title: Conditional deletion of epithelial IKKβ impairs alveolar formation through apoptosis and decreased VEGF expression during early mouse lung morphogenesis.
abstract: BACKGROUND
  Alveolar septation marks the beginning of the transition from the saccular to alveolar stage of lung development. Inflammation can disrupt this process and permanently impair alveolar formation resulting in alveolar hypoplasia as seen in bronchopulmonary dysplasia in preterm newborns. NF-κB is a transcription factor central to multiple inflammatory and developmental pathways including dorsal-ventral patterning in fruit flies; limb, mammary and submandibular gland development in mice; and branching morphogenesis in chick lungs. We have previously shown that epithelial overexpression of NF-κB accelerates lung maturity using transgenic mice. The purpose of this study was to test our hypothesis that targeted deletion of NF-κB signaling in lung epithelium would impair alveolar formation.
  
  
  METHODS
  We generated double transgenic mice with lung epithelium-specific deletion of IKKβ, a known activating kinase upstream of NF-κB, using a cre-loxP transgenic recombination strategy. Lungs of resulting progeny were analyzed at embryonic and early postnatal stages to determine specific effects on lung histology, and mRNA and protein expression of relevant lung morphoreulatory genes. Lastly, results measuring expression of the angiogenic factor, VEGF, were confirmed in vitro using a siRNA-knockdown strategy in cultured mouse lung epithelial cells.
  
  
  RESULTS
  Our results showed that IKKβ deletion in the lung epithelium transiently decreased alveolar type I and type II cells and myofibroblasts and delayed alveolar formation. These effects were mediated through increased alveolar type II cell apoptosis and decreased epithelial VEGF expression.
  
  
  CONCLUSIONS
  These results suggest that epithelial NF-κB plays a critical role in early alveolar development possibly through regulation of VEGF.
authors: Department of Pediatrics, Division of Neonatology and Developmental Biology, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Mailcode 175217, Los Angeles, CA, USA. vlondhe@mednet.ucla.edu
authors: Vedang A
authors: VA
authors: Londhe
authors: Tiffany M
authors: TM
authors: Maisonet
authors: Benjamin
authors: B
authors: Lopez
authors: Jade-Ming
authors: JM
authors: Jeng
authors: Jing
authors: J
authors: Xiao
authors: Changgong
authors: C
authors: Li
authors: Parviz
authors: P
authors: Minoo
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency* / Q000235:genetics; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D051550:I-kappa B Kinase / Q000172:deficiency* / Q000235:genetics; D008168:Lung / Q000196:embryology / Q000254:growth & development / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D011650:Pulmonary Alveoli / Q000196:embryology / Q000254:growth & development* / Q000473:pathology; D020545:Respiratory Mucosa / Q000196:embryology / Q000254:growth & development / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse