title: Trichostatin A attenuates ventilation-augmented epithelial-mesenchymal transition in mice with bleomycin-induced acute lung injury by suppressing the Akt pathway.
abstract: BACKGROUND
  Mechanical ventilation (MV) used in patients with acute respiratory distress syndrome (ARDS) can cause diffuse lung inflammation, an effect termed ventilator-induced lung injury, which may produce profound pulmonary fibrogenesis. Histone deacetylases (HDACs) and serine/threonine kinase/protein kinase B (Akt) are crucial in modulating the epithelial-mesenchymal transition (EMT) during the reparative phase of ARDS; however, the mechanisms regulating the interactions among MV, EMT, HDACs, and Akt remain unclear. We hypothesized that trichostatin A (TSA), a HDAC inhibitor, can reduce MV-augmented bleomycin-induced EMT by inhibiting the HDAC4 and Akt pathways.
  
  
  METHODS
  Five days after bleomycin treatment to mimic acute lung injury (ALI), wild-type or Akt-deficient C57BL/6 mice were exposed to low-tidal-volume (low-VT, 6 mL/kg) or high-VT (30 mL/kg) MV with room air for 5 h after receiving 2 mg/kg TSA. Nonventilated mice were examined as controls.
  
  
  RESULTS
  Following bleomycin exposure in wild-type mice, high-VT MV induced substantial increases in microvascular leaks; matrix metalloproteinase-9 (MMP-9) and plasminogen activator inhibitor-1 proteins; free radical production; Masson's trichrome staining; fibronectin, MMP-9, and collagen 1a1 gene expression; EMT (identified by increased localized staining of α-smooth muscle actin and decreased staining of E-cadherin); total HDAC activity; and HDAC4 and Akt activation (P < 0.05). In Akt-deficient mice, the MV-augmented lung inflammation, profibrotic mediators, EMT profiles, Akt activation, and pathological fibrotic scores were reduced and pharmacologic inhibition of HDAC4 expression was triggered by TSA (P < 0.05).
  
  
  CONCLUSIONS
  Our data indicate that TSA treatment attenuates high-VT MV-augmented EMT after bleomycin-induced ALI, in part by inhibiting the HDAC4 and Akt pathways.
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.|Department of Respiratory Therapy, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Li-Fu
authors.initials: LF
authors.lastname: Li
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chung-Shu
authors.initials: CS
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chang-Wei
authors.initials: CW
authors.lastname: Lin
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.|Department of Respiratory Therapy, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Ning-Hung
authors.initials: NH
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.
authors.forename: Li-Pang
authors.initials: LP
authors.lastname: Chuang
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chen-Yiu
authors.initials: CY
authors.lastname: Hung
authors.affiliation: Chest Department, Taipei Veterans General Hospital, Taipei, Taiwan.|Institutes of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yung-Yang
authors.initials: YY
authors.lastname: Liu
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D055371:Acute Lung Injury / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D001761:Bleomycin; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005609:Free Radicals / Q000037:antagonists & inhibitors / Q000378:metabolism; D005786:Gene Expression Regulation; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D012121:Respiration, Artificial / Q000009:adverse effects; D058258:Serpin E2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013990:Tidal Volume; D055397:Ventilator-Induced Lung Injury / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*
chemical_list: D000199:Actins; D015820:Cadherins; C000611838:Cdh1 protein, mouse; D024042:Collagen Type I; D005609:Free Radicals; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D058258:Serpin E2; C511869:Serpine2 protein, mouse; C544013:alpha-smooth muscle actin, mouse; D001761:Bleomycin; C012589:trichostatin A; D051057:Proto-Oncogene Proteins c-akt; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases