Abstract
Neonatal respiratory distress syndrome (RDS) is mainly the result of perturbation in surfactant production and is a common complication seen in premature infants. Normal fetal lung development and alveolar cell differentiation is regulated by a network of transcription factors. Functional loss of any of these factors will alter the developmental program and impact surfactant production and normal gas exchange. During development, the fetus is exposed to varying oxygen concentrations and must be able to quickly adapt to these changes in order to survive. Hypoxia-inducible factor 1alpha (HIF1alpha) is the primary transcription factor that is responsible for regulating the cellular response to changes in oxygen tension and is essential for normal development. Its role in lung maturation is not well defined and to address this knowledge gap, a lung-specific HIF1alpha knock-out model has been developed. Loss of HIF1alpha early in lung development leads to pups that die within hours of parturition, exhibiting symptoms similar to RDS. Lungs from these pups display impaired alveolar epithelial differentiation and an almost complete loss of surfactant protein expression. Ultrastructural analysis of lungs from HIF1alpha deletion pups had high levels of glycogen, aberrant septal development, and decreased expression of several factors necessary for proper lung development, including HIF2alpha, beta-catenin, and vascular endothelial growth factor. These results suggest that HIF1alpha is essential for proper lung maturation and alteration in its normal signaling during premature delivery might explain the pathophysiology of neonatal RDS.
Highlights
Thyroid transcription factor-1 regulates the expression of the genes for Clara cell secretory protein (CCSP)2 produced in Clara cells in the tracheobronchial airways and various surfactants produced by alveolar type II cells in the lung parenchyma [5, 6]
Conditional Inactivation of HIF1␣ in the Lung—The HIF1␣ gene was inactivated in the lung by mating HIF1␣-conditional null mice (HIF1␣flox/flox) [10] to an inducible bitransgenic mouse, SPC-rtTA, that expresses the reverse tetracycline transactivator under the control of the human surfactant protein using Rabbit Vector Elite ABC kit (Vector Laboratories), C (SP-C) promoter and the Cre recombinase gene with a tetracyaccording to the manufacturer’s recommendations
SPC-rtTA mice have been shown to Transmission Electron Microscopy—Neonatal lung sections express Cre recombinase in the epithelial cells of the were fixed in 4% buffered glutaraldehyde overnight at 4 °C, and stored in the 10% neutral-buffered formalin (NBF) fixative until postfixation with 1% phosphate-buffered osmium tetroxide
Summary
CCAAT-enhancerbinding protein ␣ (CEBP␣) is essential for proper regulation of alveolar Type II cell differentiation, and Forkhead box A2 (Foxa2) controls various cellular programs involved in lung development (e.g. surfactant expression) (6 – 8). Loss of HIF2␣ perturbs normal lung development through loss of VEGF expression and to subsequently decrease alveolar type II cell production of pulmonary surfactants [15].
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