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

• Project/Area Number: 21K08176
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53030:Respiratory medicine-related
• 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
• Project Status: Granted (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2023: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• 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 Research at the Start

肺線維症形成におけるCIRBPの役割を明らかにし，治療標的としての有用性を検討するため，次の研究を行う．
1.BLMモデルにおいて，野生型マウスとCIRBP欠損マウスの肺線維化の程度を比較する．
2.野生型マウスから単離した肺線維芽細胞とCIRBP欠損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．
3.肺線維芽細胞に対するCIRBP遺伝子ノックダウンの効果（増殖能，分化能，コラーゲン産生能）を評価する．
4.野生型マウスのBLM肺線維症モデルにおける，抗CIRBP中和抗体の治療効果を検討する．

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、1）BLMモデルを用いて野生型およびCIRBP欠損マウスを比較した。CIRBP欠損マウスでは野生型マウスと比較して、有意に生存率が高く、体重減少率が低かった。また、BLM投与後22日目に肺組織等を採取したところ、欠損マウスの方が有意にハイドロキシプロリン量が低値で、COL1A1発現量も低かった。2）BLMモデルを用いて野生型マウスにCIRBP由来ペプチド（C23）もしくはプラセボを投与する比較実験を行った。C23投与群はプラセボ群と比較して、有意に生存率が高く、体重減少率が低かった。また、肺組織の評価では投与群の方が有意にハイドロキシプロリン量が低値で、COL1A1発現量も低かった。現在は、マウス肺から得た線維芽細胞を用いて、CIRBPの機能の解析を行っている。

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、実験計画に遅れが生じたため。

Strategy for Future Research Activity

<計画1>　野生型マウスから単離した肺線維芽細胞とCIRBP欠損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。
<計画2>　野生型マウスから単離した肺線維芽細胞にCIRBPリコンビナント蛋白の添加、あるいはCIRBPノックダウンを行い、CIRBPの肺線維芽細胞の増殖能や筋線維芽細胞への分化、コラーゲン産生への影響を評価する。

