Regulation of Elastin Assembly during Saccular Stage Lung Development

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PROJECT SUMMARY Perinatal inflammation is an established risk factor for bronchopulmonary dysplasia (BPD), a major morbidity of prematurity characterized by abnormal saccular stage lung development. As the airway epithelium is present at the interface of the amniotic sac environment and the fetal lung, it is well positioned to respond to inflammatory stimuli in amniotic fluid. Therefore, we developed a transgenic mouse model to inducibly express the master inflammatory transcription factor NF-κB, in the airway epithelium (IKTA mice). Using this model, we showed that epithelial-derived inflammation results in profound dilation of terminal airspaces during the saccular stage, but does not alter earlier stages of lung development. Airspace dilation in saccular stage IKTA lungs was associated with reduced expression of important elastin assembly components, especially fibulin-5, by interstitial fibroblasts, leading to altered elastic fiber assembly around distal airspaces. In new preliminary data generated to identify epithelial-derived inhibitors of elastin assembly components in fibroblasts, we found that lungs of IKTA mice and tracheal aspirates (TA) from preterm infants exposed to antenatal inflammation had high levels of IL-1 (both IL- 1α and IL-1β). Neutralizing IL-1α or IL-1β restored fibulin-5 expression in fibroblasts exposed to bronchoalveolar lavage fluid (BAL) from IKTA mice or TA from preterm infants. Since IL-1 triggers intracellular signaling via NF- κB, we tested the direct impact of NF-κB on saccular stage lung fibroblasts and observed that NF-κB signaling inhibited fibulin-5 mRNA expression. Finally, by modifying our transgenic mouse model to enable survival beyond the early postnatal period, we found that inflammation-induced disruption in saccular stage elastin organization results in persistent abnormalities in lung structure. Proposed studies will test the hypothesis that during the saccular stage of lung development, epithelial-derived inflammation propagates down-stream NF-κB activation in fibroblasts through IL-1 signaling, resulting in down-regulation of fibulin-5 and other critical elastin assembly components. Disruption of elastin organization during this critical developmental window impairs lung development, leading to abnormalities in lung structure and function that persist into adulthood. Specific aims are: 1) to define the role of IL-1 signaling in regulation of elastic fiber assembly components, 2) to determine the transcriptional regulation of fibulin-5 in lung fibroblasts during development and in response to inflammation, and 3) to investigate the long-term impact of impaired saccular stage elastin assembly. Together, our studies will determine how inflammation during a critical developmental window can modulate lung structure and function, thus providing new insights into BPD pathogenesis and the long-term consequences of altered saccular stage lung development.