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A novel phosphodiesterase 4 inhibitor, AA6216, reduces macrophage activity and fibrosis in the lung.

Author information

Affiliations

  • 1. Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine, 377-2 Onohigashi, Osakasayama, Osaka, 589-8511, Japan; Pharmaceutical Research Center, Meiji Seika Pharma Co., Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama, Kanagawa, 222-8567, Japan.
      Authors
    • Matsuhira T 1
    (1 author)
  • 2. Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine, 377-2 Onohigashi, Osakasayama, Osaka, 589-8511, Japan.
      Authors
    • Nishiyama O 2
    • Sano H 2
    • Iwanaga T 2
    • Tohda Y 2
    (4 authors)
  • 3. Pharmaceutical Research Center, Meiji Seika Pharma Co., Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama, Kanagawa, 222-8567, Japan.
      Authors
    • Tabata Y 3
    • Kaji C 3
    • Kubota-Ishida N 3
    (3 authors)
  • 4. Division of Biostatistics, Clinical Research Center, Kindai University Faculty of Medicine, 377-2 Onohigashi, Osakasayama, Osaka, 589-8511, Japan.
      Authors
    • Chiba Y 4
    (1 author)

European Journal of Pharmacology, 25 Aug 2020, 885:173508
https://doi.org/10.1016/j.ejphar.2020.173508 PMID: 32858049 

Abstract 

Idiopathic pulmonary fibrosis (IPF) is an intractable disease with poor prognosis, and therapeutic options are limited. While the pathogenic mechanism is unknown, cytokines, such as transforming growth factor (TGF)-β, and immune cells, such as monocytes and macrophages, that produce them, seem to be involved in fibrosis. Some phosphodiesterase 4 (PDE4) inhibitors reportedly have anti-fibrotic potential by acting on these disease-related factors. Therefore, we evaluated the effect of a novel PDE4 inhibitor, AA6216, on nonclinical IPF-related models and samples from IPF patients. First, we examined the inhibitory effect of AA6216 on the production of TGF-β1 from a human monocytic cell line, THP-1. Second, we analyzed the impact of AA6216 on TNF-α production by human alveolar macrophages collected from patients with IPF. Finally, we investigated the anti-fibrotic potency of AA6216 on bleomycin-induced lung fibrosis in mice. We found that AA6216 significantly inhibited TGF-β1 production by THP-1 cells. It also significantly suppressed TNF-α production by alveolar macrophages from patients with IPF. In the mouse model of bleomycin-induced pulmonary fibrosis, therapeutic administration of AA6216 significantly reduced fibrosis scores, collagen-stained areas, and TGF-β1 in bronchoalveolar lavage fluid. AA6216 may represent a new agent for the treatment of IPF with a distinct mechanism of action from that of conventional anti-fibrotic agents.

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Read article at publisher's site: https://doi.org/10.1016/j.ejphar.2020.173508

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Funding 

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Meiji Seika Pharma Co., Ltd. (1)