Development of innovative molecularly targeted therapies for idiopathic pulmonary fibrosis.

• Project/Area Number: 18K08145
• 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: Yamaguchi University (2020-2023); Nagasaki University (2018-2019)
• Principal Investigator: Kakugawa Tomoyuki 山口大学, 医学部, 教授(特命) (90570953)
• Project Period (FY): 2018-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 特発性肺線維症 / HSP47 / 抗線維化 / 分子標的治療 / 肺癌 / クローン病 / 炎症性腸疾患

Outline of Final Research Achievements

The HSP47 inhibitor was found to suppress fibroblast proliferation and migration. Moreover, the HSP47 inhibitor suppressed the production of type I collagen in fibroblasts by inhibiting the chaperone function of HSP47. This suggests that the HSP47 inhibitor may be an ideal drug for inhibiting the progression of fibrosis.
The patients with a high number of HSP47-positive fibroblasts had a shorter disease-free survival than those with a low number of HSP47-positive fibroblasts. Multivariate analysis identified only the presence of a high number of HSP47-positive fibroblasts as an independent risk factor for recurrence of lung cancer after surgery.
The serum anti-HSP47 antibody titer was found to be associated with the activity of Crohn's disease.

Academic Significance and Societal Importance of the Research Achievements

特発性肺線維症は不可逆的な肺線維化をきたす進行性難治性疾患である。本邦だけでも1万人以上の特発性肺線維症患者がいるが、根本的治療法はなく、診断後の平均生存期間は3年程度と予後は極めて不良である。そのため、特発性肺線維症の根治治療を可能にする新規治療薬の開発は喫緊の課題である。この問題を解決するべく本研究課題では、特発性肺線維症の新規治療ターゲットおよびバイオマーカーとしてHSP47の有用性を提案し、実地臨床での応用実現を目指し研究を行った。本研究結果からは、HSP47 inhibitorは線維化進展を抑制するための理想的な薬剤となる可能性があるものと考えられた。

