Pulmonary fibrosis treatment with pulmonary surfactant as a TLR regulatory molecule and HSP47 inhibition

• Project/Area Number: 17K09662
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Sapporo Medical University
• Principal Investigator: Takahashi Hiroki 札幌医科大学, 医学部, 教授 (60231396)
• Co-Investigator(Kenkyū-buntansha): 高橋 素子 札幌医科大学, 医学部, 教授 (00303941) ; 千葉 弘文 札幌医科大学, 医学部, 准教授 (40347175) ; 大塚 満雄 札幌医科大学, 医学部, 研究員 (10398323) ; 黒沼 幸治 札幌医科大学, 医学部, 講師 (40563250)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 肺サーファクタント / 肺傷害 / 間質性肺炎 / 内科 / 免疫学

Outline of Final Research Achievements

Objective: To develop a new therapeutic method for idiopathic pulmonary fibrosis under the hypothesis that surfactant protein (SP) -A supplementation and HSP47 siRNA suppress lung inflammation and fibrosis. Method: BLM was intratracheally administered to SP-A (-/-) and wild-type mice to prepare a lung injury / fibrosis model, and siRNA HSP47 was intravenously administered. Results: Inflammation and fibrosis were enhanced in SP-A deficient mice compared to wild type. In addition, siRNA HSP47 reduced lung injury and suppressed BLM-induced airway inflammation. Conclusion: SP-A supplementation and siRNA HSP47 suppressed the formation of lung injury / fibrotic lesions, and it was shown that the combination of both could be one of the new treatments for pulmonary fibrosis.

Academic Significance and Societal Importance of the Research Achievements

特発性肺線維症は予後が三年程度の難治性疾患であり、自然免疫の破綻と線維の過剰産生が悪化のメカニズムに関与している。肺線維症の動物モデルで検討した結果、自然免疫調整因子であるサーファクタント蛋白質(SP)-Aが欠損すると病変が悪化し、また、siRNA HSP47で線維生成を抑制することによって悪化が抑制された。したがって、両者の併用が肺線維症の新たな治療法のひとつになりうることが示された。

Research Products

• [Journal Article] Surfactant protein A as a biomarker of outcomes of anti-fibrotic drug therapy in patients with idiopathic pulmonary fibrosis (2020)
  • Author(s): Yoshikawa Takumi、Otsuka Mitsuo、Chiba Hirofumi、Ikeda Kimiyuki、Mori Yuki、Umeda Yasuaki、Nishikiori Hirotaka、Kuronuma Koji、Takahashi Hiroki
  • Journal Title: BMC Pulmonary Medicine Volume: 20 Issue: 1 Pages: 2727-2727
  • DOI: 10.1186/s12890-020-1060-y
  • Peer Reviewed / Open Access
• [Journal Article] Respiratory reactance in forced oscillation technique reflects disease stage and predicts lung physiology deterioration in idiopathic pulmonary fibrosis (2020)
  • Author(s): Mori Y、Nishikiori H、Chiba H、Yamada G、Kuronuma K、Takahashi H.
  • Journal Title: Respir Physiol Neurobiol Volume: 275 Pages: 103386-103386
  • DOI: 10.1016/j.resp.2020.103386
  • Peer Reviewed / Open Access
• [Journal Article] Aberrant populations of circulating T follicular helper cells and regulatory B cells underlying idiopathic pulmonary fibrosis (2019)
  • Author(s): Asai Yuichiro、Chiba Hirofumi、Nishikiori Hirotaka、Kamekura Ryuta、Yabe Hayato、Kondo Shun、Miyajima Satsuki、Shigehara Katsunori、Ichimiya Shingo、Takahashi Hiroki
  • Journal Title: Respiratory Research Volume: 20 Issue: 1 Pages: 244-244
  • DOI: 10.1186/s12931-019-1216-6
  • Peer Reviewed / Open Access
• [Journal Article] Immunogenicity of pneumococcal vaccines in comorbid autoimmune and chronic respiratory diseases. (2019)
  • Author(s): Kuronuma K, Takahashi H.
  • Journal Title: Hum Vaccin Immunother Volume: - Pages: 1-4
  • Peer Reviewed / Open Access
• [Journal Article] Poorer Prognosis of Idiopathic Pleuroparenchymal Fibroelastosis Compared with Idiopathic Pulmonary Fibrosis in Advanced Stage (2018)
  • Author(s): Shioya Makoto、Otsuka Mitsuo、Yamada Gen、Umeda Yasuaki、Ikeda Kimiyuki、Nishikiori Hirotaka、Kuronuma Koji、Chiba Hirofumi、Takahashi Hiroki
  • Journal Title: Canadian Respiratory Journal Volume: 2018 Pages: 1-7
  • DOI: 10.1155/2018/6043053
  • Peer Reviewed / Open Access
• [Journal Article] Response to pneumococcal vaccine in interstitial lung disease patients: Influence of systemic immunosuppressive treatment (2018)
  • Author(s): Kuronuma Koji、Honda Hiroyuki、Mikami Tessei、Saito Atsushi、Ikeda Kimiyuki、Otsuka Mitsuo、Chiba Hirofumi、Yamada Gen、Sato Toyotaka、Yokota Shin-ichi、Takahashi Hiroki
  • Journal Title: Vaccine Volume: 36 Issue: 33 Pages: 4968-4972
  • DOI: 10.1016/j.vaccine.2018.06.062
  • Peer Reviewed / Open Access
• [Journal Article] Impaired diversity of the lung microbiome predicts progression of idiopathic pulmonary fibrosis (2018)
  • Author(s): Takahashi Youhei、Saito Atsushi、Chiba Hirofumi、Kuronuma Koji、Ikeda Kimiyuki、Kobayashi Tomofumi、Ariki Shigeru、Takahashi Motoko、Sasaki Yasushi、Takahashi Hiroki
  • Journal Title: Respir Res Volume: 19 Issue: 1 Pages: 34-34
  • DOI: 10.1186/s12931-018-0736-9
  • Peer Reviewed / Open Access
• [Journal Article] Significance of molecular biomarkers in idiopathic pulmonary fibrosis: A mini review (2018)
  • Author(s): Chiba Hirofumi、Otsuka Mitsuo、Takahashi Hiroki
  • Journal Title: Respiratory Investigation Volume: 56 Issue: 5 Pages: 384-391
  • DOI: 10.1016/j.resinv.2018.06.001
  • Peer Reviewed / Open Access
• [Journal Article] Serum surfactant protein D predicts the outcome of patients with idiopathic pulmonary fibrosis treated with pirfenidone. (2017)
  • Author(s): Ikeda K, Shiratori M, Chiba H, Nishikiori H, Yokoo K, Saito A, Hasegawa Y, Kuronuma K, Otsuka M, Yamada G, Takahashi H.
  • Journal Title: Respiratoru Medicine Volume: 131 Pages: 184-191
  • Peer Reviewed / Open Access
• [Journal Article] Treatment of pulmonary fibrosis with siRNA against a collagen-specific chaperone HSP47 in vitamin A-coupled liposomes. (2017)
  • Author(s): Otsuka M, Shiratori M, Chiba H, Kuronuma K, Sato Y, Niitsu Y, Takahashi H.
  • Journal Title: Experimental Lung Research Volume: 43 Pages: 271-282
  • Peer Reviewed / Open Access