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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-V T , 6 mL/kg) or high-V T  (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-V T  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-V T  MV-augmented EMT after bleomycin-induced ALI, in part by inhibiting the HDAC4 and Akt pathways.

plos one

Trichostatin A attenuates ventilation-augmented epithelial-mesenchymal transition in mice with bleomycin-induced acute lung injury by suppressing the Akt pathway