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

Autor: Matsuhira T; 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., Nishiyama O; Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine, 377-2 Onohigashi, Osakasayama, Osaka, 589-8511, Japan. Electronic address: nishiyama_o@yahoo.co.jp., Tabata Y; Pharmaceutical Research Center, Meiji Seika Pharma Co., Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama, Kanagawa, 222-8567, Japan., Kaji C; Pharmaceutical Research Center, Meiji Seika Pharma Co., Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama, Kanagawa, 222-8567, Japan., Kubota-Ishida N; Pharmaceutical Research Center, Meiji Seika Pharma Co., Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama, Kanagawa, 222-8567, Japan., Chiba Y; Division of Biostatistics, Clinical Research Center, Kindai University Faculty of Medicine, 377-2 Onohigashi, Osakasayama, Osaka, 589-8511, Japan., Sano H; Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine, 377-2 Onohigashi, Osakasayama, Osaka, 589-8511, Japan., Iwanaga T; Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine, 377-2 Onohigashi, Osakasayama, Osaka, 589-8511, Japan., Tohda Y; Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine, 377-2 Onohigashi, Osakasayama, Osaka, 589-8511, Japan.
Jazyk: angličtina
Zdroj: European journal of pharmacology [Eur J Pharmacol] 2020 Oct 15; Vol. 885, pp. 173508. Date of Electronic Publication: 2020 Aug 25.
DOI: 10.1016/j.ejphar.2020.173508
Abstrakt: 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.
(Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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