Conditional deletion of epithelial IKKβ impairs alveolar formation through apoptosis and decreased VEGF expression during early mouse lung morphogenesis

Respiratory Research

Parviz Minoo³  Changgong Li³  Jing Xiao²  Jade-Ming Jeng¹  Benjamin Lopez¹  Tiffany M Maisonet¹  Vedang A Londhe¹ 

[1] 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;College of Stomatology, Dalian Medical University, Dalian 116027, China;Department of Pediatrics, Division of Neonatology, USC Keck School of Medicine, 1801 E. Marengo St., Rm. 1G1, Los Angeles, CA, USA

关键词: Nuclear factor κB (NF-κB), Nkx2.1, surfactant protein C (SP-C), thyroid transcription factor (TTF-1), apoptosis, vascular endothelial growth factor (VEGF);    alveolar maturation;    alveolar development;    Inhibitor of kappa-B kinase beta (IKKβ);   

Others  :  796788
DOI  :  10.1186/1465-9921-12-134

 received in 2011-06-03, accepted in 2011-10-10,  发布年份 2011

【 摘 要 】

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.

【 授权许可】

   
2011 Londhe et al; licensee BioMed Central Ltd.

【 图 表 】

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