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

Yang G, Hinson MD, Bordner JE, Lin QS, Fernando AP, La P, Wright CJ, Dennery PA. Silencing hyperoxia-induced C/EBP alpha in neonatal mice improves lung architecture via enhanced proliferation of alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 301: L187-L196, 2011. First published May 13, 2011; doi:10.1152/ajplung.00082.2011.-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-alpha (C/EBP alpha) is highly expressed in the lung and plays a role in cell proliferation and differentiation in many tissues. After 72 h of hyperoxia, C/EBP alpha expression was significantly enhanced in the lungs of newborn mice. The increased C/EBP alpha protein was predominantly located in alveolar type II cells. Silencing of C/EBP alpha with a transpulmonary injection of C/EBP alpha 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/EBP alpha 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/EBP alpha is an important regulator of postnatal alveolar epithelial cell proliferation and differentiation during injury and repair.