FGF-10 Expression in a Fetal Mouse Lung Model of Bronchopulmonary Dysplasia

描述(申请人提供)：早产仍然是产科和新生儿科面临的最重要的健康问题之一。在早产的并发症中，支气管肺发育不良(BPD)是最常见的，高达50%的早产儿在28周前出生。由于发育停滞，BPD患者的肺缺乏正常数量的球状气道和成熟的肺泡。临床和实验证据表明，BPD患者肺发育受阻可能是由于炎症和随后的炎性介质释放所致。BPD患者的肺部也降低了关键生长因子FGF-10的水平。 在胎鼠中，微生物产品和释放的炎症介质通过激活肺间充质细胞中的转录因子NF-κB来抑制FGF10的表达。由于这种炎症介导的发育基因表达的变化，囊状阶段的呼吸道分支形态发生被抑制，从而产生简化的肺结构。胎肺巨噬细胞是炎性介质的主要来源，包括抑制成纤维细胞生长因子10表达和呼吸道形态形成的IL-1。然而，关于这一机制的几个问题仍然存在。首先，似乎有一个发育的易感性窗口，在此期间炎症可以改变胎儿肺的形态发生。对早期阶段缺乏影响可能是由于未成熟的肺巨噬细胞无法对微生物刺激做出反应，或在释放炎症介质(如IL-1？)方面效率低下。作为炎症反应的一部分，多蛋白炎性小体复合体处理并释放IL-1？初步数据表明，炎症体的表达和功能可能受到发育调节。除了围绕巨噬细胞反应成熟的问题外，炎症介质如何扰乱目标间充质细胞的正常发育基因表达尚不清楚。最近的数据显示，NF-κB干扰转录因子Sp1和Sp3对成纤维细胞生长因子10启动子活性的正常调节。NF-κB亚单位RelA和Sp3之间的相互作用似乎将Sp3转换为转录抑制因子。这项建议包括三个具体目标，以研究炎症和肺发育异常之间的细胞和分子机制。第一个目标将确定肺巨噬细胞先天性免疫反应的哪些方面是发育调节的。第二个目标将测试炎症小体功能和caspase介导的IL-1？处理是否必需且足以抑制肺呼吸道形态发生。第三个目的是进一步研究NF-FGFB与κ-10表达变化之间的分子机制。这些研究将更好地确定炎症如何影响肺形态发生，并确定潜在的靶点，以开发预防和治疗早产儿BPD的新治疗策略。

DESCRIPTION (provided by applicant): 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-κB 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-1ß 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-1ß. As part of the inflammatory response, multi-protein inflammasome complexes process and release IL-1ß. 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-κB disrupts the normal regulation of FGF-10 promoter activity by the transcription factors Sp1 and Sp3. Interactions between the NF-κB 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-1ß processing is required and sufficient to inhibit lung airway morphogenesis. The third aim will further investigate the molecular mechanisms linking NF-κB 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.