Elucidation of the pathogenesis of pulmonary fibrosis and development of novel treatment based on cold-inducible RNA-binding protein

2021 Fiscal Year Research-status Report

• Project/Area Number: 21K08176
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: 穗積 宏尚 浜松医科大学, 医学部, 特任助教 (40771457)
• Co-Investigator(Kenkyū-buntansha): 須田 隆文 浜松医科大学, 医学部, 教授 (30291397)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 特発性肺線維症 / 低温誘導性RNA結合タンパク / ブレオマイシン / CIRBP

Outline of Annual Research Achievements

特発性肺線維症（IPF）は，極めて予後不良な原因不明の間質性肺疾患である．我々はIPF患者の臨床検体からプロテオーム解析技術を駆使して低温誘導性RNA結合タンパク（CIRBP）を同定し，この分子がIPF患者の血液や肺組織で高発現し，呼吸機能の悪化や予後不良と有意に関連することを発見した．本研究では，ブレオマイシン（BLM）肺線維症モデルマウスおよび線維芽細胞培養モデルを用いて，CIRBPの肺線維症形成における役割や肺線維芽細胞の機能への影響を明らかにする．そして，CIRBPの制御が線維化を抑制するかどうかを検討する．
今年度は、まずBLMモデル作成の手技およびその評価方法の確立を行った。その後、BLMモデルにおける野生型マウスとCIRBP欠損マウスの肺線維化の比較検討に移行した。野生型C57BL/6雄およびCIRBP欠損C57BL/6雄マウスに，BLMを経気道的に投与し，肺線維症を誘導した。投与後7，14，21，28日目に肺組織と気管支肺胞洗浄液（BALF）等を採取し，野生型マウスとCIRBP欠損マウスとで、病理学的評価、肺コラーゲン定量、線維化に関連する遺伝子（COL1A1，Acta2等）やCIRBP遺伝子の発現量、線維化の指標となるタンパク（COL1A1やαSMA等）やCIRBPタンパクの発現量の比較を行っている。

Current Status of Research Progress

3: Progress in research has been slightly delayed.

Reason

新型コロナウイルス感染症の拡大により、臨床業務との両立が難しく、マウス肺線維症モデル作成に関する手技およびモデルの確立が遅れることとなったため。また、CIRBPノックアウトマウスの入手計画にも遅れが生じたため。

Strategy for Future Research Activity

<計画1>引き続き、BLM肺線維症モデルにおける野生型マウスとCIRBP欠損マウスの肺線維化の比較実験を行う。
<計画2>BMLモデル野生型マウス肺におけるCIRBP発現細胞を検討する。
<計画3>野生型マウスから単離した肺線維芽細胞とCIRP-KOマウスから単離した肺線維芽細胞の増殖能や筋線維芽細胞への分化能、コラーゲン産生能を比較する。

