肥満喘息の難治化メカニズムと新規治療基盤の創出

2020 Fiscal Year Research-status Report

• Project/Area Number: 19K17632
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: 鈴木 勇三 浜松医科大学, 医学部, 助教 (00758435)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 肥満喘息 / オートファジー / TSLP / IL-33

Outline of Annual Research Achievements

肥満は喘息患者に高頻度に見られ，肥満喘息は重症喘息の中で最も難治な一群である．肥満喘息は非肥満喘息と同様に均一な病態でなく，Th2-lowやTh2-highなど種々に分類されるとされているが，その病態は十分に解明されていない． そこで，本研究では肥満喘息におけるオートファジーの意義を明らかにすることを目的とした．全身性および気道上皮特異的Atg5-/-マウスを用いた.肥満喘息モデルは，高脂肪食を16週間負荷した後にHDM感作を行い作成した．肥満Atg5-/-マウスは肥満野生型マウスと比較して，BAL中の好酸球数の上昇と気道過敏性の亢進が認められ，これらはステロイド抵抗性であった．肥満Atg5-/-マウス肺ではTh2細胞が増加していたが，一方でILC2s数は肥満野生型マウスと同等であった．気道上皮特異的肥満Atg5-/-マウスではBAL中の好酸球上昇が確認された．肥満Atg5-/-マウス気道上皮ではTSLPおよびIL-33発現が亢進し，肥満Atg5-/-マウスの好酸球炎症と気道過敏性はTSLP依存性，IL-33に抑制された．これらの結果から，オートファジー制御はは肥満喘息の新規治療標的となりうると考えられた．

Current Status of Research Progress

1: Research has progressed more than it was originally planned.

Reason

肥満Atg5-/-マウス気道上皮ではTSLPおよびIL-33発現が亢進し，肥満Atg5-/-マウスの好酸球炎症と気道過敏性はTSLP依存性，IL-33に抑制されることを明らかにした．これらの結果から，本研究はオートファジー制御はは肥満喘息の新規治療標的となりうることを示した．

