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NF-kappa B signaling and inflammasome activation in developing fetal lung macrophages

dc.creatorStouch, Ashley Nicole
dc.description.abstractBronchopulmonary dysplasia is a life-threatening lung disease affecting low birth weight preterm infants. While the occurrence of BPD is correlated with chorioamnionitis, the origination and pathway of fetal lung inflammation is less clear. It is unknown which cell type in the fetal lung detect pathogens and initiate inflammation. We hypothesized that fetal lung macrophages drive development-inhibiting inflammation through NF-κB activation, and that NF-κB activation alters macrophage development. While LPS normally inhibits airway branching in fetal lung explants, depleting macrophages with clodronate or inhibiting NF-κB activation in macrophages protected fetal lung explants from the effects of LPS. Activating NF-κB in macrophages inhibited airway branching, lead to abnormal lung morphogenesis, and induced perinatal lethality. In addition to the effects of macrophage activation on lung morphogenesis, NF-κB signaling can alter normal macrophage maturation. Flow cytometry experiments show two macrophage populations in the fetal lung, CD11bhiF4/80lo and CD11bloF4/80hi, with most macrophages being CD11bhiF4/80lo. After NF-κB activation, there is an increase in the CD11bhiF4/80lo subpopulation, which expressed higher levels of CD204 and CD206. High levels of CD204 and CD206 are also found on mature, alveolar macrophages, indicating similarities in marker expression with the CD11bloF4/80hi subpopulation. Fetal lung macrophages are unique in that they do not follow the typical polarization paradigm, but rather a maturation pathway towards alveolar macrophages. Overall, macrophages have a primary role in the fetal lung inflammatory. NF-κB activation in macrophages inhibits lung development and influences fetal macrophage maturation.
dc.titleNF-kappa B signaling and inflammasome activation in developing fetal lung macrophages
dc.contributor.committeeMemberLawrence Prince
dc.contributor.committeeMemberTimothy Blackwell
dc.contributor.committeeMemberGuoqiang Gu
dc.contributor.committeeMemberAlyssa Hasty
dc.type.materialtext and Developmental Biology University
dc.contributor.committeeChairChristopher Wright

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