HDAC6-selective inhibitor CAY10603 ameliorates cigarette smoke-induced small airway remodeling by regulating epithelial barrier dysfunction and reversing EMT

Abstract

Abstract Background: Small airway remodeling is one of the vital characteristics of chronic obstructive pulmonary disease (COPD), which is mainly caused by epithelial barrier dysfunction and epithelial mesenchymal transition (EMT). Recent studies have indicated that Histone deacetylase 6 (HDAC6) plays an important role in epithelial function and dysregulation. In this study, we investigated the therapeutic effect of an inhibitor with high selectivity for HDAC6 on COPD and its mechanism. Methods: Cigarette smoke (CS) exposure was used to establish a CS-induced COPD mouse model. CAY10603 at doses of 2.5 and 10 mg/kg was injected intraperitoneally on alternate days. The protective effects of CAY10603 on the morphology of CS-induced emphysema, epithelial barrier function and small airway remodeling were evaluated using Hematoxylin-eosin (H&E) staining, Masson trichrome (MT) staining, immunohistochemical staining, and western blot. Human lung bronchial epithelial cell line (HBE) was used to elucidate the underlying molecular mechanism of CAY10603. Results: Compared to the CS group, the mean linear intercept (MLI) of CAY10603 treatment groups was decreased and mean alveolar number (MAN) was increased. Collagen deposition was reduced in the groups with CAY10603 treatment. The expression of α-SMA was markedly upregulated in the CS group, which could be reversed by CAY10603 treatment. Conversely, expression of E-cadherin in CS group was further downregulated and was reversed by CAY10603 treatment. CAY10603 could affect tight junction protein expression of ZO-1 and Occludin. The expressions of ZO-1 and Occludin were markedly downregulated in the CS group. After CAY10603 intervention, the protein expression level of ZO-1 and Occludin increased significantly. In HBE cells, CAY10603 significantly attenuated the E-cadherin levels induced by TGF-β1, while concurrently increasing α-SMA expression. This effect was achieved through the suppression of Smad2 and Smad3 phosphorylation. Furthermore, CAY10603 inhibited the TGF-β1-induced cell migration. CAY10603 could reverse EMT by regulating TGF-β1 pathway and improve CS-exposed emphysema in mice. Conclusions: These findings suggested that CAY10603 inhibited cigarette smoke induced small airway remodeling by regulating epithelial barrier dysfunction and reversing EMT via TGF-β1/Smad2/3 signaling pathway.