Establishment of new treatment for suppression of lung fibrosis through regurating macrophage activation

• Project/Area Number: 17K16614
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Respiratory surgery
• Research Institution: Osaka City University
• Principal Investigator: Michihito Toda 大阪市立大学, 大学院医学研究科, 登録医 (70769835)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: マクロファージ分極制御 / 特発性肺線維症急性増悪 / 外科

Outline of Final Research Achievements

In vitro, Pifenidone (PFD) significantly reduced the expression of M2 macrophage (MΦ) markers but had no effect on the expression of M1 MΦ markers. PFD significantly reduced TGF-β1 levels in MΦ culture supernatants. The expression of Col1a1 and heat shock protein 47 mRNAs was only significantly suppressed when rat lung fibroblasts were cultured with conditioned medium from MΦ cells treated with PFD. In vivo, PFD suppressed M2MΦ polarization in lung tissue by daily oral administration.
Respiratory failure was exacerbated in Bleomycin-treated rats by Lipopolysaccharide. This model could mimic the pathophysiological changes of acute exacerbation of pulmonary fibrosis in humans.

Academic Significance and Societal Importance of the Research Achievements

ピルフェニドンが慢性肺線維化に関わるM2マクロファージの分極抑制効果を持つことが判明した。一方で急性炎症病態に関わるM1マクロファージの分極抑制効果は認めず、今後急性炎症病態（間質性肺炎急性増悪）抑制のためにはM1マクロファージを抑制する他剤との併用を行う必要がある。ラットの間質性肺炎急性増悪モデルを確立したことで今後さらに有効な実験系を計画することが可能となった。
また、M2マクロファージは肺組織における発癌とも関係があるとされ、ピルフェニドンのマクロファージ分極制御機構により線維化肺の発癌抑制効果についても期待できる。

Research Products

• [Journal Article] Pirfenidone suppresses polarization to M2 phenotype macrophages and the fibrogenic activity of rat lung fibroblasts (2018)
  • Author(s): Toda Michihito、Mizuguchi Shinjiro、Minamiyama Yukiko、Yamamoto-Oka Hiroko、Aota Takanori、Kubo Shoji、Nishiyama Noritoshi、Shibata Toshihiko、Takemura Shigekazu
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: 63 Issue: 1 Pages: 58-65
  • DOI: 10.3164/jcbn.17-111
  • NAID: 130007387138
  • ISSN: 0912-0009, 1880-5086
  • Peer Reviewed / Open Access
• [Journal Article] Suppressive effects on lung fibrosis and the polarization and populations of macrophages by liposomal clodronate combined with pirfenidone (2018)
  • Author(s): Toda Michihito、Mizuguchi Shinjiro、Minamiyama Yukiko、Takemura Shigekazu、Oka-Yamamoto Hiroko、Aota Takanori、Miyamoto Hikaru、Nishiyama Noritoshi
  • Journal Title: Free Radical Biology and Medicine Volume: 120 Pages: S102-S102
  • DOI: 10.1016/j.freeradbiomed.2018.04.338
  • Open Access
• [Journal Article] S-allyl-glutathione suppresses liver fibrosis by inhibition of excess skewing polarization of macrophages in rats (2018)
  • Author(s): Minamiyama Yukiko、Takemura Shigekazu、Azuma Hideki、Osada-Oka Mayuko、Toda Michihito、Kobayashi Hikaru Keiko、Miyamoto、ichikawa Hiroshi、Kubo Shoji
  • Journal Title: Free Radical Biology and Medicine Volume: 120 Pages: S133-S133
  • DOI: 10.1016/j.freeradbiomed.2018.04.439
  • Open Access
• [Journal Article] Effects of pirfenidone on rat alveolar macrophage skewing and macrophage-fibroblast interactions (2018)
  • Author(s): Miyamoto Hikaru、Tsukioka Takuma、Mizuguchi Shinjiro、Minamiyama Yukiko、Takemura Shigekazu、Toda Michihito、Nishiyama Noritoshi
  • Journal Title: Free Radical Biology and Medicine Volume: 120 Pages: S114-S114
  • DOI: 10.1016/j.freeradbiomed.2018.04.376
  • Open Access
• [Journal Article] Pirfenidone suppresses polarization to M2 phenotype macrophages and the fibrogenic activity of rat lung fibroblasts (2018)
  • Author(s): Michihito Toda, Shinjiro Mizuguchi, Yukiko Minamiyama, Hiroko Yamamoto-Oka, Takanori Aota, Shoji Kubo, Noritoshi Nishiyama, Toshihiko Shibata and Shigekazu Takemura.
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: -
  • NAID: 130007387138
  • Peer Reviewed / Open Access
• [Presentation] A new model of the acute exacerbation of pulmonary fibrosis in rats (2020)
  • Author(s): Hikaru Miyamoto
  • Organizer: Society for Free Radical Research International 2020
  • Int'l Joint Research
• [Presentation] ラット肺線維症急性増悪モデルの病態解析検討 (2020)
  • Author(s): 宮本光
  • Organizer: 日本酸化ストレス学会 2020
• [Presentation] Development of a new rat model to assess the acute exacerbation of pulmonary fibrosis (2019)
  • Author(s): Hikaru Miyamoto
  • Organizer: Society for Redox Biology and Medicine 2019
  • Int'l Joint Research
• [Presentation] Suppressive effects on lung fibrosis and the polarization and populations of macrophages by liposomal clodronate combined with pirfenidone (2018)
  • Author(s): Michihito Toda
  • Organizer: May 2018Free Radical Biology and Medicine
  • Int'l Joint Research
• [Presentation] S-allyl-glutathione suppresses liver fibrosis by inhibition of excess skewing polarization of macrophages in rats (2018)
  • Author(s): Yukiko Minamiyama，Michihito Toda
  • Organizer: May 2018Free Radical Biology and Medicine
  • Int'l Joint Research
• [Presentation] Effects of pirfenidone on rat alveolar macrophage skewing and macrophage-fibroblast interactions (2018)
  • Author(s): Hikaru Miyamoto, Michihito Toda
  • Organizer: May 2018Free Radical Biology and Medicine
  • Int'l Joint Research
• [Presentation] Suppressive effects on lung fibrosis and the polarization and populations of macrophages by liposomal clodronate combined with pirfenidone (2018)
  • Author(s): Michihito Toda, Shinjiro Mizuguchi, Yukiko Minamiyama, Shigekazu Takemura, Hiroko Oka-Yamamoto, Takanori Aota, Hikaru Miyamoto, Noritoshi Nishiyama
  • Organizer: 19th Biennial Meeting Society for Free Radical Research International
  • Int'l Joint Research
• [Presentation] 抗線維化薬ピルフェニドンの 肺胞マクロファージ分極制御を介した線維化抑制効果の検討 (2017)
  • Author(s): 戸田道仁 水口真二郎 南山幸子 竹村茂一 山本寛子 青田尚哲 西山典利
  • Organizer: 第70回日本酸化ストレス学会