Protective Effects of Valproic Acid, a Histone Deacetylase Inhibitor, against Hyperoxic Lung Injury in a Neonatal Rat Model.
OBJECTIVE
Histone acetylation and deacetylation may play a role in the pathogenesis of inflammatory lung diseases. We evaluated the preventive effect of valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, on neonatal hyperoxic lung injury.


METHODS
Forty newborn rat pups were randomized in normoxia, normoxia+VPA, hyperoxia and hyperoxia+VPA groups. Pups in the normoxia and normoxia+VPA groups were kept in room air and received daily saline and VPA (30 mg/kg) injections, respectively, while those in hyperoxia and hyperoxia+VPA groups were exposed to 95% O2 and received daily saline and VPA (30 mg/kg) injections for 10 days, respectively. Growth, histopathological, biochemical and molecular biological indicators of lung injury, apoptosis, inflammation, fibrosis and histone acetylation were evaluated.


RESULTS
VPA treatment during hyperoxia significantly improved weight gain, histopathologic grade, radial alveolar count and lamellar body membrane protein expression, while it decreased number of TUNEL(+) cells and active Caspase-3 expression. Expressions of TGFβ3 and phospho-SMAD2 proteins and levels of tissue proinflammatory cytokines as well as lipid peroxidation biomarkers were reduced, while anti-oxidative enzyme activities were enhanced by VPA treatment. VPA administration also reduced HDAC activity while increasing acetylated H3 and H4 protein expressions.


CONCLUSIONS
The present study shows for the first time that VPA treatment ameliorates lung damage in a neonatal rat model of hyperoxic lung injury. The preventive effect of VPA involves HDAC inhibition.
Gulhane Military Medical Academy, Department of Pediatrics, Division of Neonatology, Ankara, Turkey.
Merih
M
Cetinkaya
Uludag University Medical School, Department of Pharmacology, Bursa, Turkey.
Mehmet
M
Cansev
Gulhane Military Medical Academy, Department of Pediatrics, Division of Neonatology, Ankara, Turkey.
Ferhat
F
Cekmez
Gulhane Military Medical Academy, Department of Pediatrics, Division of Neonatology, Ankara, Turkey.
Cuneyt
C
Tayman
Gulhane Military Medical Academy, Department of Pediatrics, Division of Neonatology, Ankara, Turkey.
Fuat Emre
FE
Canpolat
Uludag University Medical School, Department of Anatomy, Bursa, Turkey.
Ilker Mustafa
IM
Kafa
Uludag University School of Arts and Sciences, Department of Biology, Bursa, Turkey.
Esra Orenlili
EO
Yaylagul
Maastricht University Medical Center, Department of Pediatrics, Maastricht, Netherlands.
Boris W
BW
Kramer
Gulhane Military Medical Academy, Department of Pediatrics, Division of Neonatology, Ankara, Turkey.
Serdar Umit
SU
Sarici
D000818:Animals; D015415:Biomarkers; D001835:Body Weight; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D018496:Hyperoxia / Q000150:complications* / Q000378:metabolism; D055370:Lung Injury / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D020011:Protective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D014635:Valproic Acid / Q000008:administration & dosage / Q000494:pharmacology*
D015415:Biomarkers; D056572:Histone Deacetylase Inhibitors; D020011:Protective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D014635:Valproic Acid; D053148:Caspase 3