Curcumin and PCI-34051 combined treatment ameliorates inflammation and fibrosis by affecting MAP kinase pathway.

Objective: Bronchoconstriction, along with inflammation and hyperresponsiveness is the characteristic feature associated with asthma, contributing to variable airflow obstruction, which manifests shortness of breath, cough and wheeze, etc. Histone deacetylases 8 (HDAC8) is the member of class I HDAC family and known to regulate microtubule integrity and muscle contraction. Therefore, we aimed to investigate the effects of HDAC8 inhibition in murine model of asthma using Pan-HDAC inhibitor curcumin (CUR) and HDAC8-specific inhibitor PCI-34051 (PCI), alone and in combination.

Materials And Methods: To develop asthmatic mouse model, Balb/c mice were sensitized and challenged with ovalbumin (OVA). CUR (10 mg/kg, pre, post, alone and combined treatment) and PCI (0.5 mg/kg), were administered through intranasal (i.n) route, an hour before OVA aerosol challenge. Effects of HDAC8 inhibition by CUR and PCI pretreatments were evaluated in terms of inflammation, oxidative stress and fibrosis markers. Efficacy of curcumin post-treatment (CUR(p)) was also evaluated simultaneously.

Results: Inflammatory cell recruitment, oxidative stress (reactive oxygen species, nitric oxide), histamine and Immunoglobulin E (IgE) levels and expression of fibrosis markers including hydroxyproline, matrix metalloproteinases-9 and alpha smooth muscle actin (MMP-9 and α-SMA) were significantly reduced by CUR, CUR(p), PCI-alone and combined treatments. Protein expressions of HDAC8, Nuclear factor-κB (NF-κB) accompanied by MAPKs (mitogen-activated protein kinases) were significantly reduced by the treatments. Structural alterations were examined by histopathological analysis and linked with the fibrotic changes.

Conclusions: Present study indicates protective effects of HDAC8 inhibition in asthma using HDAC8 using CUR and PCI alone or in combination, attenuates airway inflammation, fibrosis and remodeling; hence, bronchoconstriction was accompanied through modulation of MAP kinase pathway.