Research Products

• [Journal Article] Impact of end-of-life respiratory modalities on quality of dying and death and symptom relief in patients with interstitial lung disease: a multicenter descriptive cross-sectional study. (2022)
  • Author(s): Koyauchi T, Suzuki Y, Sato K, Hozumi H, Karayama M, Furuhashi K, Fujisawa T, Enomoto N, Nakamura Y, Inui N, Yokomura K, Imokawa S, Nakamura H, Morita T, Suda T.
  • Journal Title: Respiratory Research Volume: 23 Pages: 79
  • DOI: 10.1186/s12931-022-02004-x.
  • Peer Reviewed / Open Access
• [Journal Article] Impact of antifibrotic therapy on lung cancer development in idiopathic pulmonary fibrosis. (2022)
  • Author(s): Naoi H, Suzuki Y, Mori K, Aono Y, Kono M, Hasegawa H, Yokomura K, Inoue Y, Hozumi H, Karayama M, Furuhashi K, Enomoto N, Fujisawa T, Nakamura Y, Inui N, Nakamura H, Suda T.
  • Journal Title: Thorax Volume: - Pages: -
  • DOI: 10.1136/thoraxjnl-2021-218281.
  • Peer Reviewed
• [Journal Article] Acute exacerbation of rheumatoid arthritis-associated interstitial lung disease: mortality and its prediction model. (2022)
  • Author(s): Hozumi H, Kono M, Hasegawa H, Kato S, Inoue Y, Suzuki Y, Karayama M, Furuhashi K, Enomoto N, Fujisawa T, Inui N, Nakamura Y, Yokomura K, Nakamura H, Suda T.
  • Journal Title: Respiratory Research Volume: 23 Pages: 57
  • DOI: 10.1186/s12931-022-01978-y.
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of autophagy in exacerbation of eosinophilic airway inflammation in a murine model of obese asthma. (2022)
  • Author(s): Suzuki Y, Aono Y, Akiyama N, Horiike Y, Naoi H, Horiguchi R, Shibata K, Hozumi H, Karayama M, Furuhashi K, Enomoto N, Fujisawa T, Nakamura Y, Inui N, Suda T.
  • Journal Title: Autophagy Volume: - Pages: -
  • DOI: 10.1080/15548627.2022.2025571.
  • Peer Reviewed
• [Journal Article] Prospective nationwide multicentre cohort study of the clinical significance of autoimmune features in idiopathic interstitial pneumonias. (2022)
  • Author(s): Enomoto N, Homma S, Inase N, Kondoh Y, Saraya T, Takizawa H, et al.
  • Journal Title: Thorax Volume: 77 Pages: 143-153
  • DOI: 10.1136/thoraxjnl-2020-216263.
  • Peer Reviewed
• [Journal Article] Response to the editor (2021)
  • Author(s): Hozumi H, Kono M, Hasegawa H, Yasui H, Suzuki Y, Karayama M, Furuhashi K, Enomoto N, Fujisawa T, Inui N, Nakamura Y, Yokomura K, Nakamura H, Suda T.
  • Journal Title: Chest Volume: 160 Pages: e683-e685
  • DOI: 10.1016/j.chest.2021.07.044.
  • Peer Reviewed
• [Journal Article] Radiological pleuroparenchymal fibroelastosis-like lesion in idiopathic interstitial pneumonias. (2021)
  • Author(s): Fujisawa T, Horiike Y, Egashira R, Sumikawa H, Iwasawa T, Matsushita S, Sugiura H, Kataoka K, Hashisako M, Yasui H, Hozumi H, Karayama M, Suzuki Y, Furuhashi K, Enomoto N, Nakamura Y, Inui N, Suda T.
  • Journal Title: Respiratory Research Volume: 22 Pages: 290
  • DOI: 10.1186/s12931-021-01892-9.
  • Peer Reviewed / Open Access
• [Journal Article] Combined assessment of the GAP index and body mass index at antifibrotic therapy initiation for prognosis of idiopathic pulmonary fibrosis. (2021)
  • Author(s): Suzuki Y, Mori K, Aono Y, Kono M, Hasegawa H, Yokomura K, Naoi H, Hozumi H, Karayama M, Furuhashi K, Enomoto N, Fujisawa T, Nakamura Y, Inui N, Nakamura H, Suda T.
  • Journal Title: Scientific Reports Volume: 11 Pages: 18579
  • DOI: 10.1038/s41598-021-98161-y.
  • Peer Reviewed / Open Access
• [Journal Article] Clinical Significance of Cold-Inducible RNA-Binding Protein in Idiopathic Pulmonary Fibrosis. (2021)
  • Author(s): Hozumi H, Kataoka K, Kondoh Y, Isayama T, Okada J, Sugiura K, Mori K, Kono M, Suzuki Y, Karayama M, Furuhashi K, Enomoto N, Fujisawa T, Inui N, Nakamura Y, Suda T.
  • Journal Title: Chest Volume: 160 Pages: 2149-2157
  • DOI: 10.1016/j.chest.2021.06.067.
  • Peer Reviewed
• [Journal Article] Switching antifibrotics in patients with idiopathic pulmonary fibrosis: a multi-center retrospective cohort study. (2021)
  • Author(s): Suzuki Y, Mori K, Aono Y, Kono M, Hasegawa H, Yokomura K, Naoi H, Hozumi H, Karayama M, Furuhashi K, Enomoto N, Fujisawa T, Nakamura Y, Inui N, Nakamura H, Suda T.
  • Journal Title: BMC Pulmonary Medicine Volume: 21 Pages: 221
  • DOI: 10.1186/s12890-021-01587-3.
  • Peer Reviewed / Open Access
• [Journal Article] Serum S100A8 and S100A9 as prognostic biomarkers in acute exacerbation of idiopathic pulmonary fibrosis. (2021)
  • Author(s): anaka K, Enomoto N, Hozumi H, Isayama T, Naoi H, Aono Y, Katsumata M, Yasui H, Karayama M, Suzuki Y, Furuhashi K, Fujisawa T, Inui N, Nakamura Y, Suda T.
  • Journal Title: Respiratory Investigation Volume: 59 Pages: 827-836
  • DOI: 10.1016/j.resinv.2021.05.008.
  • Peer Reviewed
• [Journal Article] Clinical Significance of Interstitial Lung Disease and Its Acute Exacerbation in Microscopic Polyangiitis. (2021)
  • Author(s): Hozumi H, Kono M, Hasegawa H, Yasui H, Suzuki Y, Karayama M, Furuhashi K, Enomoto N, Fujisawa T, Inui N, Nakamura Y, Yokomura K, Nakamura H, Suda T.
  • Journal Title: Chest Volume: 159 Pages: 2334-2345
  • DOI: 10.1016/j.chest.2021.01.083.
  • Peer Reviewed