title: Cigarette Smoke Disrupted Lung Endothelial Barrier Integrity and Increased Susceptibility to Acute Lung Injury via Histone Deacetylase 6.
abstract: Epidemiologic evidence indicates that cigarette smoke (CS) is associated with the development of acute lung injury (ALI). We have previously shown that brief CS exposure exacerbates lipopolysaccharide (LPS)-induced ALI in vivo and endothelial barrier dysfunction in vitro. In this study, we found that CS also exacerbated Pseudomonas-induced ALI in mice. We demonstrated that lung microvascular endothelial cells (ECs) isolated from mice exposed to CS had a greater permeability or incomplete recovery after challenges by LPS and thrombin. Histone deacetylase (HDAC) 6 deacetylates proteins essential for maintenance of endothelial barrier function. We found that HDAC6 phosphorylation at serine-22 was increased in lung tissues of mice exposed to CS and in lung ECs exposed to cigarette smoke extract (CSE). Inhibition of HDAC6 attenuated CSE-induced increases in EC permeability and CS priming of ALI. Similar barrier protection was provided by the microtubule stabilizer taxol, which preserved α-tubulin acetylation. CSE decreased α-tubulin acetylation and caused microtubule depolymerization. In coordination with increased HDAC6 phosphorylation, CSE inhibited Akt and activated glycogen synthase kinase (GSK)-3β; these effects were ameliorated by the antioxidant N-acetyl cysteine. Our results suggest that CS increases lung EC permeability, thereby enhancing susceptibility to ALI, likely through oxidative stress-induced Akt inactivation and subsequent GSK-3β activation. Activated GSK-3β may activate HDAC6 via phosphorylation of serine-22, leading to α-tubulin deacetylation and microtubule disassembly. Inhibition of HDAC6 may be a novel therapeutic option for ALI in cigarette smokers.
authors.affiliation: Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Department of Medicine, Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Diana
authors.initials: D
authors.lastname: Borgas
authors.affiliation: Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Department of Medicine, Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Eboni
authors.initials: E
authors.lastname: Chambers
authors.affiliation: Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Department of Medicine, Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Julie
authors.initials: J
authors.lastname: Newton
authors.affiliation: Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Department of Medicine, Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Junsuk
authors.initials: J
authors.lastname: Ko
authors.affiliation: Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Department of Medicine, Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Rivera
authors.affiliation: Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Department of Medicine, Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Sharon
authors.initials: S
authors.lastname: Rounds
authors.affiliation: Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Department of Medicine, Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Qing
authors.initials: Q
authors.lastname: Lu
mesh_terms: D055371:Acute Lung Injury / Q000201:enzymology* / Q000382:microbiology / Q000473:pathology*; D000818:Animals; D002417:Cattle; D002463:Cell Membrane Permeability / Q000187:drug effects; D004198:Disease Susceptibility; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000382:microbiology / Q000473:pathology; D004730:Endothelium, Vascular / Q000201:enzymology / Q000473:pathology*; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000502:physiology; D012907:Smoking / Q000009:adverse effects*
chemical_list: D056572:Histone Deacetylase Inhibitors; D008070:Lipopolysaccharides; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D006655:Histone Deacetylases
keywords: acute lung injury; cigarette smoke; endothelial cells; histone deacetylase 6; permeability