trichostatin-a and Hyperoxia

Early pulmonary oxygen exposure is one of the most important factors implicated in the development of bronchopulmonary dysplasia (BPD).. Here, we analyzed short- and long-term effects of neonatal hyperoxia on NOS3 and STAT3 expression and corresponding epigenetic signatures using a hyperoxia-based mouse model of BPD.. Early hyperoxia exposure led to a significant increase in NOS3 (median fold change × 2.37, IQR 1.54-3.68) and STAT3 (median fold change × 2.83, IQR 2.21-3.88) mRNA levels in pulmonary endothelial cells with corresponding changes in histone modification patterns such as H2aZac and H3K9ac hyperacetylation at the respective gene loci. No complete restoration in histone signatures at these loci was observed, and responsivity to later hyperoxia was altered in mouse lungs. In vitro, histone signatures in human aortic endothelial cells (HAEC) remained altered for several weeks after an initial long-term exposure to trichostatin A. This was associated with a substantial increase in baseline eNOS (median 27.2, IQR 22.3-35.6) and STAT3α (median 5.8, IQR 4.8-7.3) mRNA levels with a subsequent significant reduction in eNOS expression upon exposure to hypoxia.. Early hyperoxia induced permanent changes in histones signatures at the NOS3 and STAT3 gene locus might partly explain the altered vascular response patterns in children with BPD.

Topics: Acetylation; Animals; Cell Line; Disease Models, Animal; Endothelial Cells; Epigenesis, Genetic; Female; Histones; Humans; Hydroxamic Acids; Hyperoxia; Infant, Newborn; Lung; Male; Mice; Nitric Oxide Synthase Type III; STAT3 Transcription Factor; Up-Regulation

Bronchopulmonary dysplasia (BPD) poses a significant global health problem. It mainly occurs in preterm infants. It is histopathologically characterized by fewer and larger alveoli and less secondary septa, suggesting an arrested or disordered lung development. To date, the mechanisms that lead to the pathophysiological changes in BPD have still not been totally understood. In embryonic development, histone deacetylase (HDAC) plays an important role by regulating gene transcription. Here, we hypothesize that a decreased HDAC expression and activity, caused by preterm birth or environmental stresses, contribute to a disorder in alveolar development in BPD. To this end, newborn Sprague-Dawley rats subjected to hyperoxia (85% O(2) ) were used to investigate the gene expression and protein activity of HDAC and alveolar development in lungs. Our results showed that hyperoxia exposure led to a suppression of the HDAC1/HDAC2 expression and activity, and the overall HDAC activity, as well as arrest of alveolarization, and an elevated expression of the cytokine-induced neutrophil chemoattractant-1 (CINC-1) in the lungs of newborn rats. However, preservation of HDAC activity by theophylline significantly improved alveolar development and attenuated CINC-1 release, all of which were blocked by a specific HDAC inhibitor, trichostatin A (TSA). TSA alone can disturb the alveolar development in neonatal rats. Our findings indicate that a persistent exposure to hyperoxia leads to a suppressed HDAC activity, which causes disorders in pulmonary development. This effect may be mediated by CINC-1. Attenuation of CINC-1-mediated inflammation by activating HDAC may have a protective effect in BPD.

Topics: Animals; Animals, Newborn; Chemokine CXCL1; Histone Deacetylase 1; Histone Deacetylase 2; Histone Deacetylase Inhibitors; Hydroxamic Acids; Hyperoxia; Pulmonary Alveoli; Rats; Rats, Sprague-Dawley; Theophylline