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

2019 Fiscal Year Final Research Report

• 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
• Keywords: マクロファージ分極制御

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.

Free Research Field

呼吸器外科学

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。