Investigating the role of mucin in pulmonary fibrosis-associated microbiota dysbiosis using MUC5B overexpressing mice

• Project/Area Number: 20K08564
• 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: Mie University
• Principal Investigator: Gabazza Esteban 三重大学, 医学系研究科, 教授 (00293770)
• Co-Investigator(Kenkyū-buntansha): 戸田 雅昭 三重大学, 医学系研究科, 講師 (10202201) ; 竹下 敦郎 三重大学, 医学系研究科, 助教 (10830490) ; 安間 太郎 三重大学, 医学系研究科, 助教 (80773887) ; 小林 哲 三重大学, 医学部附属病院, 准教授 (20437114)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 細菌叢 / 細胞死 / corisin / 肺線維症 / ムチン / MUC5B / 抗線維化剤 / 予後 / 急性増悪 / 肺内細菌叢 / 細胞死因子 / TGFbeta1 / 抗コリシン抗体 / トランスジェニックマウス / MUC5Bタンパク / TGFΒ1 / アポトーシス / 細胞死誘導因子 / 急性肺障害 / コリシン / 成長因子 / ブレオマイシン / ムチン過剰発現 / 肺疾患

Outline of Research at the Start

肺内細菌叢とMUC5B遺伝子の単塩基多型であるrs35705950は特発性肺線維症の病態形成に関与していることが示されているが、その機序は未だ不明である。本研究の目的はヒトMUC5Bの単塩基多型の過剰発現マウスを用いて肺線維症マウスモデルを作製し、in vivo 実験によってMUC5Bの過剰発現による肺内細菌叢のアンバランスが肺線維症の病態形成に関与するかを検討する。さらに、肺特異的ヒトTGF-beta1とMUC5Bの単塩基多型の遺伝子系を有する二重トランスジェニックマウスにおいてもMUC5Bの過剰発現による肺内細菌叢のアンバランスが肺線維症の発症機序に関与するかを検討する。

Outline of Final Research Achievements

Genome-wide linkage study has shown that patients with a single nucleotide polymorphism (rs35705950) of MUC5B have a 20-fold increased risk of developing idiopathic pulmonary fibrosis. Recently, it has been reported that microbiota dysbiosis in the lungs is involved in the progression of idiopathic pulmonary fibrosis. Therefore, in this study, we used MUC5B overexpression transgenic (TG) mice and wild-type mice to examine the characteristics of microbiota in the lungs and its involvement in the pathogenesis of pulmonary fibrosis. As a result, we found that the expression of corisin, a microbiota-derived cell death inducer, was high in MUC5B-TG mice and wild-type mice with pulmonary fibrosis and that it was involved in the promotion of inflammation and the pathogenesis of pulmonary fibrosis. Furthermore, we also found that anti-corisin monoclonal antibody had an inhibitory effect on pulmonary fibrosis.

Academic Significance and Societal Importance of the Research Achievements

本研究では、肺線維症マウスモデルを用いて、細菌由来細胞死誘導ペプチドが肺線維症の病態形成に関与することと抗corisinモノクローナル中和抗体が治療薬として有効であることを明らかにした。本研究で得た結果は抗肺線維化剤の開発につながる可能性があり、社会的意義が高いと考えられる。

