Cetinkaya Merih, Cansev Mehmet, Cekmez Ferhat, Tayman Cuneyt, Canpolat Fuat Emre, Kafa Ilker Mustafa, Yaylagul Esra Orenlili, Kramer Boris W, Sarici Serdar Umit
Gulhane Military Medical Academy, Department of Pediatrics, Division of Neonatology, Ankara, Turkey.
Uludag University Medical School, Department of Pharmacology, Bursa, Turkey.
PLoS One. 2015 May 4;10(5):e0126028. doi: 10.1371/journal.pone.0126028. eCollection 2015.
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.
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.
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.
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.
组蛋白乙酰化和去乙酰化可能在炎症性肺疾病的发病机制中起作用。我们评估了组蛋白脱乙酰酶（HDAC）抑制剂丙戊酸（VPA）对新生儿高氧性肺损伤的预防作用。
将40只新生大鼠幼崽随机分为常氧组、常氧+VPA组、高氧组和高氧+VPA组。常氧组和常氧+VPA组的幼崽置于室内空气中，分别每日注射生理盐水和VPA（30mg/kg），而高氧组和高氧+VPA组的幼崽暴露于95%氧气中，分别每日注射生理盐水和VPA（30mg/kg），持续10天。评估肺损伤、细胞凋亡、炎症、纤维化和组蛋白乙酰化的生长、组织病理学、生化和分子生物学指标。
高氧期间VPA治疗显著改善了体重增加、组织病理学分级、肺泡计数和板层小体膜蛋白表达，同时减少了TUNEL（+）细胞数量和活化的Caspase-3表达。VPA治疗降低了TGFβ3和磷酸化SMAD2蛋白的表达以及组织促炎细胞因子水平和脂质过氧化生物标志物水平，同时增强了抗氧化酶活性。VPA给药还降低了HDAC活性，同时增加了乙酰化H3和H4蛋白表达。
本研究首次表明，VPA治疗可改善新生大鼠高氧性肺损伤模型中的肺损伤。VPA的预防作用涉及HDAC抑制。
