Bronchopulmonary Dysplasia (BPD) is a frequent complication of preterm birth that results from arrested lung development in the saccular and alveolar stages of lung morphogenesis. While innate immune signaling has been implicated in the disruption of epithelial-mesenchymal interactions that regulate normal branching morphogenesis, the mechanisms linking innate immunity and abnormal lung development in BPD remain unclear. This proposal will specifically test the role of macrophages in BPD pathogenesis through regulation of innate immune signaling in the fetal lung. Our preliminary data indicate that exposing the fetal lung to inflammatory stimuli induces expression of NF-kB dependent inflammatory cytokine by fetal lung macrophages. Depletion of macrophages or targeted disruption of the NF-kB signaling pathway in macrophages prevents alterations in lung morphogenesis induced by Gram negative bacterial lipopolysaccharide (LPS). While prenatal exposure to inflammatory stimuli increases the risk of BPD in preterm infants, a second episode of significant inflammation may be key for progression to clinical disease, suggesting that exposure to prenatal inflammatory stimuli primes the innate immunity for a heightened response to subsequent noxious stimuli. Consistent with this idea, we found that in utero exposure to LPS results in a marked increase in neutrophilic lung inflammation following subsequent intratracheal LPS treatment of pups after weaning. Therefore, structural abnormalities in the lungs resulting from prenatal inflammation may define a vulnerable host in which additional insults, such as oxygen toxicity, mechanical ventilation, and recurrent infection, result in excessive lung inflammation, injury, and remodeling that is clinically manifest as BPD. In this proposal, we will test the hypothesis that infections and inflammatory stimuli lead to BPD through activation of innate immune signaling in fetal lung macrophages. Activation of NF-kB signaling in macrophages results in production of cytokines, including TNF1 and IL-12, that inhibit epithelial-mesenchymal cell interactions required for branching morphogenesis in the lungs. Activation of NF-kB in fetal lung macrophages also primes the lung for excessive immune responses later in life by altering the lung macrophage phenotype.
Three specific aims are proposed to investigate this hypothesis: 1) to determine whether fetal lung macrophages are required for inhibition of lung development by Toll-Like Receptor (TLR) agonists, 2) to identify the role of the NF-kB pathway in inhibition of lung development following innate immune activation, 3) to determine whether activation of fetal lung macrophages alters the macrophage phenotype as lungs mature. Determining the cell types and pathways that lead to arrested lung development and altered innate immunity in the setting of perinatal inflammation could lead to targeted therapies that prevent BPD or improve outcomes.

Public Health Relevance

This proposal will test novel mechanisms of disease explaining how infection and inflammation disrupt normal lung development and immune function in preterm infants. These processes contribute to the pathogenesis of bronchopulmonary dysplasia, a chronic lung disease that affects up to 10,000 former preterm children each year in the United States.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL097195-05
Application #
8519521
Study Section
Special Emphasis Panel (ZHL1-CSR-H (M2))
Program Officer
Blaisdell, Carol J
Project Start
2009-09-14
Project End
2014-07-31
Budget Start
2013-09-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$476,048
Indirect Cost
$168,920
Name
University of California San Diego
Department
Pediatrics
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Greer, Rachel M; Miller, J Davin; Okoh, Victor O et al. (2014) Epithelial-mesenchymal co-culture model for studying alveolar morphogenesis. Organogenesis 10:
Stouch, Ashley N; Zaynagetdinov, Rinat; Barham, Whitney J et al. (2014) IκB kinase activity drives fetal lung macrophage maturation along a non-M1/M2 paradigm. J Immunol 193:1184-93
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Sen, Partha; Yang, Yaping; Navarro, Colby et al. (2013) Novel FOXF1 mutations in sporadic and familial cases of alveolar capillary dysplasia with misaligned pulmonary veins imply a role for its DNA binding domain. Hum Mutat 34:801-11

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