Disrupted postnatal lung development in heme oxygenase-1 deficient mice

Tiangang Zhuang,Phyllis A Dennery,Huayan Zhang,Qing S Lin,Monica Zhang

doi:10.1186/1465-9921-11-142

Tiangang Zhuang, Phyllis A Dennery + Show 3 more

Open Access

https://doi.org/10.1186/1465-9921-11-142

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Abstract

BackgroundHeme oxygenase (HO) degrades cellular heme to carbon monoxide, iron and biliverdin. The HO-1 isoform is both inducible and cyto-protective during oxidative stress, inflammation and lung injury. However, little is known about its precise role and function in lung development. We hypothesized that HO-1 is required for mouse postnatal lung alveolar development and that vascular expression of HO-1 is essential and protective during postnatal alveolar development.MethodsNeonatal lung development in wildtype and HO-1 mutant mice was evaluated by histological and molecular methods. Furthermore, these newborn mice were treated with postnatal dexamethasone (Dex) till postnatal 14 days, and evaluated for lung development.ResultsCompared to wildtype littermates, HO-1 mutant mice exhibited disrupted lung alveolar structure including simplification, disorganization and reduced secondary crest formation. These defects in alveolar development were more pronounced when these mice were challenged with Dex treatment. Expression levels of both vascular endothelial and alveolar epithelial markers were also further decreased in HO-1 mutants after Dex treatment.ConclusionsThese experiments demonstrate that HO-1 is required in normal lung development and that HO-1 disruption and dexamethasone exposure are additive in the disruption of postnatal lung growth. We speculate that HO-1 is involved in postnatal lung development through modulation of pulmonary vascular development.

Highlights

Heme oxygenase (HO) degrades cellular heme to carbon monoxide, iron and biliverdin
These results suggest that the lethality of HO-1-/- embryos occurs in late gestation stage and during birth
Protein levels of the noninducible HO-2 isoform did not change after Dex injection (Figure 2D). These results demonstrate that Dex significantly inhibits postnatal alveolar formation and that HO-1 expression is dramatically repressed by Dex treatment, suggesting that negative regulation of HO-1 protein by Dex might contribute to the alveolar defects observed

Summary

Introduction

Heme oxygenase (HO) degrades cellular heme to carbon monoxide, iron and biliverdin. The HO-1 isoform is both inducible and cyto-protective during oxidative stress, inflammation and lung injury. We hypothesized that HO-1 is required for mouse postnatal lung alveolar development and that vascular expression of HO-1 is essential and protective during postnatal alveolar development. Disruption of alveolarization correlates directly with decreased lung compliance in pulmonary function tests both in patients with bronchopulmonary dysplasia (BPD) and in rodent models [3,4]. Certain conditions such as hypoxia, hyperoxia, or treatment with corticosteroids inhibit lung alveolarization, whereas treatment with retinoic acid and vitamin D promote alveolar development [5,6,7,8]. The exact mechanisms regulating alveolar development are not completely understood, as it requires interactions between multiple cell types, each of which responds to a variety of growth factors, hormones, and environmental conditions [9]

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