動脈硬化マウスを用いたCOPDモデルの作成とCOPDの新規治療戦略の確立に向けて

• Project/Area Number: 21K16114
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: 安井 秀樹 浜松医科大学, 医学部附属病院, 特任講師 (60804937)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2023: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: COPD / 肺気腫 / 動脈硬化 / 動脈硬化モデルマウス / 線溶系 / 線溶

Outline of Research at the Start

COPDにおいて動脈硬化は重要な併存症であり，動脈硬化がCOPDの病態に及ぼす詳細なメカニズムの解明，治療戦略の確立は急務を要する．近年ゲノム編集技術の進歩に伴いヒトの脂質異常症を再現した動脈硬化モデルマウス (LDLr-/-/Apobec1-/-マウス) が開発され，同マウスを用いてCOPDモデルを作成した際に，肺気腫等のCOPDの病態形成を促進するのか，動脈硬化とCOPDの両者をつなぐさらなる病態解明に挑む．さらには，新規治療戦略の確立のため動脈硬化のみならず，肺や気道の線維化に強く関与するPAI-1の遺伝子SERPINE1を追加でノックアウトした際に肺気腫ならびに動脈硬化性病変の形成が抑制できるか検証する．

Outline of Annual Research Achievements

慢性閉塞性肺疾患（COPD）において動脈硬化性疾患は重要な併存症であり、動脈硬化の存在がCOPDの病態形成に及ぼす詳細なメカニズムの解明及び治療戦略の確立は急務を要するものである。動脈硬化がCOPDの病態形成に及ぼす影響、およびそのメカニズムの解明のために、これまでに確立してきたタバコ煙抽出液（CSE）の腹腔内投与によるCOPDマウスモデルを用いて研究を進めてきた。CSEの腹腔内投与により、マウス肺組織では肺気腫形成が確認されたが、腹腔内投与では気道抵抗など呼吸機能への影響が小さく、CSEの投与経路について再検討した。CSE気管内投与においては、より確実な肺病理学的な変化、および気道抵抗の上昇などCOPDの病態に合致する呼吸機能の変化が確認された。また、CSEの気管内投与により、線溶系の主要な抑制因子であり、動脈硬化の初期病変である血管内皮障害に関わるplasminogen activator inhibitor-1（PAI-1）の活性が血漿中で亢進していることが確認された。
実験の次なるステップとして、CRISPR-Cas9によるゲノム編集技術にてヒトの脂質異常症の特徴を再現した動脈硬化モデルマウス (LDLr-/-/Apobec1-/-マウス) を用いて、CSE投与によるCOPDモデルの実験を行っている。予備実験においては、同動脈硬化マウスにCSE腹腔内投与を行いCOPDモデルを作成した際に、野生型マウスと比較し、肺組織において肺気腫形成が促進することが確認された。現在、動脈硬化モデルマウスに対してCSEを気管内投与した際の、肺の病理学的変化、呼吸機能検査、および血漿中のPAI-1活性に関する検討を進めている。

