HDAC8-Selective Inhibition by PCI-34051 Attenuates Inflammation and Airway Remodeling in Asthma via miR-381-3p-TGFβ3 axis

Abstract

Abstract Background: Histone deacetylase (HDAC) families regulate a wide range of physical processes and development of several diseases, and the role of HDACs in asthma development and progression is worth further investigation. This study aimed to evaluate HDAC effects in a mouse model of asthma. Methods: HDAC8 selective inhibitor PCI-34051 was administered to a mouse model of ovalbumin (OVA)-sensitized and challenged asthma. Airway responsiveness, serum cytokines, histological changes of the airway, and expression levels of α-SMA, b-actin, VEGFR, VEGF, GAPDH, HDAC8, TGF-b3, CD 105, p-ERK 1/2, ERK 1/2, PI3K, p-AKT, AKT, and PDK1 were evaluated. The miR-381-3p level was also measured. Results: All classic histologic and cellular changes of asthma in inflammation and airway remodeling were altered by HDAC8 inhibitor PCI-34051 via regulating the miR-381-3p level and its downstream gene TGF-b3. Inhibition of TGF-b3 further reduced the activation of ERK, PI3K, AKT and PDK1. Conclusions: HDAC8 inhibitor PCI-34051 exhibits comprehensive control of asthmatic changes, including inflammation and airway remodeling, in a mouse model.