Research Products

• [Journal Article] Relief of Airflow Limitation and Airway Inflammation by Endoscopic Sinus Surgery in a Patient with Severe Asthma with Eosinophilic Chronic Rhinosinusitis (2024)
  • Author(s): Matsumori K, Hamada K, Oishi K, Okimura M, Yonezawa K, Watanabe M, Hisamoto Y, Murakawa K, Fukatsu-Chikumoto A, Matsuda K, Ohata S, Suetake R, Utsunomiya T, Murata Y, Yamaji Y, Asami-Noyama M, Edakuni N, Kakugawa T, Hirano T, Matsunaga K.
  • Journal Title: Internal Medicine Volume: 63 Issue: 16 Pages: 2317-2320
  • DOI: 10.2169/internalmedicine.2918-23
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2024-08-15
  • Peer Reviewed / Open Access
• [Journal Article] Correlation between frailty and reduction in cortical thickness in patients with chronic obstructive pulmonary disease (2024)
  • Author(s): Fukatsu-Chikumoto Ayumi、Hirano Tsunahiko、Takahashi Shun、Ishida Takuya、Yasuda Kasumi、Donishi Tomohiro、Suga Kazuyoshi、Doi Keiko、Oishi Keiji、Ohata Shuichiro、Murata Yoriyuki、Yamaji Yoshikazu、Asami-Noyama Maki、Edakuni Nobutaka、Kakugawa Tomoyuki、Matsunaga Kazuto
  • Journal Title: Scientific Reports Volume: 14 Issue: 1 Pages: 6106-6106
  • DOI: 10.1038/s41598-024-53933-0
  • Peer Reviewed / Open Access
• [Journal Article] Gender Difference in the Relationship between Extrapulmonary Factors and Reduced Lung Function in Early Adulthood (2024)
  • Author(s): Keiko Doi , Tsunahiko Hirano , Kazuki Hamada, Keiji Oishi, Shuichiro Ohata, Yoriyuki Murata, Yoshikazu Yamaji, Nobutaka Edakuni, Tomoyuki Kakugawa, Kazuto Matsunaga
  • Journal Title: Journal of Clinical Medicine Volume: 13 Issue: 6 Pages: 1769-1778
  • DOI: 10.3390/jcm13061769
  • Peer Reviewed / Open Access
• [Journal Article] Utility of the Shortness of Breath in Daily Activities Questionnaire (SOBDA-Q) to Detect Sedentary Behavior in Patients with Chronic Obstructive Pulmonary Disease (COPD) (2023)
  • Author(s): Yamaji Yoshikazu、Hirano Tsunahiko、Ogawa Hiromasa、Fukatsu-Chikumoto Ayumi、Matsuda Kazuki、Hamada Kazuki、Ohata Shuichiro、Suetake Ryo、Murata Yoriyuki、Oishi Keiji、Asami-Noyama Maki、Edakuni Nobutaka、Kakugawa Tomoyuki、Matsunaga Kazuto
  • Journal Title: Journal of Clinical Medicine Volume: 12 Issue: 12 Pages: 4105-4105
  • DOI: 10.3390/jcm12124105
  • Peer Reviewed / Open Access
• [Journal Article] A Real-World Study of Achievement Rate and Predictive Factors of Clinical and Deep Remission to Biologics in Patients with Severe Asthma (2023)
  • Author(s): Oishi Keiji、Hamada Kazuki、Murata Yoriyuki、Matsuda Kazuki、Ohata Syuichiro、Yamaji Yoshikazu、Asami-Noyama Maki、Edakuni Nobutaka、Kakugawa Tomoyuki、Hirano Tsunahiko、Matsunaga Kazuto
  • Journal Title: Journal of Clinical Medicine Volume: 12 Issue: 8 Pages: 2900-2900
  • DOI: 10.3390/jcm12082900
  • Peer Reviewed / Open Access
• [Journal Article] Computed Tomography Lung Density Analysis: An Imaging Biomarker Predicting Physical Inactivity in Chronic Obstructive Pulmonary Disease: A Pilot Study (2023)
  • Author(s): Yoriyuki Murata
  • Journal Title: Journal of Clinical Medicine Volume: 12 Issue: 8 Pages: 2959-2959
  • DOI: 10.3390/jcm12082959
  • Peer Reviewed / Open Access
• [Journal Article] Kinetics of COVID-19 mRNA primary and booster vaccine-associated neutralizing activity against SARS-CoV-2 variants of concern in long-term care facility residents: a prospective longitudinal study in Japan (2023)
  • Author(s): Kakugawa Tomoyuki、Doi Keiko、Ohteru Yuichi、Kakugawa Hiroyuki、Oishi Keiji、Kakugawa Masahiro、Hirano Tsunahiko、Mimura Yusuke、Matsunaga Kazuto
