The newborn is more tolerant to hyperoxia than adults. Heme oxygenase, in particular the inducible form, is highly expressed in the neonatal lung. In the reaction catalyzed by HO, heme is degraded to generate equimolar quantities of biologically active products such as iron, biliverdin, and carbon monoxide (CO) possibly accounting for the cytoprotective effects attributed to HO-1. Nonetheless, CO can activate p38 MAP kinase signaling resulting in apoptosis. Newborn lungs have enhanced nuclear translocation of HO-1 in hyperoxia but minimal induction of HO-1 mRNA. In contrast, adult lungs have predominant cytoplasmic localization of HO-1 protein but significant induction of HO-1 mRNA in hyperoxia. The nuclear form is devoid of enzymatic activity and binds to DNA repair proteins, suggesting a role in responses to DNA damage. The cyotoplasmic and active form of HO-1 may modulate the regulation of genes with antioxidant response elements (ARE) through pathways involving p38 MAP kinase and NrF2. Overall, the predominance of nuclear or cytoplasmic forms of HO-1 could greatly alter the response to an oxidative stress. We therefore hypothesize that nuclear HO-1 undergoes post-translational modifications including acetylation and phosphorylation and that neonates with predominant lung nuclear HO-1 are more resistant to DNA damage and thereby more tolerant to hyperoxia than adults. Lastly we hypothesize that nuclear localization of HO-1 is associated with epigenetic modifications during DNA repair processes. This in turn regulates the HO-1 gene. Therefore, our Specific Aims are: To define the mechanisms of nuclear localization of HO-1 in the neonatal lung in vivo;To understand the contextual importance of subcellular localization of HO-1 protein on its function and tolerance to hyperoxia;and To understand the relationship between nuclear localization of HO-1 and epigenetic modifications of HO-1 gene in hyperoxia.
Hyperoxia accounts in part for the lung injury seen in bronchopulmonary dysplasia (BPD) in human neonates. This unfortunate consequence of premature delivery and environmental factors in the NICU has long ranging impact on lung function and neurodevelopment. Understanding of the mechanism by which HO is regulated and deciphering whether HO-1 subcellular localization affects it physiologic function may allow for the development of specific therapeutic strategies to maximize the cytoprotective effects of HO-1 and thereby improve tolerance to hyperoxia.
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