Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 885, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.ejphar.2020.173508
Keywords
Macrophage; Phosphodiesterase 4 inhibitor; Pulmonary fibrosis
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Funding
- Meiji Seika Pharma Co., Ltd. [AI000002]
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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)-beta, 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-beta 1 from a human monocytic cell line, THP-1. Second, we analyzed the impact of AA6216 on TNF-alpha 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-beta 1 production by THP-1 cells. It also significantly suppressed TNF-alpha 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-beta 1 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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