In the newborn, alveolarization continues postnatally and can be disrupted by hyperoxia, leading to long-lasting consequences on lung function. We wanted to better understand the role of heme oxygenase (HO)-1, the inducible form of the rate-limiting enzyme in heme degradation, in neonatal hyperoxic lung injury and repair. Although it was not observed after 3 days of hyperoxia alone, when exposed to hyperoxia and allowed to recover in air (O2/air recovered), neonatal HO-1 knockout (KO) mice had enlarged alveolar spaces and increased lung apoptosis as well as decreased lung protein translation and dysregulated gene expression in the recovery phase of the injury. Associated with these changes, KO had sustained low levels of active β-catenin and lesser lung nuclear heterogeneous nuclear ribonucleoprotein K (hnRNPK) protein levels, whereas lung nuclear hnRNPK was increased in transgenic mice over-expressing nuclear HO-1. Disruption of HO-1 may enhance hnRNPK-mediated inhibition of protein translation and subsequently impair the β-catenin/hnRNPK regulated gene expression required for coordinated lung repair and regeneration.
Keywords: Cell proliferation; DNA damage and repair; HO-1, heme oxygenase-1; Heme oxygenase-1; KO, knockout; MEF, mouse embryonic fibroblasts; Neonatal hyperoxic lung injury and repair; O2/air, exposed to 95% oxygen for 3 days then recovered in air; OGG1, 8-oxoguanine DNA glycosylase; RAC, radial alveolar counts; SP-B, surfactant protein B; SP-C, surfactant protein C; hnRNPK, heterogeneous nuclear ribonucleoprotein protein K; β-catenin/hnRNPK.