Heme oxygenase in neonatal lung injury and repair

Abstract

Significance: Premature and sick neonates are often exposed to high concentrations of oxygen, which results in lung injury and long-term adverse consequences. Nevertheless, neonates are more tolerant to hyperoxia than are adults. This may be, in part, explained by the high lung content of heme oxygenase-1 (HO-1), the rate-limiting enzyme in the degradation of heme and an important stress protein. The abundance of HO-1 dictates its cytoprotective and deleterious effects. Interestingly, in response to hyperoxia, lung HO-1 mRNA is not further up-regulated in neonates, suggesting that lung HO-1 gene expression is tightly regulated so as to optimize cytoprotection when faced with an oxidative stress such as hyperoxia.

Recent advances: In addition to the lack of induction of HO-1 mRNA, neonatal lung HO-1 protein is observed in the nucleus in neonatal mice exposed to hyperoxia but not in adults, which is further evidence for the developmental regulation of HO-1. Nuclear HO-1 had unique properties independent of its enzymatic activity. In addition, there has been increasing evidence that nuclear HO-1 contributes to cellular proliferation and malignant transformation in several human cancers.

Critical issues: Since HO-1 has dual effects in cytoprotection and cellular proliferation, the titration of HO-1 effects is critical to ensure beneficial actions against oxidative stress.

Future directions: Much more has to be understood about the specific roles of HO-1 so as to manipulate its abundance and/or nuclear migration to maximize the therapeutic benefit of this pleiotropic protein in the neonatal lung.

FIG. 1.

Pathophysiology of bronchopulmonary dysplasia (BPD). In the neonatal lung, hyperoxia, ventilation and inflammation contribute to changes in cellular function, leading to blunted repair and persistent distortion in lung architecture. In addition, oxidative-mediated signaling via NF-E2-related factor 2 (Nrf2) results in activation of the pentose phosphate shunt (PPS) with resultant conversion of NADP to NADPH. This provides reducing equivalents to detoxify reactive oxygen species (ROS).

FIG. 2.

Activation of the Nrf2 pathway with oxidative stress. Nrf2 is sequestered in the cytoplasm with Keap-1, facilitating its ubiquination and subsequent degradation. With oxidative stress, Nrf2 is released and migrates to the nucleus, where it binds to multiple antioxidant response elements (MARE) on heme oxygenase (HO)-1 and other genes to mediate gene transcription. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 3.

Catalytic reaction of HO. Heme is degraded in an energy requiring process to biliverdin. This is then converted to bilirubin by the nonrate limiting biliverdin reductase. Iron (Fe) and carbon monoxide (CO) are released in equimolar amounts. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 4.

Effects of HO-1 on cell proliferation. Increased proliferation is shown by a+, decreased proliferation by a −, based on existing literature. In the developing lung exposed to hyperoxia, the net effect of HO-1 on the different cell lineages prevents the phenotypic changes of BPD. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 5.

Mechanisms by which HO-1 influences inflammation. HO-1 can bind to caveolin to prevent toll-like receptor (TLR)-4 signaling. In addition, the activation of p-STAT3-RORγ and p38 MAP kinase signaling is reduced by HO-1, which also dampens inflammatory responses.

FIG. 6.

Proposed effects of promoter polymorphisms on HO-1 in lung disease. Long GT repeats on the HO-1 promoter (left) are associated with the development of several lung pathologic states. It remains to be determined whether short GT repeats are protective against lung disease.

FIG. 7.

Maturational differences in HO-1 gene regulation and protein localization. In response to hyperoxia, neonates (left) do not up-regulate HO-1 mRNA but translocate HO-1 to the nucleus. In contrast, adults (right) induce HO-1 mRNA but do not translocate HO-1 to the nucleus. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 8.

Association of nuclear HO-1 with lung cancer. In both rodents and humans, increased nuclear distribution of HO-1 (inset on the right where DAPI nuclear stain and HO-1 are co-localized as shown by the cyan color) is associated with abnormal lung histology (as shown in the hematoxylin and eosin-stained tissue on the right). With cytoplasmic localization of HO-1 (left inset), lung tissue histology is more likely to be normal (left). To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars