Silencing hyperoxia-induced C/EBP in neonatal mice improves lung architecture via enhanced proliferation of alveolar epithelial cells

Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
AJP Lung Cellular and Molecular Physiology (Impact Factor: 4.08). 05/2011; 301(2):L187-96. DOI: 10.1152/ajplung.00082.2011
Source: PubMed


Postnatal lung development requires proliferation and differentiation of specific cell types at precise times to promote proper alveolar formation. Hyperoxic exposure can disrupt alveolarization by inhibiting cell growth; however, it is not fully understood how this is mediated. The transcription factor CCAAT/enhancer binding protein-α (C/EBPα) is highly expressed in the lung and plays a role in cell proliferation and differentiation in many tissues. After 72 h of hyperoxia, C/EBPα expression was significantly enhanced in the lungs of newborn mice. The increased C/EBPα protein was predominantly located in alveolar type II cells. Silencing of C/EBPα with a transpulmonary injection of C/EBPα small interfering RNA (siRNA) prior to hyperoxic exposure reduced expression of markers of type I cell and differentiation typically observed after hyperoxia but did not rescue the altered lung morphology at 72 h. Nevertheless, when C/EBPα hyperoxia-exposed siRNA-injected mice were allowed to recover for 2 wk in room air, lung epithelial cell proliferation was increased and lung morphology was restored compared with hyperoxia-exposed control siRNA-injected mice. These data suggest that C/EBPα is an important regulator of postnatal alveolar epithelial cell proliferation and differentiation during injury and repair.

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    • "While both differentiation of the cells lining airways and alveolar spaces, as well as alveolar septation were retained, with normal lung structure, an amplified inflammatory response to hyperoxia causing severe damage is observed in these mice, suggesting that C/EBPα is required for cytoprotection [45]. Another study using siRNA to target Cebpa found that mice with inhibited expression of C/EBPα display hyperproliferation and impaired type II pneumocyte differentiation after recovery from hyperoxic challenge [46]. In addition, a recent study documented a critical role for C/EBPα in regulating the repair processes via regulation of the protease balance following airway damage [47], suggesting that C/EBPα is key in protecting the pulmonary epithelium. "
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