Selective HDAC8 inhibition by PCI-34051 attenuates inflammation and airway remodeling in asthma via miR-381-3p-TGFβ3 axis.

Abstract

Background and objectives: Histone deacetylase (HDAC) families regulate various physical processes and the development of several diseases. The role of HDACs in asthma development and progression worths further investigation. This study aims to evaluate the effect of HDACs in a mouse model of asthma.

Methods: HDAC8 selective inhibitor PCI-34051 was administered to a mouse model of ovalbumin-sensitized and challenged asthma. Airway responsiveness, serum cytokines, histological changes of the airway, and expression levels of α-SMA, β-actin, VEGFR, VEGF, GAPDH, HDAC8, TGF-β3, 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 regulation of the miR-381-3p level and its downstream gene, TGF-β3. Inhibition of TGF-β3 further reduced the activation of ERK, PI3K, AKT, and PDK1.

Conclusion: In a mouse model, HDAC8 inhibitor PCI-34051 exhibits comprehensive control of asthmatic changes, including inflammation and airway remodeling.