Regulation of lung fibrosis targeting NETs

2020 Fiscal Year Annual Research Report

• Project/Area Number: 17K09618
• Research Institution: Nagasaki University
• Principal Investigator: 坂本 憲穂 長崎大学, 医歯薬学総合研究科(医学系), 講師 (30448493)
• Co-Investigator(Kenkyū-buntansha): 迎 寛 長崎大学, 医歯薬学総合研究科(医学系), 教授 (80253821)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Keywords: NETs / デフェンシン / 特発性肺線維症 / 間質性肺炎 / ヒストン / cell free DNA

Outline of Annual Research Achievements

特発性肺線維症は原因不明の難治性疾患で、好中球が病態形成に関与していると考えられているが、機序は不明である。好中球は、好中球細胞外トラップ（NETs）と呼ばれる網を細胞外に放出する感染防御機構を備えている。過剰なNETsの放出は、血栓・癌転移・自己免疫疾患との関連が明らかとなり、肺線維化促進作用も報告され注目を集めている。本研究では、特発性肺線維症を含めた間質性肺疾患患者でのNETsの発現を調べ、さらに細胞、動物モデルを用いてNETsが持つ肺線維化促進作用を明らかにする。
本研究においては、肺線維化におけるNETsの役割を解明するために、まず、臨床像との関連を調べる目的で間質性肺炎患者検体中（血漿、気管支肺胞洗浄液）のNETsを検出し、その臨床的特徴との関連を解析した。対象は、長崎大学病院呼吸器内科で特発性肺線維症と診断された患者の血漿および気管支肺胞洗浄液。コントロールとして、健常人の血漿および気管支肺胞洗浄液を用いた。NETsの検出は、cell free DNA, histoneの定量により行った。
結果：特発性肺線維症患者血漿検体では、cell free DNA量に健常人との差はなかったが、histoneは増加していた。気管支肺胞洗浄液では健常人と比較してcell free DNA, histoneいずれも有意に高値を示した。また、臨床像との関連においては、気管支肺胞洗浄液中cell free DNA, histoneと気管支肺胞洗浄液中の好中球比率と有意な正の相関を認めた。以上の結果からNETsが特発性肺線維症の好中球性炎症のバイオマーカーとして有用である可能性が明らかとなった。一方で、特発性肺線維症患者の予後との関連などは認めず、更なる検討が必要と考えられた。

