Functional Role of Klf4 in Alveolarization and Ventilation-Induced Lung Injury of Newborn Mice

• Applicant: Professor Miguel Angel Alejandre Alcázar, Ph.D.
• Subject Area: Pediatric and Adolescent Medicine
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 276998845

Mechanical ventilation with O2-rich gas (MV-O2) offers life-saving treatment for premature infants with respiratory failure, but also promotes Ventilation-Induced Lung Injury (VILI), which in neonates results in impaired formation of alveoli and capillary hypoplasia, as seen in neonatal Chronic Lung Disease (CLD). Defective alveolar formation by both prolonged MV and O2 supplementation has been linked to increased lung cell apoptosis. Type II alveolar epithelial cells (ATII) are recognized as progenitor cells, crucial in alveolar formation and regeneration subsequent to lung injury. However, the underlying molecular mechanisms regulating alveolar epithelial cell survival and alveolar formation in lungs after MV-O2is unclear. Krüppel-like factor 4 (Klf4) is a transcription factor with diverse regulatory roles in cell pluripotency, differentiation, survival and development in epithelial cells. We recently discovered that Klf4 mRNA and protein were reduced in lungs of mechanically ventilated 5-day old mice; Klf4 expression was also diminished in cultured mouse lung type II epithelial cells (MLE-12) after exposure to cyclic stretch. Moreover, we found that loss of Klf4 in MLE-12 inhibits cell survival. Therefore, we aim now to elucidate the functional role of Klf4 in normal lung development and in defective alveolarization seen in lungs of newborn mice after MV-O2. To this end, we will address three specific aims: we will (1) analyze the expression pattern of Klf4 during late lung development and how loss of Klf4 in AT II cells during this period affects alveolar formation in mice; (2) characterize the functional role of Klf4 in survival of AT II cells during cyclic stretch ± hyperoxia in vitro; and (3) determine if Klf4 overexpression in AT II preserves alveolar formation and enables lung growth in newborn mice during MV. Funding this project should define the functional role of Klf4 in AT II and alveolarization as a modulator of cell survival, and help to develop new strategies to preserve alveolarization and promote lung growth.

• DFG Programme: Research Grants