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

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

Automated summary

The study showed that AA6216 could significantly suppress the accumulation of SatMs in the lungs of mice and also dose-dependently inhibit the production of TNF-α by SatMs.