New Mediators of Clinical Lung Maturation

描述（由申请人提供）：临床肺成熟常见于极低出生体重早产儿，早期肺成熟在临床上与慢性绒毛膜羊膜炎相关，慢性绒毛膜羊膜炎可能导致早产。羊膜内毒素可引起羊膜炎、肺部炎症和显著的肺成熟。羊膜内IL-1也引起肺成熟，IL-1和内毒素都是通过直接接触胎儿肺而不是通过诱导全身反应来诱导肺成熟反应。其他炎症介质如TNFalpha和IFNgamma对胎儿肺没有影响。初步数据表明，胎儿气道产生招募（IL-8） W的介质，将白细胞招募到胎儿肺，然后这些细胞放大成熟信号，这可能是il -1 β，导致表面活性剂增加和肺结构改变。本研究旨在探讨羊膜内促炎介质对羊膜内肺成熟的影响。实验将测试IL-1是否是肺成熟的近端介质，气道产生的IL-8是否将白细胞招募到胎儿肺，这些细胞是否是肺成熟所必需的，以及这些途径是否依赖于NFKappaB。先天宿主对炎症的反应是由病原体成分识别域的受体介导的，toll样受体（TLRs）。没有关于胎儿TLR功能的信息。由于绒毛膜羊膜炎是由不同的生物引起的，我们将描述胎儿肺对羊膜内TLR激动剂TLR2、TLR3、TLR4、TLR5和TLR9的反应。这些数据与内毒素(TLR4)/IL-1信号通路的鉴定将阐明产前感染与肺成熟之间的联系。目的是确定一种具有临床应用潜力的介质来诱导肺成熟。

DESCRIPTION (provided by applicant): 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.