Regulation of Elastin Assembly during Saccular Stage Lung Development

肺囊期发育过程中弹性蛋白组装的调节

基本信息

批准号：
9386272
负责人：
JOHN BENJAMIN
金额：
$ 14.78万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-05 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9386272
关键词：
Address Adult Affect Air Sacs Amniotic Fluid Amniotic Sac Aspirate substance Bronchoalveolar Lavage Fluid Bronchopulmonary Dysplasia Data Development Distal Down-Regulation Elastic Fiber Elastin Environment Epithelial FBLN5 gene Fetal Lung Fibroblasts Future Impairment In Vitro Infant Inflammation Inflammatory Interleukin-1 Interleukin-1 alpha Interleukin-1 beta Knowledge Link Liquid substance Long-Term Effects Lung Lung diseases Mediating Mediator of activation protein Mesenchymal Modeling Morbidity - disease rate Mus Pathogenesis Pathway interactions Perinatal Phenotype Positioning Attribute Predisposition Premature Infant Production Publishing Regulation Reporter Reporting Risk Factors Role Signal Transduction Stimulus Structure Testing Therapeutic Time Transcriptional Regulation Transgenic Mice adenoviral-mediated airway epithelium antenatal cell type chromatin immunoprecipitation emergency service responder fetal in vivo inhibitor/antagonist insight interstitial intraamniotic infection lung development mRNA Expression microbial mouse model novel overexpression postnatal premature premature lungs prevent promoter pulmonary function respiratory response therapeutic development transcription factor

项目摘要

PROJECT SUMMARY Perinatal inflammation is an established risk factor for bronchopulmonary dysplasia (BPD), a major morbidity of prematurity characterized by abnormal saccular stage lung development. As the airway epithelium is present at the interface of the amniotic sac environment and the fetal lung, it is well positioned to respond to inflammatory stimuli in amniotic fluid. Therefore, we developed a transgenic mouse model to inducibly express the master inflammatory transcription factor NF-κB, in the airway epithelium (IKTA mice). Using this model, we showed that epithelial-derived inflammation results in profound dilation of terminal airspaces during the saccular stage, but does not alter earlier stages of lung development. Airspace dilation in saccular stage IKTA lungs was associated with reduced expression of important elastin assembly components, especially fibulin-5, by interstitial fibroblasts, leading to altered elastic fiber assembly around distal airspaces. In new preliminary data generated to identify epithelial-derived inhibitors of elastin assembly components in fibroblasts, we found that lungs of IKTA mice and tracheal aspirates (TA) from preterm infants exposed to antenatal inflammation had high levels of IL-1 (both IL- 1α and IL-1β). Neutralizing IL-1α or IL-1β restored fibulin-5 expression in fibroblasts exposed to bronchoalveolar lavage fluid (BAL) from IKTA mice or TA from preterm infants. Since IL-1 triggers intracellular signaling via NF- κB, we tested the direct impact of NF-κB on saccular stage lung fibroblasts and observed that NF-κB signaling inhibited fibulin-5 mRNA expression. Finally, by modifying our transgenic mouse model to enable survival beyond the early postnatal period, we found that inflammation-induced disruption in saccular stage elastin organization results in persistent abnormalities in lung structure. Proposed studies will test the hypothesis that during the saccular stage of lung development, epithelial-derived inflammation propagates down-stream NF-κB activation in fibroblasts through IL-1 signaling, resulting in down-regulation of fibulin-5 and other critical elastin assembly components. Disruption of elastin organization during this critical developmental window impairs lung development, leading to abnormalities in lung structure and function that persist into adulthood. Specific aims are: 1) to define the role of IL-1 signaling in regulation of elastic fiber assembly components, 2) to determine the transcriptional regulation of fibulin-5 in lung fibroblasts during development and in response to inflammation, and 3) to investigate the long-term impact of impaired saccular stage elastin assembly. Together, our studies will determine how inflammation during a critical developmental window can modulate lung structure and function, thus providing new insights into BPD pathogenesis and the long-term consequences of altered saccular stage lung development.

项目概要围产期炎症是支气管肺发育不良 (BPD) 的既定危险因素，支气管肺发育不良 (BPD) 是支气管肺发育不良 (BPD) 的主要发病率早产的特征是肺囊状阶段发育异常，因为气道上皮存在于该阶段。羊膜囊环境和胎儿肺的界面，能够很好地对炎症做出反应因此，我们开发了一种转基因小鼠模型来诱导表达主人。使用该模型，我们发现气道上皮中的炎症转录因子 NF-κB（IKTA 小鼠）。上皮源性炎症导致囊状阶段末梢气腔深度扩张，但是不改变肺发育早期阶段的 IKTA 肺的空腔扩张。间质成纤维细胞重要的弹性蛋白组装成分，尤其是 fibulin-5 的表达减少，导致远端空域周围弹性纤维组装的改变。成纤维细胞中弹性蛋白组装成分的上皮源性抑制剂，我们发现 IKTA 小鼠的肺和暴露于产前炎症的早产儿的气管抽吸物 (TA) 含有高水平的 IL-1（IL-1 和 IL-1）。 1α 和 IL-1β) 中和 IL-1α 或 IL-1β 可恢复暴露于支气管肺泡的成纤维细胞中的 fibulin-5 表达。来自 IKTA 小鼠的灌洗液 (BAL) 或来自早产儿的 TA，因为 IL-1 通过 NF-触发细胞内信号传导。 κB，我们测试了 NF-κB 对囊状期肺成纤维细胞的直接影响，观察到 NF-κB 信号传导最后，通过修改我们的转基因小鼠模型，使其能够存活下来。在产后早期，我们发现炎症引起的囊状期弹性蛋白组织破坏导致肺部结构持续异常。拟议的研究将检验这一假设：肺发育的囊状阶段，上皮源性炎症传播下游 NF-κB 激活通过 IL-1 信号传导在成纤维细胞中，导致 fibulin-5 和其他关键弹性蛋白组装的下调在这个关键的发育窗口期间，弹性蛋白组织的破坏会损害肺部。发育，导致肺结构和功能异常，并持续到成年期。是：1) 定义 IL-1 信号传导在弹性纤维组装成分调节中的作用，2) 确定肺成纤维细胞在发育过程中和炎症反应中 fibulin-5 的转录调控，以及 3）为了调查囊状阶段弹性蛋白组装受损的长期影响，我们的研究将共同进行。确定关键发育窗口期间的炎症如何调节肺结构和功能，从而为 BPD 发病机制和囊状阶段改变的长期后果提供新的见解肺部发育。