Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=28234968
&cmd=llinks): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 215
Trichostatin A attenuates ventilation-augmented epithelial-mesenchymal transition
in mice with bleomycin-induced acute lung injury by suppressing the Akt pathway
#MMPMID28234968
Li LF
; Lee CS
; Lin CW
; Chen NH
; Chuang LP
; Hung CY
; Liu YY
PLoS One
2017[]; 12
(2
): e0172571
PMID28234968
show ga
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 ?-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.
|Actins/genetics/metabolism
[MESH]
|Acute Lung Injury/chemically induced/genetics/pathology/*prevention & control
[MESH]
free
free
free
