Preterm birth remains one of the most important health problems facing obstetrics and neonatology. Among the complications of preterm delivery, bronchopulmonary dysplasia (BPD) is the most common, affecting up to 50% of preterm infants born before 28 wk gestation. The lungs of patients with BPD lack normal numbers of saccular airways and mature alveoli due to arrested development. Clinical and experimental evidence now suggest the arrested lung development in BPD is likely due to inflammation and subsequent release of inflammatory mediators. Lungs from BPD patients also have reduced levels of the key growth factor FGF-10. In fetal mice, microbial products and released inflammatory mediators inhibit FGF-10 expression by activating the transcription factor NF-?B in lung mesenchymal cells. Because of this inflammation-mediated change in developmental gene expression, saccular stage airway branching morphogenesis is inhibited, producing simplified lung architecture. Fetal lung macrophages are the primary source of the inflammatory mediators including IL-1? that inhibit FGF-10 expression and airway morphogenesis. However, several questions regarding this mechanism remain. First, there appears to be a developmental window of susceptibility during which inflammation can alter fetal lung morphogenesis. The lack of effect on earlier stages could be due to inability of immature lung macrophages to respond to microbial stimuli or inefficiency in releasing inflammatory mediators such as IL-1?. As part of the inflammatory response, multi-protein inflammasome complexes process and release IL-1?. Preliminary data suggest that expression and function of the inflammasome may be developmentally regulated. In addition to the questions surrounding maturation of macrophage response, how inflammatory mediators can disrupt normal developmental gene expression in target mesenchymal cells is unknown. Recent data show that NF-?B disrupts the normal regulation of FGF-10 promoter activity by the transcription factors Sp1 and Sp3. Interactions between the NF-?B subunit RelA and Sp3 appear to convert Sp3 into a transcriptional repressor. This proposal includes three specific aims to examine the cellular and molecular mechanisms linking inflammation and abnormal lung development.
The first aim will determine which aspects of the lung macrophage innate immune response are developmentally regulated.
The second aim will test if inflammasome function and caspase-mediated IL-1? processing is required and sufficient to inhibit lung airway morphogenesis.
The third aim will further investigate the molecular mechanisms linking NF-?B and changes in FGF-10 expression. These studies will better define how inflammation affects lung morphogenesis and identify potential targets for developing novel therapeutic strategies for preventing and treating BPD in preterm infants.
Preterm birth is among the most important clinical problems affecting children. Bronchopulmonary dysplasia is a frequent complication of extremely preterm birth, and its incidence has not decreased despite advances in neonatal care. Therefore, new insight into the mechanisms of bronchopulmonary dysplasia pathogenesis and discovery of new therapeutic strategies is critical to improve the long-term health of children born preterm.
|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|
|Carver, Billy J; Plosa, Erin J; Stinnett, Amanda M et al. (2013) Interactions between NF-*B and SP3 connect inflammatory signaling with reduced FGF-10 expression. J Biol Chem 288:15318-25|
|Goudy, Steven; Angel, Peggi; Jacobs, Britni et al. (2013) Cell-autonomous and non-cell-autonomous roles for IRF6 during development of the tongue. PLoS One 8:e56270|
|Humphreys, Ryan; Zheng, Wei; Prince, Lawrence S et al. (2012) Cranial neural crest ablation of Jagged1 recapitulates the craniofacial phenotype of Alagille syndrome patients. Hum Mol Genet 21:1374-83|
|McElroy, Steven J; Prince, Lawrence S; Weitkamp, Jorn-Hendrik et al. (2011) Tumor necrosis factor receptor 1-dependent depletion of mucus in immature small intestine: a potential role in neonatal necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 301:G656-66|
|Blackwell, Timothy S; Hipps, Ashley N; Yamamoto, Yasutoshi et al. (2011) NF-?B signaling in fetal lung macrophages disrupts airway morphogenesis. J Immunol 187:2740-7|
|Benjamin, John T; Carver, Billy J; Plosa, Erin J et al. (2010) NF-kappaB activation limits airway branching through inhibition of Sp1-mediated fibroblast growth factor-10 expression. J Immunol 185:4896-903|
|Benjamin, John T; Gaston, David C; Halloran, Brian A et al. (2009) The role of integrin alpha8beta1 in fetal lung morphogenesis and injury. Dev Biol 335:407-17|