The phosphodiesterase 4 inhibitor AA6216 suppresses activity of fibrosis-specific macrophages

Takashi Matsuhira; Osamu Nishiyama; Yuji Tabata; Shinji Kurashimo; Hiroyuki Sano; Takashi Iwanaga; Yuji Tohda

doi:10.1016/j.bbrep.2021.101118

The phosphodiesterase 4 inhibitor AA6216 suppresses activity of fibrosis-specific macrophages

Biochem Biophys Rep. 2021 Aug 28:28:101118. doi: 10.1016/j.bbrep.2021.101118. eCollection 2021 Dec.

Authors

Takashi Matsuhira^{1

2}, Osamu Nishiyama¹, Yuji Tabata², Shinji Kurashimo³, Hiroyuki Sano¹, Takashi Iwanaga¹, Yuji Tohda¹

Affiliations

¹ Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine, 377-2 Onohigashi, Osakasayama, Osaka, 589-8511, Japan.
² Pharmaceutical Research Center, Meiji Seika Pharma Co., Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama, 222-8567, Japan.
³ Life Science Research Institute, Kindai University, 377-2 Onohigashi, Osakasayama, Osaka, 589-8511, Japan.

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is a form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, with a poor prognosis. We previously showed the antifibrotic effects of a novel phosphodiesterase 4 (PDE4) inhibitor, AA6216. In this study, we examined the effect of AA6216 on the pulmonary accumulation of segregated-nucleus-containing atypical monocytes (SatMs), which produce tumor necrosis factor (TNF)-α and are involved in murine lung fibrosis.

Methods: Mice were treated with bleomycin intratracheally at day 0 and either 10 mg/kg AA6216, 100 mg/kg nintedanib, or vehicle orally once daily from day 0 to 8. On day 9, we isolated the bronchoalveolar lavage fluid and analyzed the SatM ratio. In addition, we evaluated the effect of AA6216 on TNF-α production from SatMs isolated from murine bone marrow.

Results: AA6216, and not the antifibrotic agent nintedanib, significantly suppressed the pulmonary accumulation of SatMs (AA6216: 68.3 ± 5.4%, Nintedanib: 129.8 ± 19.7%). Furthermore, AA6216 dose-dependently inhibited the production of TNF-α by SatMs.

Conclusions: AA6216 suppresses pathogenic SatMs in the lung, which contributes to its antifibrotic effects.

Keywords: Idiopathic pulmonary fibrosis; Macrophage; Phosphodiesterase 4 inhibitor; Pulmonary fibrosis.