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Anti‑inflammatory effect of ciclamilast in an allergic model involving the expression of PDE4B.

Mol Med Rep. 2019 Mar;19(3):1728-1738. doi:10.3892/mmr.2019.9802. Epub 2019 Jan 02
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摘要


The present study aimed to investigate the potent inhibitory effects and possible biochemical basis of the novel phosphodiesterase 4 (PDE4) inhibitor ciclamilast, which is a derivative of piclamilast (RP 73401), on PDE4 and allergic inflammation. Ciclamilast was orally administered to allergic rats, their lungs and bronchoalveolar lavage fluid (BALF) were harvested, and their levels of inflammation and goblet cell hyperplasia, particularly cAMP‑PDE activity, and expression and distribution of PDE4 subtypes were determined. The results suggested that oral administration of ciclamilast significantly reduced the total leukocyte number and eosinophil number in BALF and suppressed lung histology changes, including the infiltration of inflammatory cells into the perivascular and peribronchial spaces, structural changes and goblet cell hyperplasia. For eosinophil infiltration, ciclamilast exhibited improved selectivity compared with piclamilast. Furthermore, ciclamilast significantly inhibited the upregulated activity of cAMP‑PDE and showed improved selective inhibition of the protein expression of PDE4B than piclamilast in a dose‑dependent manner. The mRNA expression of PDE4D was significantly increased in allergic rats, but PDE4B was not. PDE4B was mainly distributed in the cytoplasm, whereas PDE4D was mainly distributed in the cell membrane. The improved anti‑inflammatory activity of ciclamilast compared with piclamilast may be due to its higher level of inhibition of the activity, mRNA and protein expression of PDE4, particularly its effect on PDE4B.

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