Current interventions and treatments have not been able to significantly reduce the incidence of bronchopulmonary dysplasia, a chronic disease of abnormal saccular and alveolar lung development. Novel and innovative studies investigating the causes and molecular mechanisms leading to bronchopulmonary dysplasia are therefore critical. Prenatal exposure to chorioamnionitis (inflammation of the maternal membranes, placenta, and uterus) increases the risk of bronchopulmonary dysplasia in preterm infants. Experimental mouse models of chorioamnionitis will allow investigation of how inflammatory signals might alter fetal lung development. Bacterial endotoxin inhibits saccular airway branching in fetal mouse lungs. Endotoxin exposure decreases the expression of FGF-10, a critical growth factor for airway branching and lung development. This proposal tests the hypothesis that endotoxins release inflammatory mediators that inhibit FGF-10 expression in the fetal mouse lung, leading to abnormal saccular airway branching and contributing to bronchopulmonary dysplasia.
Aim 1 will rigorously test if decreased FGF-10 is responsible for the abnormal lung development observed with endotoxin exposure.
Aim 2 will test if activation of the transcription factor NF-(B leads to inflammatory signals that inhibit FGF-10 expression. Chemical NF-(B inhibition and genetically engineered mouse strains with defective NF-(B signaling will test if this pathway is required for inhibiting FGF-10. Also, using endotoxin-conditioned media and preventing the release of intermediate factors will test if secondary inflammatory mediators can mediate the downstream effects of endotoxin on lung development.
Aim 3 will then develop novel experimental models to test if NF-(B activation and inflammatory signaling in specific cell types in the developing lung are required for decreased FGF-10 expression and abnormal lung morphogenesis. This proposal therefore tests if inflammation-mediated loss of FGF-10 leads to abormal fetal lung development and potentially contributes to chronic lung disease in preterm infants. PROJECT NARRATIVE: This proposal investigates potential molecular mechanisms leading to bronchopulmonary dysplasia, an important disease aflicting preterm infants. Up to 10,000 new cases of bronchopulmonary dysplasia occur each year in the United States, making it one of the most common and costly diseases of childhood.
|Medal, Rachel M; Im, Amanda M; Yamamoto, Yasutoshi et al. (2017) The innate immune response in fetal lung mesenchymal cells targets VEGFR2 expression and activity. Am J Physiol Lung Cell Mol Physiol 312:L861-L872|
|McCoy, Alyssa M; Herington, Jennifer L; Stouch, Ashley N et al. (2017) IKK? Activation in the Fetal Lung Mesenchyme Alters Lung Vascular Development but Not Airway Morphogenesis. Am J Pathol 187:2635-2644|
|Lakhdari, Omar; McAllister, Christopher S; Wang, Michael et al. (2016) TLR3 signaling is downregulated by a MAVS isoform in epithelial cells. Cell Immunol 310:205-210|
|Benjamin, John T; van der Meer, Riet; Im, Amanda M et al. (2016) Epithelial-Derived Inflammation Disrupts Elastin Assembly and Alters Saccular Stage Lung Development. Am J Pathol 186:1786-1800|
|Han, Wei; Zaynagetdinov, Rinat; Yull, Fiona E et al. (2015) Molecular imaging of folate receptor ?-positive macrophages during acute lung inflammation. Am J Respir Cell Mol Biol 53:50-9|
|Mak, Robert H; Hoffman, Hal M (2015) Transplantation: Outcomes of prenatal immunosuppression. Nat Rev Nephrol 11:390-1|
|Greer, Rachel M; Miller, J Davin; Okoh, Victor O et al. (2014) Epithelial-mesenchymal co-culture model for studying alveolar morphogenesis. Organogenesis 10:340-9|
|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) I?B kinase activity drives fetal lung macrophage maturation along a non-M1/M2 paradigm. J Immunol 193:1184-93|
|Plosa, Erin J; Young, Lisa R; Gulleman, Peter M et al. (2014) Epithelial ?1 integrin is required for lung branching morphogenesis and alveolarization. Development 141:4751-62|
Showing the most recent 10 out of 25 publications