Strategy for Future Research Activity

オートファジー低下によってもたらされる，気道上皮からのTSLPやIL-33の産生亢進のメカニズムを明らかにする．

Causes of Carryover

2021年度に予定していた遺伝子解析およびELISAによるサイトカイン計測は2022年度に行う予定である。

Research Products

• [Journal Article] Exposure to PM2.5 is a risk factor for acute exacerbation of surgically diagnosed idiopathic pulmonary fibrosis: a case?control study (2021)
  • Author(s): Tahara Masahiro、Fujino Yoshihisa、Yamasaki Kei、Oda Keishi、Kido Takashi、Sakamoto Noriho、Kawanami Toshinori、Kataoka Kensuke、Egashira Ryoko、Hashisako Mikiko、Suzuki Yuzo、Fujisawa Tomoyuki、Mukae Hiroshi、Suda Takafumi、Yatera Kazuhiro
  • Journal Title: Respiratory Research Volume: 22 Pages: －
  • DOI: 10.1186/s12931-021-01671-6
  • 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 Yoichiro、Karayama Masato、Horiike Yasuoki、Mori Kazutaka、Yasui Hideki、Hozumi Hironao、Suzuki Yuzo、Furuhashi Kazuki、Fujisawa Tomoyuki、Enomoto Noriyuki、Nakamura Yutaro、Inui Naoki、Suda Takafumi
  • Journal Title: BMC Pulmonary Medicine Volume: 21 Pages: －
  • DOI: 10.1186/s12890-021-01428-3
  • Peer Reviewed / Open Access
• [Journal Article] Predictors for bronchoalveolar lavage recovery failure in diffuse parenchymal lung disease (2021)
  • Author(s): Koda Keigo、Hozumi Hironao、Yasui Hideki、Suzuki Yuzo、Karayama Masato、Furuhashi Kazuki、Enomoto Noriyuki、Fujisawa Tomoyuki、Inui Naoki、Nakamura Yutaro、Suda Takafumi
  • Journal Title: Scientific Reports Volume: 11 Pages: －
  • 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 Pages: 19～26
  • DOI: 10.1159/000511965
  • Peer Reviewed
• [Journal Article] Quality of dying and death in patients with interstitial lung disease compared with lung cancer: an observational study (2020)
  • 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: Thorax Volume: 76 Pages: 248～255
  • DOI: 10.1136/thoraxjnl-2020-215917
  • Peer Reviewed / Open Access
• [Journal Article] Cause of mortality and sarcopenia in patients with idiopathic pulmonary fibrosis receiving antifibrotic therapy (2020)
  • Author(s): Suzuki Yuzo、Aono Yuya、Kono Masato、Hasegawa Hirotsugu、Yokomura Koushi、Naoi Hyogo、Hozumi Hironao、Karayama Masato、Furuhashi Kazuki、Enomoto Noriyuki、Fujisawa Tomoyuki、Nakamura Yutaro、Inui Naoki、Nakamura Hidenori、Suda Takafumi
  • Journal Title: Respirology Volume: 26 Pages: 171～179
  • DOI: 10.1111/resp.13943
  • Peer Reviewed
• [Journal Article] Disease course and prognosis of pleuroparenchymal fibroelastosis compared with idiopathic pulmonary fibrosis (2020)
  • Author(s): Suzuki Yuzo、Fujisawa Tomoyuki、Sumikawa Hiromitsu、Tanaka Tomonori、Sugimoto Chikatoshi、Kono Masato、Hozumi Hironao、Karayama Masato、Furuhashi Kazuki、Enomoto Noriyuki、Nakamura Yutaro、Inui Naoki、Suda Takafumi
  • Journal Title: Respiratory Medicine Volume: 171 Pages: 106078～106078
  • DOI: 10.1016/j.rmed.2020.106078
  • Peer Reviewed
• [Journal Article] CD200 and CD200R1 are differentially expressed and have differential prognostic roles in non-small cell lung cancer (2020)
  • Author(s): Yoshimura Katsuhiro、Suzuki Yuzo、Inoue Yusuke、Tsuchiya Kazuo、Karayama Masato、Iwashita Yuji、Kahyo Tomoaki、Kawase Akikazu、Tanahashi Masayuki、Ogawa Hiroshi、Inui Naoki、Funai Kazuhito、Shinmura Kazuya、Niwa Hiroshi、Sugimura Haruhiko、Suda Takafumi
  • Journal Title: OncoImmunology Volume: 9 Pages: 1746554～1746554
  • DOI: 10.1080/2162402X.2020.1746554
  • Peer Reviewed / Open Access
• [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 Pages: 370～377
  • DOI: 10.1111/resp.13978
  • Peer Reviewed
• [Journal Article] Influenza A virus enhances ciliary activity and mucociliary clearance via TLR3 in airway epithelium (2020)
  • Author(s): Kamiya Yosuke、Fujisawa Tomoyuki、Katsumata Mineo、Yasui Hideki、Suzuki Yuzo、Karayama Masato、Hozumi Hironao、Furuhashi Kazuki、Enomoto Noriyuki、Nakamura Yutaro、Inui Naoki、Setou Mitsutoshi、Ito Masahiko、Suzuki Tetsuro、Ikegami Koji、Suda Takafumi
  • Journal Title: Respiratory Research Volume: 21 Pages: －
  • DOI: 10.1186/s12931-020-01555-1
  • Peer Reviewed / Open Access
• [Journal Article] Evaluation of Programmed Death Ligand 1 (PD-L1) Gene Amplification and Response to Nivolumab Monotherapy in Non?small Cell Lung Cancer (2020)