Research Products

• [Journal Article] Enhanced immune complex formation in the lungs of patients with dermatomyositis (2023)
  • Author(s): Zaizen Yoshiaki、Okamoto Masaki、Azuma Koichi、Fukuoka Junya、Hozumi Hironao、Sakamoto Noriho、Suda Takafumi、Mukae Hiroshi、Hoshino Tomoaki
  • Journal Title: Respiratory Research Volume: 24 Issue: 1 Pages: 1-1
  • DOI: 10.1186/s12931-023-02362-0
  • Peer Reviewed / Open Access
• [Journal Article] A predictive model for acute exacerbation of idiopathic interstitial pneumonias (2023)
  • Author(s): Karayama Masato、Aoshima Yoichiro、Suzuki Takahito、Mori Kazutaka、Yoshizawa Nobuko、Ichikawa Shintaro、Kato Shinpei、Yokomura Koshi、Kono Masato、Hashimoto Dai、Inoue Yusuke、Yasui Hideki、Hozumi Hironao、Suzuki Yuzo、Furuhashi Kazuki、Fujisawa Tomoyuki、Enomoto Noriyuki、Goshima Satoshi、Inui Naoki、Suda Takafumi
  • Journal Title: European Respiratory Journal Volume: 61 Issue: 5 Pages: 2201634-2201634
  • DOI: 10.1183/13993003.01634-2022
  • Peer Reviewed
• [Journal Article] CD109 on Dendritic Cells Regulates Airway Hyperreactivity and Eosinophilic Airway Inflammation (2023)
  • Author(s): Aono Yuya、Suzuki Yuzo、Horiguchi Ryo、Inoue Yusuke、Karayama Masato、Hozumi Hironao、Furuhashi Kazuki、Enomoto Noriyuki、Fujisawa Tomoyuki、Nakamura Yutaro、Inui Naoki、Mii Shinji、Takahashi Masahide、Suda Takafumi
  • Journal Title: American Journal of Respiratory Cell and Molecular Biology Volume: 68 Issue: 2 Pages: 201-212
  • DOI: 10.1165/rcmb.2022-0109oc
  • Peer Reviewed
• [Journal Article] Changes in the characteristics and outcomes of COVID-19 patients from the early pandemic to the delta variant epidemic: a nationwide population-based study (2022)
  • Author(s): Miyashita Koichi、Hozumi Hironao、Furuhashi Kazuki、Nakatani Eiji、Inoue Yusuke、Yasui Hideki、Karayama Masato、Suzuki Yuzo、Fujisawa Tomoyuki、Enomoto Noriyuki、Inui Naoki、Ojima Toshiyuki、Suda Takafumi
  • Journal Title: Emerging Microbes &amp; Infections Volume: 12 Issue: 1
  • DOI: 10.1080/22221751.2022.2155250
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic significance of radiological pleuroparenchymal fibroelastosis in<i>Mycobacterium avium</i>complex lung disease: a multicentre retrospective cohort study (2022)
  • Author(s): Aono Yuya、Hozumi Hironao、Kono Masato、Hashimoto Dai、Nakamura Hidenori、Yokomura Koshi、Imokawa Shiro、Shirai Masahiro、Akahori Daisuke、Inoue Yusuke、Mori Kazutaka、Karayama Masato、Suzuki Yuzo、Furuhashi Kazuki、Enomoto Noriyuki、Fujisawa Tomoyuki、Nakamura Yutaro、Inui Naoki、Suda Takafumi
  • Journal Title: Thorax Volume: － Issue: 8 Pages: 825-834
  • DOI: 10.1136/thorax-2022-219116
  • Peer Reviewed
• [Journal Article] Frequency, proportion of PF-ILD, and prognostic factors in patients with acute exacerbation of ILD related to systemic autoimmune diseases (2022)
  • Author(s): Enomoto Noriyuki、Naoi Hyogo、Mochizuka Yasutaka、Isayama Takuya、Tanaka Yuko、Fukada Atsuki、Aono Yuya、Katsumata Mineo、Yasui Hideki、Mori Kazutaka、Karayama Masato、Hozumi Hironao、Suzuki Yuzo、Furuhashi Kazuki、Fujisawa Tomoyuki、Inui Naoki、Nakamura Yutaro、Suda Takafumi
  • Journal Title: BMC Pulmonary Medicine Volume: 22 Issue: 1
  • DOI: 10.1186/s12890-022-02197-3
  • Peer Reviewed / Open Access
• [Journal Article] Clinical practice of high-flow nasal cannula therapy in COVID-19 pandemic era: a cross-sectional survey of respiratory physicians (2022)
  • Author(s): Koyauchi Takafumi、Suzuki Yuzo、Inoue Yusuke、Hozumi Hironao、Karayama Masato、Furuhashi Kazuki、Fujisawa Tomoyuki、Enomoto Noriyuki、Inui Naoki、Suda Takafumi
