Beneficial effects of HDAC6 inhibition on airway epithelial barrier function

Chronic obstructive pulmonary disease (COPD) is a heterogeneous respiratory condition characterized by airway inflammation, remodeling and restricted pulmonary air flow. Novel therapies are required to treat underlying causes, such as cigarette smoke (CSE)-induced epithelium stress and destruction, as well as breakdown of tight junctions. HDAC6 is a deacetylase that is involved in posttranslational modification of the cytoskeleton with the most prominent substrates being α-tubulin, cortactin and Hsp90. Recently, pharmacological inhibition of HDAC6 has been shown to be efficacious in treating several cancers but HDAC6 has also been reported to be involved in barrier function, EMT, oxidative stress and cilia disassembly. We have shown, in human primary COPD bronchial epithelial cells at the air-liquid interface, that HDAC6 inhibition can maintain epithelial features and function in models of epithelial damage (TNFα/CSE). Histopathological evaluation showed that compound-treated cultures had reduced damage, kept their polarity and ciliated cells. Functionally they showed reduced paracellular permeability and production of inflammatory mediators such as MMP-9, CXCL10 and IL-6, all of which have been implicated as detrimental in COPD. We also generated HDAC6 KO mice with CRISPR, which were used in a three day whole smoke model where reduced numbers of neutrophils were observed in the BALF as well as reduced SP-D in plasma. Our hypothesis is that HDAC6 inhibition could modulate key factors driving COPD: destruction of barrier function, decreased mucociliary clearance, induction of EMT and could have the potential to modulate disease progression by maintaining lung epithelial barrier integrity.