  • Author(s): Inoue Yusuke、Yoshimura Katsuhiro、Nishimoto Koji、Inui Naoki、Karayama Masato、Yasui Hideki、Hozumi Hironao、Suzuki Yuzo、Furuhashi Kazuki、Fujisawa Tomoyuki、Enomoto Noriyuki、Nakamura Yutaro、Sugimura Haruhiko、Suda Takafumi
  • Journal Title: JAMA Network Open Volume: 3 Pages: －
  • DOI: 10.1001/jamanetworkopen.2020.11818
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic significance of forced vital capacity decline prior to and following antifibrotic therapy in idiopathic pulmonary fibrosis (2020)
  • Author(s): Aono Yuya、Nakamura Yutaro、Kono Masato、Nakamura Hidenori、Yokomura Koshi、Imokawa Shiro、Toyoshima Mikio、Yasui Hideki、Hozumi Hironao、Karayama Masato、Suzuki Yuzo、Furuhashi Kazuki、Enomoto Noriyuki、Fujisawa Tomoyuki、Inui Naoki、Suda Takafumi
  • Journal Title: Therapeutic Advances in Respiratory Disease Volume: 14 Pages: －
  • DOI: 10.1177/1753466620953783
  • Peer Reviewed / Open Access
• [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 Pages: 210～216
  • DOI: 10.1007/s10637-020-00988-1
  • Peer Reviewed
• [Journal Article] Development of a novel T cell‐oriented vaccine using CTL/Th‐hybrid epitope long peptide and biodegradable microparticles, against an intracellular bacterium (2020)
  • Author(s): Tanaka Kazuki、Enomoto Noriyuki、Uehara Masahiro、Furuhashi Kazuki、Sakurai Shogo、Yasui Hideki、Karayama Masato、Hozumi Hironao、Suzuki Yuzo、Fujisawa Tomoyuki、Inui Naoki、Nakamura Yutaro、Nagata Toshi、Suda Takafumi
  • Journal Title: Microbiology and Immunology Volume: 64 Pages: 666～678
  • DOI: 10.1111/1348-0421.12836
  • Peer Reviewed
• [Journal Article] Pneumothorax in connective tissue disease-associated interstitial lung disease (2020)
  • Author(s): Nishimoto Koji、Fujisawa Tomoyuki、Yoshimura Katsuhiro、Enomoto Yasunori、Yasui Hideki、Hozumi Hironao、Karayama Masato、Suzuki Yuzo、Furuhashi Kazuki、Enomoto Noriyuki、Nakamura Yutaro、Inui Naoki、Sumikawa Hiromitsu、Johkoh Takeshi、Suda Takafumi
  • Journal Title: PLOS ONE Volume: 15 Pages: －
  • DOI: 10.1371/journal.pone.0235624
  • Peer Reviewed / Open Access
• [Journal Article] Acute exacerbation of unclassifiable idiopathic interstitial pneumonia: comparison with idiopathic pulmonary fibrosis (2020)
  • Author(s): Enomoto Noriyuki、Naoi Hyogo、Aono Yuya、Katsumata Mineo、Horiike Yasuoki、Yasui Hideki、Karayama Masato、Hozumi Hironao、Suzuki Yuzo、Furuhashi Kazuki、Fujisawa Tomoyuki、Inui Naoki、Nakamura Yutaro、Suda Takafumi
  • Journal Title: Therapeutic Advances in Respiratory Disease Volume: 14 Pages: －
  • DOI: 10.1177/1753466620935774
  • Peer Reviewed / Open Access
• [Journal Article] Palliative Care for Idiopathic Pulmonary Fibrosis Patients: Pulmonary Physicians' View (2020)
  • Author(s): Akiyama Norimichi、Fujisawa Tomoyuki、Morita Tatsuya、Mori Kazutaka、Yasui Hideki、Hozumi Hironao、Suzuki Yuzo、Karayama Masato、Furuhashi Kazuki、Enomoto Noriyuki、Nakamura Yutaro、Inui Naoki、Suda Takafumi
  • Journal Title: Journal of Pain and Symptom Management Volume: 60 Pages: 933～940
  • DOI: 10.1016/j.jpainsymman.2020.06.012
  • Peer Reviewed
• [Journal Article] Comprehensive assessment of multiple tryptophan metabolites as potential biomarkers for immune checkpoint inhibitors in patients with non-small cell lung cancer (2020)
  • Author(s): Karayama M.、Masuda J.、Mori K.、Yasui H.、Hozumi H.、Suzuki Y.、Furuhashi K.、Fujisawa T.、Enomoto N.、Nakamura Y.、Inui N.、Suda T.、Maekawa M.、Sugimura H.、Takada A.
  • Journal Title: Clinical and Translational Oncology Volume: 23 Pages: 418～423
  • DOI: 10.1007/s12094-020-02421-8
• [Journal Article] Imaging mass spectrometry to visualise increased acetylcholine in lungs of asthma model mice (2020)
  • Author(s): Matsuda Takeshi、Suzuki Yuzo、Fujisawa Tomoyuki、Suga Yasunori、Saito Nobuyuki、Suda Takafumi、Yao Ikuko
  • Journal Title: Analytical and Bioanalytical Chemistry Volume: 412 Pages: 4327～4341
  • DOI: 10.1007/s00216-020-02670-0
• [Presentation] Pleuroparenchymal Fibroelastosis (PPFE): Prognostic Concordance Of Clinical Diagnosis, Acute Exacerbation And Prognosis Comparison With IPF (2020)
  • Author(s): YUZO SUZUKI
  • Organizer: American Thoracic Society Annual Meeting 2020
  • Int'l Joint Research
• [Presentation] 肺機能低下は免疫関連肺障害の予測因子である：多施設共同前向き研究 (2020)
  • Author(s): 鈴木勇三
  • Organizer: 日本呼吸器学会学術講演会
• [Presentation] PPFE臨床診断の確からしさ、急性増悪と予後：IPFとの比較 (2020)
  • Author(s): 鈴木勇三
  • Organizer: 日本呼吸器学会学術講演会