Histone Deacetylase 6 Mediates Cigarette Smoke‐Induced Increase in Lung Endothelial Permeability and Susceptibility to Acute Lung Injury

Abstract

Cigarette smoke (CS) is associated with the development of acute lung injury (ALI) in humans. We have shown that acute CS exposure increases susceptibility to lipopolysaccharide (LPS)-induced ALI in vivo and endothelial cell (EC) permeability in vitro. Here, we examined the effects of subacute CS exposure on ALI development, and underlying mechanism, using animal models of CS exposure and lung EC exposed to cigarette smoke extract (CSE). We found 3 wks of CS exposure exacerbated LPS-induced ALI. Histone deacetylase 6 (HDAC6) deacetylates proteins essential for endothelial barrier function. HDAC6 phosphorylation, which potentially activates its deacetylase activity, increased in lung of mice exposed to CS and EC exposed to CSE. CSE also decreased acetylation of α-tubulin, the major target of HDAC6, causing microtubule depolymerization. HDAC6 inhibition attenuated CS-induced increase in EC permeability and exacerbation of ALI. Similar protection was seen with taxol, which preserved α-tubulin acetylation. GSK-3β is activated by inhibiting Akt. In coordination with HDAC6 phosphorylation, CSE decreased phosphorylation of Akt and GSK-3β; effects were ameliorated by the antioxidant N-acetylcysteine. Our results suggest CS increases EC permeability, thereby enhancing susceptibility to ALI, by oxidative stress-dependent Akt inhibition and subsequent GSK-3β/HDAC6-mediated α-tubulin deacetylation. Specific inhibition of HDAC6 may help treatment of CS-associated ALI. PH-05-015 (QL), P20GM103652 (QL, SR), PULM-811-10S (SR), R25 HL088992 (SR), T32 ES007272 (EC), Brown SRA (MX).