2010)
  • Author(s): Murata M, Otsuka M, Mizuno H, Shiratori M, Miyazaki S, Nagae H, Kanazawa S, Hamaoki M, Kuroki Y, Takahashi H.
  • Journal Title: Exp Lung Res 36 Pages: 463-468
  • Peer Reviewed
• [Journal Article] Development of an enzyme-linked immunosorbent assay for measurement of rat pulmonary surfactant protein D using monoclonal antibodies. (2010)
  • Author(s): Murata M, Takahashi H, et al.
  • Journal Title: Exp Lung Res Volume: 36・8 Pages: 463-468
  • Peer Reviewed
• [Journal Article] Pulmonary collectins protect macrophages against pore-forming activity of legionella pneumophila and suppress its intracellular growth. (2010)
  • Author(s): Sawada K, Takahashi H, et al.
  • Journal Title: J Biol Chem Volume: 285・11 Pages: 8434-8443
  • Peer Reviewed
• [Journal Article] Increasing antiviral activity of surfactant protein d trimers by introducing residues from bovine serum collectins : dissociation of mannan-binding and antiviral activity (2010)
  • Author(s): Hartshorn KL, Kuroki Y, et al.
  • Journal Title: Scand J Immunol Volume: 72・1 Pages: 22-30
  • Peer Reviewed
• [Journal Article] Vpr induces TLR4/MyD88-mediated IL-6 production and reactivates viral production from latency. (2010)
  • Author(s): Hoshino S, Kuroki Y, et al.
  • Journal Title: J Leukoc Biol. Volume: 87・6 Pages: 1133-1143
  • Peer Reviewed
• [Journal Article] Pulmonary Collectins Protect Macrophages against Pore-forming Activity of Legionella pneumophila and Suppress Its Intracellular Growth (2010)
  • Author(s): Sawada K, et al
  • Journal Title: J Biol Chem
  • Peer Reviewed
• [Journal Article] Anionic pulmonary surfactant phospholipids inhibit inflammatory responses from alveolar macrophages and U937 cells by binding the lipopolysaccharide-interacting proteins CD14 and MD-2 (2009)
  • Author(s): Kuronuma K, et al
  • Journal Title: J Biol Chem 284 Pages: 25488-25500
  • Peer Reviewed
• [Journal Article] Pulmonary surfactant protein D binds MD-2 through the carbohydrate recognition domain. (2008)
  • Author(s): Nie X, Nishitani C, Yamazoe M, Ariki S, Takahashi M, Shimizu T, Mitsuzawa H, Sawada K, Smith K, Crouch E, Nagae H, Takahashi H, Kuroki Y.
  • Journal Title: Biochemistry 47 Pages: 12878-12885
  • Peer Reviewed
• [Journal Article] Pulmonary Surfactant Protein D Inhibits Lipopolysaccharide (LPS)-induced Inflammatory cell responses by altering LPS binding to its receptors. (2008)
  • Author(s): Yamazoe M, Nishitani C, Takahashi M, Katoh T, Ariki S, Shimizu T, Mitsuzawa H, Sawada K, Voelker DR, Takahashi H, Kuroki Y.
  • Journal Title: J Biol Chem 283 Pages: 35878-35888
  • Peer Reviewed
• [Journal Article] Pulmonary surfactant protein D binds MD-2 through the carbohydrate recognition domain. (2008)
  • Author(s): Nie X, et al
  • Journal Title: Biochemistry 47 Pages: 12878-12885
  • Peer Reviewed
• [Journal Article] Pulmonary surfactant protein D inhibits lipopolysaccharide (LPS)-induced inflammatory cell responses by altering LPS binding to its receptors. (2008)
  • Author(s): Yamazoe M, et al
  • Journal Title: J Biol Chem 283 Pages: 35878-35888
  • Peer Reviewed
• [Journal Article] Circulating surfactant protein A (SP-A), a marker of lung injury, is associated with insulin resistance. (2008)
  • Author(s): Fernandez-Real JM, et al
  • Journal Title: Diabetes Care 31 Pages: 958-63
  • Peer Reviewed
• [Presentation] Surfactant protein A modulate bleomycin-induced lung injury in toll-like receptor 2 dependent pathway (2010)
  • Author(s): Kuronuma K, Takahashi H, et al
  • Organizer: European Respiratory Society
  • Place of Presentation: スペイン バルセロナ
  • Year and Date: 2010-09-20
• [Presentation] Surfactant protein A modulate bleomycininduced lung injury in toll-like receptor 2 dependent pathway. (2010)
  • Author(s): Kuronuma K, Kudo K, Kuroki Y, Takahashi H.
  • Organizer: In : 20^<th> European Respiratory Society Annual Congress
  • Place of Presentation: Barcelona, Spain
• [Presentation] Anionic surfactant phospholipids modulate Mycoplasma pneumoniae-induced inflammatory response from alveolar macrophages and U937 cells (2009)
  • Author(s): Kuronuma K
  • Organizer: European Respiratory Society
  • Place of Presentation: オーストリア ウィーン
  • Year and Date: 2009-09-16
• [Presentation] Anionic surfactant phospholipids modulate Mycoplasma pneumoniae-Induced inflammatory response from alveolar macrophages and U937 Cells. (2009)
  • Author(s): Kuronuma K, Chiba H, Takahshi H, Voelker D.
  • Organizer: In : The 19^<th> European Respiratory Society Annual Congress
  • Place of Presentation: Wien, Austria
• [Presentation] Autoantibodies to the surfactant protein D in patientswith interstitial lung diseases associated with amyopathic dermatomyositis and systemic sclerosis. (2008)
  • Author(s): Chiba H
  • Organizer: European Respiratory Society
  • Place of Presentation: ドイツ ベルリン
  • Year and Date: 2008-10-06
• [Presentation] 間質性肺炎とバイオマーカー (2008)
  • Author(s): 高橋 弘毅
  • Organizer: 日本呼吸器学会
  • Place of Presentation: 兵庫県神戸市 神戸コンベンションセンター
  • Year and Date: 2008-06-16
• [Presentation] Pulmonary collectins exhibit bactericidal activity against Legionella pneumophila. (2008)
  • Author(s): Sawada K, Ariki S, Yamazoe M, Nishitani C, Shimizu T, Takahashi M, Yokota S, Fujii N, Takahashi H, Kuroki Y.
  • Organizer: In : The 8^<th> Awaji International Forum on Infection and Immunity
  • Place of Presentation: Awaji, Japan
• [Presentation] Surfactant protein D in sera as a prognostic factor of idiopathic pulmonary fibrosis. (2008)
  • Author(s): Shiratori M, Kanai A, Otsuka M, Chiba H, Takahashi H.
  • Organizer: In : The 103^<th> International Conference of American Thoracic Society
  • Place of Presentation: Toronto, Canada
• [Book] Annual Rewiew 呼吸器2010(III. 診断の進歩:3.肺線維症におけるバイオマーカーの最近の知見)(永井厚志 他編)東京 (2010)
  • Author(s): 高橋弘毅、白鳥正典、千葉弘文
  • Publisher: 中外医学社
• [Book] 間質性肺疾患診療マニュアル(間質性肺疾患の診断・検査:E1B.サーファクタント蛋白質(SP-A, SP-D))(杉山幸比古、藤田次郎編)東京 (2010)
  • Author(s): 高橋弘毅
  • Publisher: 南光堂
• [Remarks] ホームページ等