Research Products

• [Journal Article] Human immunodeficiency virus-associated vacuolar encephalomyelopathy with granulomatous-lymphocytic interstitial lung disease improved after antiretroviral therapy: a case report (2020)
  • Author(s): Akagi Kazumasa、Yamamoto Kazuko、Umemura Asuka、Ide Shotaro、Hirayama Tatsuro、Takazono Takahiro、Imamura Yoshifumi、Miyazaki Taiga、Sakamoto Noriho、Shiraishi Hirokazu、Takahata Hideaki、Zaizen Yoshiaki、Fukuoka Junya、Morikawa Minoru、Ashizawa Kazuto、Teruya Katsuji、Izumikawa Koichi、Mukae Hiroshi
  • Journal Title: AIDS Research and Therapy Volume: 17 Pages: 38
  • DOI: 10.1186/s12981-020-00295-y
  • Peer Reviewed
• [Journal Article] Comparison of lung microbiota between antineutrophil cytoplasmic antibody-associated vasculitis and sarcoidosis (2020)
  • Author(s): Fukui Shoichi、Morimoto Shimpei、Ichinose Kunihiro、Nakashima Shota、Ishimoto Hiroshi、Hara Atsuko、Kakugawa Tomoyuki、Sakamoto Noriho、et al.
  • Journal Title: Scientific Reports Volume: 10 Pages: 9466
  • DOI: 10.1038/s41598-020-66178-4
  • Peer Reviewed
• [Journal Article] Prediction of Anti-Cancer Drug-Induced Pneumonia in Lung Cancer Patients: Novel High-Resolution Computed Tomography Fibrosis Scoring (2020)
  • Author(s): Gyotoku Hiroshi、Yamaguchi Hiroyuki、Ishimoto Hiroshi、Sato Shuntaro、Taniguchi Hirokazu、Senju Hiroaki、Kakugawa Tomoyuki、Nakatomi Katsumi、Sakamoto Noriho、Fukuda Minoru、Obase Yasushi、Soda Hiroshi、Ashizawa Kazuto、Mukae Hiroshi
  • Journal Title: Journal of Clinical Medicine Volume: 9 Pages: 1045～1045
  • DOI: 10.3390/jcm9041045
  • Peer Reviewed
• [Journal Article] Corticosteroids are associated with reduced skeletal muscle function in interstitial lung disease patients with mild dyspnea (2020)
  • Author(s): Hanada Masatoshi、Ishimatsu Yuji、Sakamoto Noriho、Nagura Hiroki、Oikawa Masato、Morimoto Yosuke、Sato Shuntaro、Mukae Hiroshi、Kozu Ryo
  • Journal Title: Respiratory Medicine Volume: 174 Pages: 106184～106184
  • DOI: 10.1016/j.rmed.2020.106184
  • Peer Reviewed
• [Journal Article] Pneumoconiosis with a Sarcoid-Like Reaction Other than Beryllium Exposure: A Case Report and Literature Review (2020)
  • Author(s): Hayashi Fumiko、Kido Takashi、Sakamoto Noriho、Zaizen Yoshiaki、Ozasa Mutsumi、Yokoyama Mitsuru、Yura Hirokazu、Hara Atsuko、Ishimoto Hiroshi、Yamaguchi Hiroyuki、Miyazaki Taiga、Obase Yasushi、Ishimatsu Yuji、Eishi Yoshinobu、Fukuoka Junya、Mukae Hiroshi
  • Journal Title: Medicina Volume: 56 Pages: 630～630
  • DOI: 10.3390/medicina56110630
  • Peer Reviewed
• [Journal Article] Thrombomodulin Alfa for Acute Exacerbation of Idiopathic Pulmonary Fibrosis. A Randomized, Double-Blind Placebo-controlled Trial (2020)
  • Author(s): Kondoh Yasuhiro、Azuma Arata、Inoue Yoshikazu、Ogura Takashi、Sakamoto Susumu、Tsushima Kenji、Johkoh Takeshi、Fujimoto Kiminori、Ichikado Kazuya、Matsuzawa Yasuo、Saito Takefumi、Kishi Kazuma、Tomii Keisuke、Sakamoto Noriho、et al.
  • Journal Title: American Journal of Respiratory and Critical Care Medicine Volume: 201 Pages: 1110～1119
  • DOI: 10.1164/rccm.201909-1818OC
  • Peer Reviewed
• [Journal Article] Presence of heat shock protein 47-positive fibroblasts in cancer stroma is associated with increased risk of postoperative recurrence in patients with lung cancer (2020)
  • Author(s): Miyamura Takuto、Sakamoto Noriho、Ishida Kaori、Kakugawa Tomoyuki、Taniguchi Hirokazu、Akiyama Yoshiko、Okuno Daisuke、Hara Atsuko、Kido Takashi、Ishimoto Hiroshi、Miyazaki Takuro、Matsumoto Keitaro、Tsuchiya Tomoshi、Yamaguchi Hiroyuki、Miyazaki Taiga、Obase Yasushi、Ishimatsu Yuji、Nagayasu Takeshi、Mukae Hiroshi
  • Journal Title: Respiratory Research Volume: 21 Pages: 234
  • DOI: 10.1186/s12931-020-01490-1
  • Peer Reviewed / Open Access
• [Journal Article] Small molecule inhibitor of HSP47 prevents pro-fibrotic mechanisms of fibroblasts in?vitro (2020)
  • Author(s): Miyamura Takuto、Sakamoto Noriho、Kakugawa Tomoyuki、Taniguchi Hirokazu、Akiyama Yoshiko、Okuno Daisuke、Moriyama Sakiko、Hara Atsuko、Kido Takashi、Ishimoto Hiroshi、Yamaguchi Hiroyuki、Miyazaki Taiga、Obase Yasushi、Ishimatsu Yuji、Tanaka Yoshimasa、Mukae Hiroshi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 530 Pages: 561～565
  • DOI: 10.1016/j.bbrc.2020.07.085
  • Peer Reviewed
• [Journal Article] Coinfection With Multiple Nontuberculous Mycobacteria as a Possible Exacerbating Factor in Pulmonary Nontuberculous Mycobacteriosis (2020)