Research Products

• [Journal Article] COPDにおける気道系の定量的CT解析 (2023)
  • Author(s): 安井秀樹，須田隆文
  • Journal Title: 呼吸器内科 Volume: 44 Pages: 534-540
• [Journal Article] Predictors of poor clinical outcomes including in-hospital death and low ability to perform activities of daily living at discharge in hospitalized patients with chronic obstructive pulmonary disease exacerbation (2023)
  • Author(s): Murakami Yurina、Yasui Hideki、Sato Jun、Uto Tomohiro、Inui Naoki、Suda Takafumi、Imokawa Shiro
  • Journal Title: Therapeutic Advances in Respiratory Disease Volume: 17 Pages: 175346662311729-175346662311729
  • DOI: 10.1177/17534666231172924
• [Journal Article] Association of the Geriatric Nutritional Risk Index with the survival of patients with non-small-cell lung cancer after platinum-based chemotherapy (2021)
  • Author(s): Masato Karayama, Yusuke Inoue, Hideki Yasui, Hironao Hozumi, Yuzo Suzuki, Kazuki Furuhashi, Tomoyuki Fujisawa, Noriyuki Enomoto, Yutaro Nakamura, Naoki Inui, Takafumi Suda
  • Journal Title: BMC Pulm Med . Volume: 21(1) Issue: 1 Pages: 409-409
  • DOI: 10.1186/s12890-021-01782-2
  • Peer Reviewed / Open Access
• [Journal Article] Prophylactic granulocyte-colony stimulating factor in patients with lung neuroendocrine carcinoma receiving platinum agents plus etoposide. (2021)
  • Author(s): Watanabe H, Karayama M, Yasui H, Inoue Y, Hozumi H, Suzuki Y, Furuhashi K, Fujisawa T, Enomoto N, Nakamura Y, Inui N, Suda T.
  • Journal Title: Cancer Treat Res Commun. Volume: 29 Pages: 100493-100493
  • DOI: 10.1016/j.ctarc.2021.100493
  • Peer Reviewed / Open Access
• [Journal Article] MET Amplification and Efficacy of Nivolumab in Patients With NSCLC. (2021)
  • Author(s): Yoshimura K, Inoue Y, Inui N, Karayama M, Yasui H, Hozumi H, Suzuki Y, Furuhashi K, Fujisawa T, Enomoto N, Nakamura Y, Sugimura H, Suda T.
  • Journal Title: JTO Clin Res Rep. Volume: 2(11) Issue: 11 Pages: 100239-100239
  • DOI: 10.1016/j.jtocrr.2021.100239
  • Peer Reviewed / Open Access
• [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] Comparative assessment of NOIR-SS and ddPCR for ctDNA detection of EGFR L858R mutations in advanced L858R-positive lung adenocarcinomas. (2021)
  • Author(s): Akahori D, Inoue Y, Inui N, Karayama M, Yasui H, Hozumi H, Suzuki Y, Furuhashi K, Fujisawa T, Enomoto N, Nakamura Y, Suda T.
  • Journal Title: Sci Rep. Volume: 11(1) Issue: 1 Pages: 14999-14999
  • DOI: 10.1038/s41598-021-94592-9
  • 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] Prognostic and Clinical Value of Cluster Analysis in Idiopathic Pleuroparenchymal Fibroelastosis Phenotypes (2021)
  • Author(s): Nakamura Yutaro、Mori Kazutaka、Enomoto Yasunori、Kono Masato、Sumikawa Hiromitsu、Johkoh Takeshi、Colby Thomas V.、et al.
  • Journal Title: Journal of Clinical Medicine Volume: 10 Issue: 7 Pages: 1498-1498
  • DOI: 10.3390/jcm10071498
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Impact of bronchoalveolar lavage lymphocytosis on the effects of anti-inflammatory therapy in idiopathic non-specific interstitial pneumonia, idiopathic pleuroparenchymal fibroelastosis, and unclassifiable idiopathic interstitial pneumonia (2021)
  • Author(s): Yamagata Akira、Arita Machiko、Tachibana Hiromasa、Tokioka Fumiaki、Sugimoto Chikatoshi、Sumikawa Hiromitsu、Tanaka Tomonori、Yasui Hideki、Fujisawa Tomoyuki、Nakamura Yutaro、Suda Takafumi、Ishida Tadashi
  • Journal Title: Respiratory Research Volume: 22 Issue: 1 Pages: 115-115
  • DOI: 10.1186/s12931-021-01726-8
  • Peer Reviewed / Open Access
• [Journal Article] Simple method for detecting idiopathic interstitial pneumonias by measuring vertical lung length on chest X-ray. (2021)