  • Journal Title: Respiratory Investigation Volume: 60 Issue: 6 Pages: 779-786
  • DOI: 10.1016/j.resinv.2022.08.007
  • Peer Reviewed / Open Access
• [Journal Article] Effect of Hypoxia on Pulmonary Endothelial Cells from Bleomycin-Induced Pulmonary Fibrosis Model Mice (2022)
  • Author(s): Akahori Daisuke、Inui Naoki、Inoue Yusuke、Yasui Hideki、Hozumi Hironao、Suzuki Yuzo、Karayama Masato、Furuhashi Kazuki、Enomoto Noriyuki、Fujisawa Tomoyuki、Suda Takafumi
  • Journal Title: International Journal of Molecular Sciences Volume: 23 Issue: 16 Pages: 8996-8996
  • DOI: 10.3390/ijms23168996
  • Peer Reviewed / Open Access
• [Journal Article] Associations of serum long-chain fatty acids with multiple organ involvement in patients with sarcoidosis (2022)
  • Author(s): Suzuki Takahito、Karayama Masato、Inoue Yusuke、Hozumi Hironao、Suzuki Yuzo、Furuhashi Kazuki、Fujisawa Tomoyuki、Enomoto Noriyuki、Nakamura Yutaro、Inui Naoki、Suda Takafumi
  • Journal Title: BMC Pulmonary Medicine Volume: 22 Issue: 1
  • DOI: 10.1186/s12890-022-02084-x
  • Peer Reviewed / Open Access
• [Journal Article] Serum immune modulators associated with immune-related toxicities and efficacy of atezolizumab in patients with non-small cell lung cancer (2022)
  • Author(s): Inoue Yusuke、Inui Naoki、Karayama Masato、Asada Kazuhiro、Matsuura Shun、Ikeda Masaki、Uto Tomohiro、Fujii Masato、Hashimoto Dai、Matsui Takashi、Matsuda Hiroyuki、Inami Nao、Toyoshima Mikio、Kaida Yusuke、Yasui Hideki、Hozumi Hironao、Suzuki Yuzo、Furuhashi Kazuki、Enomoto Noriyuki、Fujisawa Tomoyuki、Suda Takafumi
  • Journal Title: Journal of Cancer Research and Clinical Oncology Volume: － Issue: 7 Pages: 2963-2974
  • DOI: 10.1007/s00432-022-04193-w
  • Peer Reviewed
• [Journal Article] Idiopathic pleuroparenchymal fibroelastosis: three-dimensional computed tomography assessment of upper-lobe lung volume (2022)
  • Author(s): Fukada Atsuki、Suzuki Yuzo、Mori Kazutaka、Kono Masato、Hasegawa Hirotsugu、Hashimoto Dai、Yokomura Koshi、Imokawa Shiro、Tanaka Yuko、Inoue Yusuke、Hozumi Hironao、Karayama Masato、Furuhashi Kazuki、Enomoto Noriyuki、Fujisawa Tomoyuki、Nakamura Yutaro、Inui Naoki、Fujino Yoshihisa、Nakamura Hidenori、Suda Takafumi
  • Journal Title: European Respiratory Journal Volume: 60 Issue: 6 Pages: 2200637-2200637
  • DOI: 10.1183/13993003.00637-2022
  • Peer Reviewed / Open Access
• [Journal Article] Standardised 3D-CT lung volumes for patients with idiopathic pulmonary fibrosis (2022)
  • Author(s): Tanaka Yuko、Suzuki Yuzo、Hasegawa Hirotsugu、Yokomura Koshi、Fukada Atsuki、Inoue Yusuke、Hozumi Hironao、Karayama Masato、Furuhashi Kazuki、Enomoto Noriyuki、Fujisawa Tomoyuki、Nakamura Yutaro、Inui Naoki、Suda Takafumi
  • Journal Title: Respiratory Research Volume: 23 Issue: 1
  • DOI: 10.1186/s12931-022-02062-1
  • Peer Reviewed / Open Access
• [Journal Article] Effects of long-acting muscarinic antagonists on promoting ciliary function in airway epithelium (2022)
  • Author(s): Katsumata Mineo、Fujisawa Tomoyuki、Kamiya Yosuke、Tanaka Yuko、Kamiya Chiaki、Inoue Yusuke、Hozumi Hironao、Karayama Masato、Suzuki Yuzo、Furuhashi Kazuki、Enomoto Noriyuki、Nakamura Yutaro、Inui Naoki、Maekawa Masato、Setou Mitsutoshi、Watanabe Hiroshi、Ikegami Koji、Suda Takafumi
  • Journal Title: BMC Pulmonary Medicine Volume: 22 Issue: 1 Pages: 186-186
  • DOI: 10.1186/s12890-022-01983-3
  • Peer Reviewed / Open Access
• [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 Takafumi, Suzuki Yuzo, Sato Kazuki, Hozumi Hironao, Karayama Masato, Furuhashi Kazuki, Fujisawa Tomoyuki, Enomoto Noriyuki, Nakamura Yutaro, Inui Naoki, Yokomura Koshi, Imokawa Shiro, Nakamura Hidenori, Morita Tatsuya, Suda Takafumi
  • Journal Title: Respiratory Research Volume: in press Issue: 1 Pages: 79-79
  • 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 Hyogo、Suzuki Yuzo、Mori Kazutaka、Aono Yuya、Kono Masato、Hasegawa Hirotsugu、Yokomura Koshi、Inoue Yusuke、Hozumi Hironao、Karayama Masato、Furuhashi Kazuki、Enomoto Noriyuki、Fujisawa Tomoyuki、Nakamura Yutaro、Inui Naoki、Nakamura Hidenori、Suda Takafumi
  • Journal Title: Thorax Volume: in press Issue: 7 Pages: 1-1
  • DOI: 10.1136/thoraxjnl-2021-218281
  • Peer Reviewed / Open Access
• [Journal Article] Acute exacerbation of rheumatoid arthritis-associated interstitial lung disease: mortality and its prediction model (2022)
  • Author(s): Hozumi Hironao、Kono Masato、Hasegawa Hirotsugu、Kato Shinpei、Inoue Yusuke、Suzuki Yuzo、Karayama Masato、Furuhashi Kazuki、Enomoto Noriyuki、Fujisawa Tomoyuki、Inui Naoki、Nakamura Yutaro、Yokomura Koshi、Nakamura Hidenori、Suda Takafumi
  • Journal Title: Respiratory Research Volume: 23 Issue: 1 Pages: 57-57
  • 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 Yuzo、Aono Yuya、Akiyama Norimichi、Horiike Yasuoki、Naoi Hyogo、Horiguchi Ryo、Shibata Kiyoshi、Hozumi Hironao、Karayama Masato、Furuhashi Kazuki、Enomoto Noriyuki、Fujisawa Tomoyuki、Nakamura Yutaro、Inui Naoki、Suda Takafumi
  • Journal Title: Autophagy Volume: － Issue: 9 Pages: 1-13
  • DOI: 10.1080/15548627.2022.2025571
  • Peer Reviewed / Open Access
• [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 Issue: 6 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: Respir Res. Volume: 22(1) Issue: 1 Pages: 290-290
  • 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 Yuzo、Mori Kazutaka、Aono Yuya、Kono Masato、Hasegawa Hirotsugu、Yokomura Koshi、Naoi Hyogo、Hozumi Hironao、Karayama Masato、Furuhashi Kazuki、Enomoto Noriyuki、Fujisawa Tomoyuki、Nakamura Yutaro、Inui Naoki、Nakamura Hidenori、Suda Takafumi
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 18579-18579
  • DOI: 10.1038/s41598-021-98161-y
  • Peer Reviewed / Open Access
• [Journal Article] Prospective nationwide multicentre cohort study of the clinical significance of autoimmune features in idiopathic interstitial pneumonias (2021)
  • Author(s): Enomoto Noriyuki、Homma Sakae、Inase Naohiko、Kondoh Yasuhiro、Saraya Takeshi et al.
  • Journal Title: Thorax Volume: 77 Issue: 2 Pages: 143-153
  • DOI: 10.1136/thoraxjnl-2020-216263
  • Peer Reviewed
• [Journal Article] Clinical Significance of Cold-Inducible RNA-Binding Protein in Idiopathic Pulmonary Fibrosis (2021)
  • Author(s): Hozumi Hironao、Kataoka Kensuke、Kondoh Yasuhiro、Isayama Takuya、Okada Jun、Sugiura Katsunori、Mori Kazutaka、Kono Masato、Suzuki Yuzo、Karayama Masato、Furuhashi Kazuki、Enomoto Noriyuki、Fujisawa Tomoyuki、Inui Naoki、Nakamura Yutaro、Suda Takafumi
  • Journal Title: Chest Volume: 160 Issue: 6 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 Yuzo、Mori Kazutaka、Aono Yuya、Kono Masato、Hasegawa Hirotsugu、Yokomura Koshi、Naoi Hyogo、Hozumi Hironao、Karayama Masato、Furuhashi Kazuki、Enomoto Noriyuki、Fujisawa Tomoyuki、Nakamura Yutaro、Inui Naoki、Nakamura Hidenori、Suda Takafumi
  • Journal Title: BMC Pulmonary Medicine Volume: 21 Issue: 1 Pages: 221-221
  • 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): Tanaka 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: Respir Investig. Volume: 59(6) Issue: 6 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: S0012-3692(21) Issue: 6 Pages: 00259-2
  • DOI: 10.1016/j.chest.2021.01.083
  • Peer Reviewed