  • Author(s): Naito Keisuke、Noguchi Shingo、Yatera Kazuhiro、Kawanami Toshinori、Yamasaki Kei、Fukuda Kazumasa、Ikegami Hiroaki、Akata Kentaro、Kido Takashi、Sakamoto Noriho、Saito Mitsumasa、Mukae Hiroshi
  • Journal Title: Chest Volume: 158 Pages: 2304～2313
  • DOI: 10.1016/j.chest.2020.06.027
  • Peer Reviewed
• [Journal Article] Comparison of a Novel Bisphosphonate Prodrug and Zoledronic Acid in the Induction of Cytotoxicity in Human Vγ2Vδ2 T Cells (2020)
  • Author(s): Okuno Daisuke、Sugiura Yuki、Sakamoto Noriho、Tagod Mohammed S. O.、Iwasaki Masashi、Noda Shuto、Tamura Akihiro、Senju Hiroaki、Umeyama Yasuhiro、Yamaguchi Hiroyuki、Suematsu Makoto、Morita Craig T.、Tanaka Yoshimasa、Mukae Hiroshi
  • Journal Title: Frontiers in Immunology Volume: 11 Pages: 1405
  • DOI: 10.3389/fimmu.2020.01405
  • Peer Reviewed
• [Journal Article] Novel and potent antimicrobial effects of caspofungin on drug-resistant Candida and bacteria (2020)
  • Author(s): Sumiyoshi Makoto、Miyazaki Taiga、Makau Juliann Nzembi、Mizuta Satoshi、Tanaka Yoshimasa、Ishikawa Takeshi、Makimura Koichi、Hirayama Tatsuro、Takazono Takahiro、Saijo Tomomi、Yamaguchi Hiroyuki、Shimamura Shintaro、Yamamoto Kazuko、Imamura Yoshifumi、Sakamoto Noriho、et al.
  • Journal Title: Scientific Reports Volume: 10 Pages: 17745
  • DOI: 10.1038/s41598-020-74749-8
  • Peer Reviewed
• [Journal Article] A 71-Year-Old Man With Dyspnea and Cough During Chemotherapy (2020)
  • Author(s): Yamamoto Kazuko、Ando Koji、Tanaka Moe、Yura Hirokazu、Sakamoto Noriho、Zaizen Yoshiaki、Ashizawa Kazuto、Fukuoka Junya、Miyazaki Yasushi、Mukae Hiroshi
  • Journal Title: Chest Volume: 157 Pages: e165～e171
  • DOI: 10.1016/j.chest.2019.12.008
  • Peer Reviewed
• [Presentation] The Role of Epstein-Barr Virus-Encoded microRNAs in Pulmonary Fibrosis (2020)
  • Author(s): N. Sakamoto, H. Yura, D. Okuno, T. Miyamura, A. Hara, T. Kido, H. Ishimoto, Y. Ishimatsu, H. Mukae
  • Organizer: ATS 2020－American Thoracic Society International Conference. Virtual
  • Int'l Joint Research
• [Presentation] Immune Complexome Analysis Detects Apolipoprotein E as a Disease-Specific Immune Complex Antigen in Bronchoalveolar Fluids from Patients with Summer-Type Hypersensitivity Pneumonitis (2020)
  • Author(s): Y. Ishimatsu, A. Hara, N. Aibara, K. Ohyama, Y. Akiyama, D. Okuno, T. Miyamura, T. Kido, H. Ishimoto, N. Sakamoto, H. Mukae
  • Organizer: ATS 2020－American Thoracic Society International Conference. Virtual
  • Int'l Joint Research
• [Presentation] The Utility Of Combinate Detection Of Igh And Tcr Gene Rearrangement, And Malt1 Gene Translocation In Balf For The Diagnosis Of Pulmonary Lymphoma (2020)
  • Author(s): T. Kido, H. Ishimoto, H. Ishii, K. Hara, H. Kawabata, T. Kawanami, Y. Suzuki, H. Yoshikawa, A. Hara, N. Sakamoto, N. Matsumoto, C. Yoshii, M. Fujita, M. Nakazato, J. Kadota, H. Mukae, K. Yatera
  • Organizer: ATS 2020－American Thoracic Society International Conference. Virtual
  • Int'l Joint Research
• [Presentation] Effect of Zoledronic Acid and a Bisphosphonate Prodrug on γδ T Cell-Mediated Cytotoxicity Against Lung Cancer Cells (2020)
  • Author(s): D. Okuno, N. Sakamoto, T. Miyamura, A. Hara, T. Kido, H. Ishimoto, H. Yamaguchi, Y. Ishimatsu, Y. Tanaka, H. Mukae
  • Organizer: ATS 2020－American Thoracic Society International Conference. Virtual
  • Int'l Joint Research
• [Presentation] Heat Shock Protein 47 (HSP47) Positive Fibroblasts in Cancer Stroma Are Associated with Increased Risk of Postoperative Recurrence in Patients with Lung Cancer (2020)
  • Author(s): T. Miyamura, N. Sakamoto, T. Kakugawa, K. Ishida, H. Taniguchi, D. Okuno, A. Hara, T. Kido, H. Ishimoto, T. Miyazaki, K. Matsumoto, T. Tsuchiya, H. Yamaguchi, Y. Obase, Y. Ishimatsu, T. Nagayasu, H. Mukae
  • Organizer: ATS 2020－American Thoracic Society International Conference. Virtual
  • Int'l Joint Research
• [Presentation] 医療用人工知能（胸部CT自動計測ソフト）を用いたCT肺気腫，気腫合併肺線維症，間質性肺炎の客観的評価 (2020)
  • Author(s): 福島 喜代康、近藤 晃、金子 祐子、江原 尚美、松竹 豊司、吉田 伸太郎、坂本 憲穂、尾長谷 靖、迎 寛
  • Organizer: 第60回日本呼吸器学会学術講演会
• [Presentation] 膵癌化学療法中に生じた薬剤性肺障害の検討 (2020)
  • Author(s): 宮下 律子、石本 裕士、奥野 大輔、宮村 拓人、由良 博一、高園 貴弘、原 敦子、坂本 憲穂、石松 祐二、尾長谷 靖、迎 寛
  • Organizer: 第60回日本呼吸器学会学術講演会
• [Presentation] 肺癌手術検体における，Heat shock protein 47発現の検討 (2020)
  • Author(s): 宮村 拓人、坂本 憲穂、角川 智之、石田 佳央理、奥野 大輔、原 敦子、宮崎 拓郎、城戸 貴志、石本 裕士、松本 桂太郎、土谷 智史、石松 祐二、永安 武、迎 寛
  • Organizer: 第60回日本呼吸器学会学術講演会