In vivo Functions of Heme Oxygenase‐1 in Postnatal Lung Development

Abstract

Postnatal maturation of the lung requires proper alveolar development. In neonatal mice, daily injection of Dexamethasone (Dex) resulted in severe disruption of lung septation, whereas injection with Retinoic Acid (RA) showed more numerous and smaller alveoli. Heme oxygenase-1 (HO1) is expressed at high levels in the lung during neonatal stage. HO1 is also shown to have protective function in oxidative stress and can increase cell proliferation. We hypothesize that HO1 is involved in postnatal lung alveolar development and that alteration of HO1 expression will contribute to the protection against lung injury. To determine whether Dex can regulate HO1 via transcriptional control, Dex/RA was injected into transgenic mice expressing HO1 promoter driven luciferase reporter (HO1-luc). These mice were given daily Dex/RA injection for 14 days after birth and monitored with In Vitro Imaging System. This method allows us to monitor the photon emission imaging which directly represents the HO-1 promoter activity in the same animal during the entire experiment. Lung samples were harvested at various time points for histology and protein analysis. HO1 promoter activities and protein expression were down-regulated in the lungs of Dex-injected neonatal mice. HO-1 deficient mice displayed disrupted lung development with disorganized and simplified alveolar structure. The lung phenotypes in HO-1 mutants were also enhanced with the same postnatal Dex treatment. These results suggest that HO1 plays an important role during postnatal alveolar development. Further analysis with the HO1-luc mice will shed lights on the transcriptional regulation of HO1 during the process.