Bronchopulmonary 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.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-12302014-220743 |
| Date | 31 December 2014 |
| Creators | Stouch, Ashley Nicole |
| Contributors | Christopher Wright, Lawrence Prince, Timothy Blackwell, Guoqiang Gu, Alyssa Hasty |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-12302014-220743/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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