  • Author(s): Karayama M, Aoshima Y, Yasui H, Hozumi H, Suzuki Y, Furuhashi K, Fujisawa T, Enomoto N, Nakamura Y, Inui N, Suda T.
  • Journal Title: Sci Rep. Volume: 11(1) Issue: 1 Pages: 7669-7669
  • DOI: 10.1038/s41598-021-87452-z
  • Peer Reviewed / Open Access
• [Journal Article] Conventional type 2 lung dendritic cells are potent inducers of follicular helper T cells in the asthmatic lung (2021)
  • Author(s): Sakurai S, Furuhashi K, Horiguchi R, Nihashi F, Yasui H, Karayama M, Suzuki Y, Hozumi H, Enomoto N, Fujisawa T, Nakamura Y, Inui N, Suda T,
  • Journal Title: Allergology International Volume: - Issue: 3 Pages: 351-359
  • DOI: 10.1016/j.alit.2021.01.008
  • NAID: 130008064053
  • Peer Reviewed / Open Access
• [Journal Article] Cluster analysis-based clinical phenotypes of idiopathic interstitial pneumonias: associations with acute exacerbation and overall survival (2021)
  • Author(s): Aoshima Y, Karayama M, Horiike Y, Mori K, Yasui H, Hozumi H, Suzuki Y, Furuhashi K, Fujisawa T, Enomoto N, Nakamura Y, Inui N, Suda T.
  • Journal Title: BMC Pulm Med. Volume: 21(1) Issue: 1 Pages: 63-63
  • DOI: 10.1186/s12890-021-01428-3
  • Peer Reviewed / Open Access
• [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
• [Journal Article] Predictors for bronchoalveolar lavage recovery failure in diffuse parenchymal lung disease (2021)
  • Author(s): Koda K, Hozumi H, Yasui H, Suzuki Y, Karayama M, Furuhashi K, Enomoto N, Fujisawa T, Inui N, Nakamura Y, Suda T.
  • Journal Title: Sci Rep . Volume: 11(1) Issue: 1 Pages: 1682-1682
  • DOI: 10.1038/s41598-021-81313-5
  • Peer Reviewed / Open Access
• [Journal Article] Pneumothorax in Patients with Idiopathic Pleuroparenchymal Fibroelastosis: Incidence, Clinical Features, and Risk Factors (2021)
  • Author(s): Kono Masato、Nakamura Yutaro、Enomoto Yasunori、Yasui Hideki、Hozumi Hironao、Karayama Masato、Suzuki Yuzo、Furuhashi Kazuki、Miki Yoshihiro、Hashimoto Dai、Fujisawa Tomoyuki、Enomoto Noriyuki、Inui Naoki、Suda Takafumi
  • Journal Title: Respiration Volume: 100 Issue: 1 Pages: 19-26
  • DOI: 10.1159/000511965
  • Peer Reviewed
• [Journal Article] Prednisolone and tacrolimus versus prednisolone and cyclosporin A to treat polymyositis/dermatomyositis‐associated ILD : A randomized, open‐label trial (2020)
  • Author(s): Fujisawa Tomoyuki、Hozumi Hironao、Kamiya Yosuke、Kaida Yusuke、Akamatsu Taisuke、Kusagaya Hideki、Satake Yasuomi、Mori Kazutak、Suzuki Yuzo、Karayama Masato、Furuhashi Kazuki、Enomoto Noriyuki、Nakamura Yutaro、Inui Naoki、Suda Takafumi
  • Journal Title: Respirology Volume: 26 Issue: 4 Pages: 370-377
  • DOI: 10.1111/resp.13978
  • Peer Reviewed
• [Journal Article] Erlotinib and bevacizumab in elderly patients ?75?years old with non-small cell lung cancer harboring epidermal growth factor receptor mutations (2020)
  • Author(s): Aoshima Yoichiro、Karayama Masato、Inui Naoki、Yasui Hideki、Hozumi Hironao、Suzuki Yuzo、Furuhashi Kazuki、Fujisawa Tomoyuki、Enomoto Noriyuki、Nakamura Yutaro、Mikamo Masashi、Matsuura Shun、Kusagaya Hideki、Kaida Yusuke、Uto Tomohiro、Hashimoto Dai、Matsui Takashi、Asada Kazuhiro、Suda Takafumi
  • Journal Title: Investigational New Drugs Volume: 39 Issue: 1 Pages: 210-216
  • DOI: 10.1007/s10637-020-00988-1
  • NAID: 120007143503
  • Peer Reviewed / Open Access
• [Presentation] COPD患者における動脈硬化指標CAVIの重症度予測マーカーとしての検討 (2024)
  • Author(s): 安井秀樹、大石享平、井上裕介、柄山正人、鈴木勇三、穗積宏尚、古橋一樹、榎本紀之、藤澤朋幸、乾直輝、須田隆文
  • Organizer: 第64回日本呼吸器学会学術講演会
• [Presentation] 慢性閉塞性肺疾患(COPD)の疾患進行に及ぼす動脈硬化の影響 (2024)
  • Author(s): 安井秀樹、大石享平、井上裕介、柄山正人、鈴木勇三、穗積宏尚、古橋一樹、榎本紀之、藤澤朋幸、堀之内孝広、岩城孝行、鈴木優子、乾直輝、須田隆文
  • Organizer: 第46回日本血栓止血学会学術集会