Abstract
ObjectiveHistone 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.MethodsForty 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.ResultsVPA 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.ConclusionsThe 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.
Highlights
Bronchopulmonary dysplasia (BPD) is a chronic lung disease developing especially in premature infants with significant morbidity and mortality [1]
The present study shows for the first time that valproic acid (VPA) treatment ameliorates lung damage in a neonatal rat model of hyperoxic lung injury
The pathogenesis of BPD is multifactorial resulting in chronic inflammation of the airways that results in a simplified lung structure [2]
Summary
Bronchopulmonary dysplasia (BPD) is a chronic lung disease developing especially in premature infants with significant morbidity and mortality [1]. In a recent Cochrane review, late steroid therapy after 7 days of life for chronic lung disease was suggested to reduce neonatal mortality without significantly increasing the risk of adverse long-term neurodevelopmental outcomes [6].it is necessary to develop new strategies for the prevention of BPD. Differentially-regulated chromatin remodeling pathways were reported in umbilical cord samples of infants who developed BPD by altering HDAC ratio, resulting in histone hypoacetylation. This suggests the use of HDAC inhibitors for the prevention of BPD development [10]. Current therapies of BPD do not modulate the epigenetic compound of chronic inflammation
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