  • Journal Title: Immunity & Ageing Volume: 20 Issue: 1 Pages: 42-42
  • DOI: 10.1186/s12979-023-00368-2
  • Peer Reviewed / Open Access
• [Journal Article] A case of development of autoimmune pulmonary alveolar proteinosis during the treatment of hypersensitivity pneumonitis (2023)
  • Author(s): Asami-Noyama Maki、Ito Kosuke、Harada Misa、Hisamoto Yukari、Kunihiro Yoshie、Ikeda Eiji、Yamamoto Tasuku、Suizu Junki、Fukatsu Ayumi、Ohata Syuichiro、Murata Yoriyuki、Oishi Keiji、Yamaji Yoshikazu、Edakuni Nobutaka、Kakugawa Tomoyuki、Hirano Tsunahiko、Matsunaga Kazuto
  • Journal Title: Respiratory Medicine Case Reports Volume: 44 Pages: 101862-101862
  • DOI: 10.1016/j.rmcr.2023.101862
  • Peer Reviewed / Open Access
• [Journal Article] False-positive Elevation of Beta-D-glucan and <i>Aspergillus</i> Galactomannan Levels Due to Mendelson&apos;s Syndrome after Rice Aspiration (2022)
  • Author(s): Yamamoto, T. Oishi, K. Suizu, J. Murakawa, K. Hisamoto, Y. Fujii, T. Harada, M. Chikumoto, A. Kikuchi, Y. Hamada, K. Uehara, S. Ohata, S. Murata, Y. Sakamoto, K. Yamaji, Y. Asami-Noyama, M. Edakuni, N. Kakugawa, T. Hirano, T. Matsunaga, K.
  • Journal Title: Internal Medicine Volume: 61 Issue: 19 Pages: 2935-2939
  • DOI: 10.2169/internalmedicine.8805-21
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2022-10-01
  • Peer Reviewed
• [Journal Article] The 1-minute sit-to-stand test to detect desaturation during 6-minute walk test in interstitial lung disease (2022)
  • Author(s): Oishi Keiji、Kakugawa Tomoyuki、et al.
  • Journal Title: npj Primary Care Respiratory Medicine Volume: 32 Issue: 1 Pages: 5-5
  • DOI: 10.1038/s41533-022-00268-w
  • Peer Reviewed / Open Access
• [Journal Article] Improved Prognostic Prediction by Combination of Early Initiation of Polymyxin B Hemoperfusion with Modified Gender-Age-Physiology Index in Acute Exacerbation of Idiopathic Pulmonary Fibrosis (2022)
  • Author(s): Oishi Keiji、Azuma Arata、Abe Shinji、Murata Yoriyuki、Sakamoto Kenji、Mimura Yusuke、Asami-Noyama Maki、Kakugawa Tomoyuki、Hirano Tsunahiko、Matsunaga Kazuto
  • Journal Title: Blood Purification Volume: 51 Issue: 6 Pages: 485-491
  • DOI: 10.1159/000518705
  • Peer Reviewed
• [Journal Article] Antineutrophil cytoplasmic antibody-negative granulomatosis with polyangiitis localized to the lungs (2022)
  • Author(s): Ohteru Yuichi、Kakugawa Tomoyuki、et al.
  • Journal Title: Respiratory Medicine Case Reports Volume: 36 Pages: 101600-101600
  • DOI: 10.1016/j.rmcr.2022.101600
  • Peer Reviewed
• [Journal Article] Investigating the role of heat shock protein 47 in fibrosis in Crohn’s disease (2022)
  • Author(s): Kurumi Hiroki、Takata Tomoaki、Kanda Tsutomu、Sugihara Takaaki、Kakugawa Tomoyuki、Yokota Shin-ichi、Morisaki Tomohito、Akashi Taro、Isomoto Hajime
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 10966-10966
  • DOI: 10.1038/s41598-022-15153-2
  • Peer Reviewed
• [Journal Article] Sequential Biotherapy Targeting IL-5 and IL-4/13 in Patients with Eosinophilic Asthma with Sinusitis and Otitis Media (2022)
  • Author(s): Chikumoto Ayumi、Oishi Keiji、Hamada Kazuki、Hirano Tsunahiko、Kakugawa Tomoyuki、Kanesada Keiko、Matsunaga Kazuto
  • Journal Title: Biomolecules Volume: 12 Issue: 4 Pages: 522-522
  • DOI: 10.3390/biom12040522
  • Peer Reviewed / Open Access
• [Journal Article] Platypnea-orthodeoxia syndrome in a patient with ongoing COVID-19 (2022)
