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Protective Effects of Valproic Acid, a Histone Deacetylase Inhibitor, against Hyperoxic Lung Injury in a Neonatal Rat Model.

Cetinkaya M, Cansev M, Cekmez F, Tayman C, Canpolat FE, Kafa IM, Yaylagul EO, Kramer BW, Sarici SU - PLoS ONE (2015)

Bottom Line: 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.The preventive effect of VPA involves HDAC inhibition.

View Article: PubMed Central - PubMed

Affiliation: Gulhane Military Medical Academy, Department of Pediatrics, Division of Neonatology, Ankara, Turkey.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus

Bar graph depicting body weights of rat pups at birth and P10.*p<0.05 compared to Normoxia group; #p<0.05 compared to Normoxia+VPA group; and †p<0.05 compared to Hyperoxia group using One-Way ANOVA followed by post-hoc Tukey test.
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pone.0126028.g002: Bar graph depicting body weights of rat pups at birth and P10.*p<0.05 compared to Normoxia group; #p<0.05 compared to Normoxia+VPA group; and †p<0.05 compared to Hyperoxia group using One-Way ANOVA followed by post-hoc Tukey test.

Mentions: We started the experiment with 10 rat pups in each group. No pups died in Normoxia or Normoxia+VPA groups throughout the study period. On the other hand, one pup in each Hyperoxia or Hyperoxia+VPA group died on the 2nd or the 3rd postnatal days, respectively. No significant difference was found in terms of survival rate among experimental groups (p>0.05) and our analyses were not affected by the number of surviving pups. A survival curve has been presented in Fig 1. The well-being of the rat pups was, in part, assessed with the weight gain during the experiment. Mean birth weights of pups in Normoxia, Normoxia+VPA, Hyperoxia and Hyperoxia+VPA groups (5.1±0.3 g vs. 5.1±0.2g vs. 5.0±0.4 g vs. 5.0±0.3 g, respectively) did not differ significantly. At the end of the experiment, the mean body weight of pups in Hyperoxia group (12.4±1.2 g) was significantly (p<0.05) lower than that of pups in Normoxia (17.1±1.5 g), Normoxia+VPA (16.8±1.4 g) and Hyperoxia+VPA (15.4±1.3 g) groups (Fig 2). The weight of the Hyperoxia+VPA group was not different to the Normoxia and Normoxia+VPA group.


Protective Effects of Valproic Acid, a Histone Deacetylase Inhibitor, against Hyperoxic Lung Injury in a Neonatal Rat Model.

Cetinkaya M, Cansev M, Cekmez F, Tayman C, Canpolat FE, Kafa IM, Yaylagul EO, Kramer BW, Sarici SU - PLoS ONE (2015)

Bar graph depicting body weights of rat pups at birth and P10.*p<0.05 compared to Normoxia group; #p<0.05 compared to Normoxia+VPA group; and †p<0.05 compared to Hyperoxia group using One-Way ANOVA followed by post-hoc Tukey test.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4418724&req=5

pone.0126028.g002: Bar graph depicting body weights of rat pups at birth and P10.*p<0.05 compared to Normoxia group; #p<0.05 compared to Normoxia+VPA group; and †p<0.05 compared to Hyperoxia group using One-Way ANOVA followed by post-hoc Tukey test.
Mentions: We started the experiment with 10 rat pups in each group. No pups died in Normoxia or Normoxia+VPA groups throughout the study period. On the other hand, one pup in each Hyperoxia or Hyperoxia+VPA group died on the 2nd or the 3rd postnatal days, respectively. No significant difference was found in terms of survival rate among experimental groups (p>0.05) and our analyses were not affected by the number of surviving pups. A survival curve has been presented in Fig 1. The well-being of the rat pups was, in part, assessed with the weight gain during the experiment. Mean birth weights of pups in Normoxia, Normoxia+VPA, Hyperoxia and Hyperoxia+VPA groups (5.1±0.3 g vs. 5.1±0.2g vs. 5.0±0.4 g vs. 5.0±0.3 g, respectively) did not differ significantly. At the end of the experiment, the mean body weight of pups in Hyperoxia group (12.4±1.2 g) was significantly (p<0.05) lower than that of pups in Normoxia (17.1±1.5 g), Normoxia+VPA (16.8±1.4 g) and Hyperoxia+VPA (15.4±1.3 g) groups (Fig 2). The weight of the Hyperoxia+VPA group was not different to the Normoxia and Normoxia+VPA group.

Bottom Line: 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.The preventive effect of VPA involves HDAC inhibition.

View Article: PubMed Central - PubMed

Affiliation: Gulhane Military Medical Academy, Department of Pediatrics, Division of Neonatology, Ankara, Turkey.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus