Heme oxygenase-1 regulates postnatal lung repair after hyperoxia: Role of β-catenin/hnRNPK signaling

Abstract

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.

Heme Oxygenase in Neonatal Lung Injury and Repair

“…In addition to energy, glycolysis generates intermediates that are important to cell growth such as ribose-5-phosphate, a key intermediate in nucleotide biosynthesis (17) which supports the proliferation of tumor cells. In neonatal HO-1 null mutant mice and WT littermates exposed to hyperoxia for 3 days and allowed to recover in room air for 11 days, six DNA damage-response genes were down-regulated in the WT; whereas these were up-regulated many-fold in the knockout, suggesting that HO-1 disruption modifies DNA repair pathways which are important in tumorigenesis (115). We also show that transgenic mice with cytoplasmic over-expression of HO-1 in type II cells exposed to 3 days of hyperoxia as neonates had increased numbers of multinucleated hyper-proliferating type II cells and foamy macrophages but no evidence of fibrosis or inflammation (69).…”

“…Nevertheless, longterm suppression of cell proliferation could lead to arrested lung development. In vivo, disruption of HO-1 in the neonatal mice had little effect at 3 days or exposure (23), but when the animals were allowed to recover in air for 11 days, they had significant dysregulation of cell-cycle gene expression compared with similarly exposed wild-type (WT) (115). In vitro, tracheal smooth muscle cells from human fetuses exposed to hyperoxia showed nuclear distribution of HO-1 only when they were in a nonproliferative state (73).…”

“…Enhanced lung nuclear HO-1 impairs recovery by disabling poly (ADP-ribose)-dependent regulation of DNA repair (69). Interestingly, when HO-1 null mutant mice exposed to hyperoxia as neonates were evaluated after 11 days of recovery in room air, these mice exhibited significant changes in lung alveolarization and altered expression of genes which were important in cell proliferation and DNA damage (115). With regard to fibroblasts' myofibroblast proliferation, myocardial infarct was reduced with both in vivo and in vitro HO-1 over-expression (62) Overall, as a regulator of cell proliferation and differentiation, moderate levels of HO-1 could have a significant impact on lung injury and repair processes in hyperoxia.…”

“…In the acute phase of hyperoxic exposure (3 days), neonatal mice have increased nuclear HO-1 compared with similarly exposed adults (115). This pattern of overexpression may be beneficial, because adults that induce lung HO-1 and do not demonstrate nuclear localization are more susceptible to oxidative stress.…”

Exposure Memory and Lung Regeneration

“…For instance, components of the microbiome may be activating or inhibitory factors for specific lung cells and/or structures ( Figure 4). Recent research on microbiomemetabolome interactions (85) shows that microbial groups associate with metabolic pathways, indicating that microbial populations could affect regeneration potential (Figure 4) including genomics, epigenomics, metabolomics, and proteomics, have been used in studies for lung development, remodeling, and regeneration (86)(87)(88). In many cases, discovery was limited and partially understood due to single-molecule approaches at the level of cellular and molecular signaling.…”