  • Author(s): Asami‐Noyama Maki、Harada Misa、Hisamoto Yukari、Kobayashi Taiga、Oishi Keiji、Edakuni Nobutaka、Hirano Tsunahiko、Kakugawa Tomoyuki、Matsunaga Kazuto
  • Journal Title: Respirology Case Reports Volume: 10 Issue: 8
  • DOI: 10.1002/rcr2.1009
  • Peer Reviewed / Open Access
• [Journal Article] Invasive thymoma extending to the right atrium with superior vena cava syndrome presenting massive intracardiac thrombosis immediately after the start of chemotherapy: an autopsy case report (2022)
  • Author(s): Asami-Noyama Maki、Furuya-Kondo Tomoko、Suetake Ryo、Matsuda Kazuki、Oishi Keiji、Yamaji Yoshikazu、Hirano Tsunahiko、Kakugawa Tomoyuki、Itoh Hiroshi、Matsunaga Kazuto
  • Journal Title: International Cancer Conference Journal Volume: 11 Issue: 2 Pages: 158-163
  • DOI: 10.1007/s13691-022-00541-2
  • Peer Reviewed
• [Journal Article] Non-pneumophila Legionella species pneumonia with orange-coloured sputum (2021)
  • Author(s): Asami-Noyama, M. Harada, M. Murakawa, K. Suizu, J. Murakawa, K. Chikumoto, A. Hamada, K. Murata, Y. Oishi, K. Yamaji, Y. Edakuni, N. Hirano, T. Kakugawa, T. Matsunaga, K.
  • Journal Title: Respirol Case Rep Volume: 9 Issue: 9
  • DOI: 10.1002/rcr2.814
  • 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): Hiroshi Gyotoku, Hiroyuki Yamaguchi, Hiroshi Ishimoto, Shuntaro Sato, Hirokazu Taniguchi, Hiroaki Senju, Tomoyuki Kakugawa, Katsumi Nakatomi, Noriho Sakamoto, Minoru Fukuda, Yasushi Obase, Hiroshi Soda, Kazuto Ashizawa, Hiroshi Mukae
  • Journal Title: J Clin Med Volume: 9(4) Issue: 4 Pages: 1045-1045
  • DOI: 10.3390/jcm9041045
  • Peer Reviewed / Open Access
• [Journal Article] Comparison of lung microbiota between antineutrophil cytoplasmic antibody-associated vasculitis and sarcoidosis. (2020)
  • Author(s): Shoichi Fukui, Shimpei Morimoto, Kunihiro Ichinose, Shota Nakashima, Hiroshi Ishimoto, Atsuko Hara, Tomoyuki Kakugawa, et al.
  • Journal Title: Sci Rep Volume: 10(1) Issue: 1 Pages: 9466-9466
  • DOI: 10.1038/s41598-020-66178-4
  • NAID: 120006988158
  • Peer Reviewed / Open Access
• [Journal Article] A Novel Role of Growth Differentiation Factor (GDF)-15 in Overlap with Sedentary Lifestyle and Cognitive Risk in COPD (2020)
  • Author(s): Tsunahiko Hirano, Keiko Doi, Kazuto Matsunaga, Tomoyuki Kakugawa et al.
  • Journal Title: Journal of Clinical Medecine Volume: 9(9) Issue: 9 Pages: 2737-2737
  • DOI: 10.3390/jcm9092737
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Small molecule inhibitor of HSP47 prevents pro-fibrotic mechanisms of fibroblasts in vitro. (2020)
  • Author(s): Takuto Miyamura, Noriho Sakamoto, Tomoyuki Kakugawa, Hirokazu Taniguchi, Yoshiko Akiyama, Daisuke Okuno, Sakiko Moriyama, Atsuko Hara, Takashi Kido, Hiroshi Ishimoto, Hiroyuki Yamaguchi, Taiga Miyazaki, Yasushi Obase, Yuji Ishimatsu, Yoshimasa Tanaka, Hiroshi Mukae
  • Journal Title: Biochem Biophys Res Commun Volume: 530(3) Issue: 3 Pages: 561-565
  • DOI: 10.1016/j.bbrc.2020.07.085
  • 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): Takuto Miyamura, Noriho Sakamoto, Kaori Ishida, Tomoyuki Kakugawa, Hirokazu Taniguchi , Yoshiko Akiyama, Daisuke Okuno, Atsuko Hara, Takashi Kido, Hiroshi Ishimoto, Takuro Miyazaki, Keitaro Matsumoto, Tomoshi Tsuchiya, Hiroyuki Yamaguchi, Taiga Miyazaki, Yasushi Obase, Yuji Ishimatsu, Takeshi Nagayasu, Hiroshi Mukae
  • Journal Title: Respiratory Research Volume: 21(1) Issue: 1 Pages: 234-234
  • DOI: 10.1186/s12931-020-01490-1
  • Peer Reviewed / Open Access