BPD Interactions Between Inflammation and Morphogenesis

支气管肺发育不良，BPD的特点是肺泡发育不全和血管 异常，被认为是由远端肺形态发生停滞引起的。TNF-α和TGF-β 可能在BPD的发病机制中起关键作用，但它们与结构性肺缺陷的机制联系 仍然难以捉摸我们在早产儿的肺部发现了大量的TNF-α和TGF-β 有患BPD的风险TGF-β通过SMAD 3干扰NKX2.1活性，这是严格要求的 正常肺形态发生、细胞分化和表面活性蛋白（SP）基因表达。我们 还发现TNF-α通过NF-kB、RelA（p65）抑制Bmp 4转录，另一个 中央远端肺形态调节分子。此应用程序的目的是仔细 检查损伤介质之间的相互作用和胎儿中的形态发生介质， 新生儿肺 假设：损伤介质，TGF-β激活的SMAD 3和TNF-α激活的NF-κ B干扰 肺发育正常并导致BPD的发病。这一假设得到了 可用的数据和它的一些预测可以直接通过以下特定目标进行测试： 目标1.为了确定新生Smad 3（-/-）小鼠是否以及在多大程度上受到保护， 高氧、病毒传递的TGF-β和LPS诱导的肺泡发育不全？具体目标2。到 确定SMAD 3是否在体内介导TGF-β诱导的SpB转录抑制。 具体目标3。为了确定SMAD 3抑制细胞因子活性的确切机制， NKX2.1。具体目的4：确定TNF-α抑制Bmp 4基因的机制 表情具体目标5.为了确定RelA在形态发生和发病机制中的作用， 新生儿肺通过完成上述目标，可以更机械地理解 在BPD的背景下，应该出现损伤介质与肺发育之间的相互作用。 我们希望这一理解将推动对抗人类premies BPD的新方法。

Bronchopulmonary dysplasia, BPD is characterized by alveolar hypoplasia & vascular abnormalities, thought to result from arrested distal lung morphogenesis. TNF-alpha & TGF-beta may play key roles in pathogenesis of BPD, but their mechanistic linkages to structural lung defects have remained elusive. We found abundant TNF-alpha & TGF-beta in the lungs of preterm infants at risk for BPD. TGF-beta, through SMAD3, interferes with NKX2.1 activity, which is strictly required for normal lung morphogenesis, cell differentiation & surfactant protein (SP), gene expression. We also found that TNF-alpha, through NF-kB, RelA (p65) represses Bmp4 transcription, another central distal lung morphoregulatory molecule. The purpose of this application is to carefully examine the interactions between mediators of injury & those of morphogenesis in the fetal and neonatal lung. Hypothesis: Mediators of injury, TGF-beta-activated SMAD3 & TNF-alpha-activated NF-kB interfere with normal lung development & result in pathogenesis of BPD. This hypothesis is supported by the available data & some of its predictions are directly testable by the following specific aims: Specific Aim 1. To determine whether, & to what extent, neonatal Smad3(-/-) mice are protected against hyperoxia, virally delivered TGF-beta, and LPS-induced alveolar hypoplasia? Specific Aim 2. To determine whether SMAD3 mediates TGF-beta-induced repression of SpB transcription in vivo. Specific aim 3. To determine the precise mechanisms by which SMAD3 represses the activity of NKX2.1. Specific aim 4: To determine the mechanism by which TNF-alpha represses Bmp4 gene expression. Specific aim 5. To determine the role of RelA in morphogenesis & pathogenesis of neonatal lung. By the completion of the goals outlined above, a more mechanistic understanding of interactions between mediators of injury & lung development, in the context of BPD should emerge. We hope that this understanding would fuel novel ways of countering BPD in human premies.