Clinical lung maturation is frequent in very low birth weight preterm infants and early lung maturation is associated clinically with the chronic chorioamnionitis that seems to cause preterm delivery. Intra-amniotic endotoxin causes chorioamnionitis, lung inflammation and striking lung maturation in fetal sheep. Intra-amniotic IL-1 also causes lung maturation, and both IL-1 and endotoxin induce the lung maturation response by direct contact with the fetal lung and not by inducing a systemic response. Other inflammatory mediators such as TNFalpha and IFNgamma have no effect on the fetal lung. Preliminary data suggest that the fetal airways produce mediators that recruit (IL-8) W that recruit WBC to the fetal lungs and that those cells then amplify the maturation signal, which may be IL-1beta, resulting in increased surfactant and lung structural changes. This proposal explores the pathways leading from the intra-amniotic pro-inflammatory mediator to lung maturation using the fetal sheep model. Experiments will test if IL-1 is the proximal mediator of lung maturation, if IL-8 produced by the airway recruits WBC to the fetal lungs, if those cells are required for lung maturation, and if these pathways are NFKappaB dependent. The innate host response to inflammation is mediated by receptors for pathogen component recognition domains, the Toll-Like Receptors (TLRs). There is no information about TLR function in the fetus. Because chorioamnionitis is caused by different organisms, we will characterize the fetal lung responses to intra-amniotic TLR agonists for TLR2, TLR3, TLR4, TLR5 and TLR9. These data together with identification of the signaling pathways for endotoxin (TLR4)/IL-1 will elucidate the links between antenatal infection and lung maturation. A goal is to identify a mediator with potential for clinical use to induce lung maturation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL065397-07
Application #
7118971
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Berberich, Mary Anne
Project Start
2000-09-01
Project End
2008-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
7
Fiscal Year
2006
Total Cost
$364,340
Indirect Cost
Name
Children's Hospital Med Ctr (Cincinnati)
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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Jobe, Alan H; Nitsos, Ilias; Pillow, J Jane et al. (2009) Betamethasone dose and formulation for induced lung maturation in fetal sheep. Am J Obstet Gynecol 201:611.e1-7
Kallapur, Suhas G; Nitsos, Ilias; Moss, Timothy J M et al. (2009) IL-1 mediates pulmonary and systemic inflammatory responses to chorioamnionitis induced by lipopolysaccharide. Am J Respir Crit Care Med 179:955-61

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