Research Products

• [Journal Article] Inhibition of a Microbiota-Derived Peptide Ameliorates Established Acute Lung Injury (2023)
  • Author(s): D'Alessandro Fridman V, D'Alessandro-Gabazza CN, Yasuma T, Toda M, Takeshita A, Tomaru A, Tharavecharak S, Lasisi IO, Hess RY, Nishihama K, Fujimoto H, Kobayashi T, Cann I, Gabazza EC.
  • Journal Title: American Journal of Pathology Volume: 23 Issue: 6 Pages: 740-754
  • DOI: 10.1016/j.ajpath.2023.03.003
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Is Helicobacter pylori infection inversely correlated with atopic, skin, and autoimmune diseases? (2022)
  • Author(s): Yasuma T, D'Alessandro-Gabazza CN, Fujimoto H, Kobayashi T, Imoto I, Gabazza EC.
  • Journal Title: Allergy Volume: 77 Issue: 10 Pages: 3165-3166
  • DOI: 10.1111/all.15306
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Complete Genome Sequences of Three Staphylococcus haemolyticus Strains Isolated from the Lung of a TGFβ1 Transgenic Mouse with Lung Fibrosis (2022)
  • Author(s): Abdel-Hamid AM, D'Alessandro-Gabazza CN, Yasuma T, Walden KKO, Fields CJ, Gabazza EC, Cann I.
  • Journal Title: Microbiology Resource Announcements Volume: 11 Issue: 4
  • DOI: 10.1128/mra.01176-21
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Correlation of total serum HDL particles with a predictor of mortality risk in idiopathic pulmonary fibrosis (2022)
  • Author(s): Yasuma T, D'Alessandro-Gabazza CN, Fujimoto H, Kobayashi T, Gabazza EC.
  • Journal Title: European Respiratory Journal Volume: 59 Issue: 4 Pages: 2103175-2103175
  • DOI: 10.1183/13993003.03175-2021
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Inhibition of lung microbiota-derived proapoptotic peptides ameliorates acute exacerbation of pulmonary fibrosis. (2022)
  • Author(s): D'Alessandro-Gabazza CN, Yasuma T, Kobayashi T, Toda M, Abdel-Hamid AM, Fujimoto H, Hataji O, Nakahara H, Takeshita A, Nishihama K, Okano T, Saiki H, Okano Y, Tomaru A, D'Alessandro VF, Shiraishi M, Mizoguchi A, Ono R, Ohtsuka J, Fukumura M, Nosaka T, et al. & Gabazza EC
  • Journal Title: Nat Commun Volume: 13 Issue: 1 Pages: 1558-1558
  • DOI: 10.1038/s41467-022-29064-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Response of Lung Microbiota to Changes of Pulmonary Innate Immunity under Healthy Conditions (2022)
  • Author(s): Yasuma Taro、D’Alessandro-Gabazza Corina N.、Fujimoto Hajime、Kobayashi Tetsu、Gabazza Esteban C.
  • Journal Title: American Journal of Respiratory and Critical Care Medicine Volume: 205 Issue: 4 Pages: 477-477
  • DOI: 10.1164/rccm.202109-2187le
  • Peer Reviewed / Open Access
• [Journal Article] The Potential of Digital Polymerase Chain Reaction for Improving Diagnostic Yield of Nontuberculous Mycobacteria Pulmonary Disease (2021)
  • Author(s): Nishii Yoichi、Furuhashi Kazuki、Nakamura Saki、Nishio Miho、Nakamura Yuki、Ushiro Kengo、Ito Kentaro、Sakaguchi Tadashi、Suzuki Yuta、Fujiwara Kentaro、Yasuma Taro、Kobayashi Tetsu、D'Alessandro-Gabazza Corina、Gabazza Esteban C、Taguchi Osamu、Hataji Osamu
  • Journal Title: Infection and Drug Resistance Volume: Volume 14 Pages: 5079-5087
  • DOI: 10.2147/idr.s338165
  • Peer Reviewed / Open Access
• [Journal Article] A Microbiome-Derived Peptide Induces Apoptosis of Cells from Different Tissues (2021)
  • Author(s): Saiki Haruko、Okano Yuko、Yasuma Taro、Toda Masaaki、Takeshita Atsuro、Abdel-Hamid Ahmed M.、Fridman D’Alessandro Valeria、Tsuruga Tatsuki、D’Alessandro-Gabazza Corina N.、Katayama Kan、Sugimoto Masahiko、Fujimoto Hajime、Yamanaka Keiichi、Kobayashi Tetsu、Cann Isaac、Gabazza Esteban C.
  • Journal Title: Cells Volume: 10 Issue: 11 Pages: 2885-2885
  • DOI: 10.3390/cells10112885
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Degradation of complex arabinoxylans by human colonic Bacteroidetes (2021)
  • Author(s): Pereira Gabriel V.、Abdel-Hamid Ahmed M.、Dutta Soumajit、D’Alessandro-Gabazza Corina N.、Wefers Daniel、Farris Jacob A.、Bajaj Shiv、Wawrzak Zdzislaw、Atomi Haruyuki、Mackie Roderick I.、Gabazza Esteban C.、Shukla Diwakar、Koropatkin Nicole M.、Cann Isaac
  • Journal Title: Nature Communications Volume: 12 Issue: 1
  • DOI: 10.1038/s41467-020-20737-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Too Premature to Deny the Potential of Thrombomodulin-alfa in Idiopathic Pulmonary Fibrosis (2020)
  • Author(s): Kobayashi Tetsu、Hataji Osamu、Fujimoto Hajime、D'Alessandro-Gabazza Corina、Yasuma Taro、Gabazza Esteban C
  • Journal Title: American Journal of Respiratory and Critical Care Medicine Volume: - Issue: 11 Pages: 1449-1450
  • DOI: 10.1164/rccm.202002-0271le
  • Peer Reviewed / Open Access
• [Journal Article] Low-Dose of Intrapulmonary Pirfenidone Improves Human Transforming Growth Factorβ1-Driven Lung Fibrosis (2020)
  • Author(s): Okano Tomohito、Kobayashi Tetsu、Yasuma Taro、D’Alessandro-Gabazza Corina N.、Toda Masaaki、Fujimoto Hajime、Nakahara Hiroki、Okano Yuko、Takeshita Atsuro、Nishihama Kota、Saiki Haruko、Tomaru Atsushi、Fridman D’Alessandro Valeria、Ishida Satoru、Sugimoto Hiromi、Takei Yoshiyuki、Gabazza Esteban C.
  • Journal Title: Frontiers in Pharmacology Volume: 11
  • DOI: 10.3389/fphar.2020.593620
  • Peer Reviewed / Open Access
• [Presentation] 肺線維症モデルマウスにおける肺内細菌叢の検討 (2022)
  • Author(s): 藤本 源、小林 哲、ガバザ エステバン
  • Organizer: 第71回日本アレルギー学会学術大会
• [Presentation] ブドウ球菌由来のアポトーシス促進ペプチドはブレオマイシン誘発肺線維症モデルにおいて慢性期の肺線維化を促進する (2022)
  • Author(s): 岡野 智仁、Valeria Fridman D’Alessandro、古橋 一樹、大岩 綾香、鶴賀 龍樹、齋木 晴子、藤原 拓海、浅山 健太郎、高橋 佳紀、都丸 敦史、中原 博紀、藤本 源、岡野 優子、竹下 敦郎、安間 太郎、Corina N. D’Alessandro-Gabazza、Esteban C. Gabazza、小林 哲
  • Organizer: 第62回日本呼吸器学会学術講演会
• [Presentation] マトリックスメタロプロテアーゼ-2（MMP-2）の肺線維症への役割 (2022)
  • Author(s): 鶴賀 龍樹、小林 哲、齋木 晴子、岡野 智仁、藤原 拓海、浅山 健太郎、都丸 敦史、高橋 佳紀、藤本 源、Corina N. D’Alessandro-Gabazza、Esteban C. Gabazza
  • Organizer: 第62回日本呼吸器学会学術講演会
• [Presentation] The Role of the Lung Microbiota in Acute Exacerbation of Pulmonary Fibrosis (2022)
  • Author(s): Valeria Fridman D’Alessandro, Tomohito Okano, Haruko Saiki, Tatsuki Tsuruga, Kentaro Asayama, Atsushi Tomaru, Hiroki Nakahara, Hajime Fujimoto, Corina N. D’Alessandro-Gabazza, Esteban C. Gabazza, Tetsu Kobayashi
  • Organizer: 第62回日本呼吸器学会学術講演会
• [Presentation] Amelioration of kidney fibrosis and dysfunction by recombinant thrombomodulin (2021)
  • Author(s): Asturo Takeshita, Taro Yasuma, Yuko Okano, Kota Nishihama, Valeria Fridman D'Alessandro, Masaaki Toda, Corina N. D'Alessandro-Gabazza, Yutaka Yano, Esteban C. Gabazza
  • Organizer: 第50回日本免疫学会学術集会
• [Presentation] A microbiome-derived peptide induces apoptosis of cells from different tissues (2021)
  • Author(s): Yuko Okano1, Atsuro Takeshita, Kota Nishihama, Valeria Fridman, Taro Yasuma, Corina Gabazza, Masaaki Toda, Yutaka Yano, Esteban Gabazza
  • Organizer: 第50回日本免疫学会学術集会
• [Presentation] Thrombomodulin suppresses apoptosis of podocytes by activating Akt signal pathway (2021)
  • Author(s): Valeria Fridman D'Alessandro, Taro Yasuma, Masaaki Toda, Atsuro Takeshita, Corina D'Alessandro Gabazza, Yuko Okano, Yutaka Yano, Esteban Gabazza
  • Organizer: 第50回日本免疫学会学術集会
• [Presentation] 抗甲状腺薬によるANCA関連間質性肺炎と考えられた1例 (2020)
  • Author(s): 岡野 智仁、鶴賀 龍樹、齊木 晴子、藤原 拓海、浅山 健太郎、高橋 佳紀、都丸 敦史、中原 博紀、藤本 源、小林 哲、ガバザ エステバン
  • Organizer: 第117回日本呼吸器学会東海地方会
• [Presentation] TGF-Β1過剰発現マウスを用いた肺線維化と発癌に関する検討 (2020)
  • Author(s): 中原 博紀、小林 哲、齊木 晴子、藤原 拓海、岡野 智仁、浅山 健太郎、都丸 敦史、高橋 佳紀、藤本 源、ガバザ コリナ、ガバザ エステバン
  • Organizer: 第60回日本呼吸器学会学術講演会
• [Presentation] MUC5Bのrs35705950単塩基多型過剰発現トランスジェニックマウスの作製 (2020)
  • Author(s): 都丸 敦史、小林 哲、齊木 晴子、浅山 健太郎、岡野 智仁、藤原 拓海、高橋 佳紀、中原 博紀、藤本 源、ガバザ エステバン
  • Organizer: 第60回日本呼吸器学会学術講演会
• [Presentation] The Role of Matrix Metalloproteinase-2 in Pulmonary Fibrosis (2020)
  • Author(s): Tomohito Okano, Tetsu Kobayashi, Haruko Saiki, Takumi Fujiwara, Kentaro Asayama, Yoshinori Takahashi, Atsushi Tomaru, Hiroki Nakahara, Hajime Fujimoto, Corina N. D’Alessandro-Gabazza, Esteban C. Gabazza
  • Organizer: 第60回日本呼吸器学会学術講演会