Developmental Origins of COPD

慢性阻塞性肺病的发展起源

基本信息

批准号：
10596661
负责人：
JOHN BENJAMIN
金额：
$ 58.54万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-05 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10596661
关键词：
Acceleration Adult Age Months Alveolar Area Birth Bronchopulmonary Dysplasia Cause of Death Cells Childhood Chronic Chronic Obstructive Pulmonary Disease Chronic lung disease Complication Data Development Disease Distal Down-Regulation Doxycycline Elastic Fiber Elastin Epidermal Growth Factor Receptor Epithelial Cells Epithelium Escherichia coli Exposure to FBLN5 gene Failure Fibroblasts Future Growth Hyperoxia Impairment In Situ Hybridization Infant Inflammation Inflammatory Investigation Leukocyte Elastase Life Lipopolysaccharides Long-Term Effects Longevity Lung Lung diseases Mediating Mesenchymal Mesenchyme Modeling Mus Neonatal Neutrophil Activation Newborn Infant Patients Phenotype Population Predisposition Premature Infant Pulmonary Emphysema Pulmonary Inflammation RNA Receptor Signaling Regulation Risk Role Signal Pathway Slice Stimulus Structure Survivors Testing Therapeutic Transgenic Mice Transgenic Model age related airway epithelium cigarette smoke clinically relevant design disease phenotype emerging adult empowerment exposure to cigarette smoke genetic approach infancy lung development mouse model neonate neutrophil novel pharmacologic pre-clinical premature prevent pulmonary function respiratory morbidity scaffold single-cell RNA sequencing stem

项目摘要

Abstract Emerging data indicate that up to 50% of Chronic Obstructive Pulmonary Disease (COPD) results from failure to attain maximal lung function in early adulthood, rather than accelerated decline in lung function later in life. Because lung function trajectories are established soon after birth, deficits in lung function in infancy may persist and predispose to COPD in adulthood. Many preterm infants are born with lungs in the saccular stage of development. Lung inflammation in these infants can lead to bronchopulmonary dysplasia (BPD), a complication of prematurity characterized by altered development with dilated and fewer airspaces in the distal lung. Along with respiratory morbidity during childhood, patients with BPD are at risk for reduced peak lung function in their adult years and may develop COPD. To understand mechanisms connecting aberrant early lung development to long-term abnormalities in lung growth and function, we developed a transgenic model in which IKKβ, an upstream activator of NF-κB, can be expressed in the lungs in a developmental-stage specific manner. Using this model, we found that transient inflammation in the saccular stage (but not the alveolar stage) reduced expression of fibulin-5, a critical elastin assembly component, and resulted in altered elastic fiber organization and dilated terminal airspaces. Remarkably, mice with saccular stage inflammation demonstrated persistent abnormalities in lung elastic fiber organization and developed a COPD-like phenotype with emphysema and loss of alveolar attachments that progressed from 2 to 24 months of age. Neutrophil depletion during the saccular stage rescued the lung phenotype in these mice. Further, we found that neutrophil elastase downregulates fibulin-5 expression by mouse lung fibroblasts and alters saccular stage elastin assembly ex vivo, potentially through activation of epidermal growth factor receptor signaling. These findings support the hypothesis that neutrophil elastase downregulates fibulin-5 expression and alters elastic fiber assembly in the saccular stage lung, thereby predisposing to COPD in adulthood. Specific aims are designed to: 1) delineate the mechanisms by which neutrophils impair elastic fiber assembly in the saccular stage, 2) determine the role and regulation of mesenchymal-derived fibulin-5 in elastic fiber assembly during lung development, and 3) investigate the long-term effects of impaired elastic fiber assembly in the lung. Collectively, proposed studies will determine the impact of inflammation during a critical developmental window on both neonatal and adult lung disease. A mechanistic understanding of the developmental origins of COPD will empower future investigations to prevent and/or treat this debilitating disease.

抽象的新数据表明，多达 50% 的慢性阻塞性肺疾病 (COPD) 是由于失败造成的在成年早期获得最大的肺功能，而不是在以后的生活中加速肺功能的下降。由于肺功能轨迹在出生后很快就建立起来，婴儿期肺功能缺陷可能会许多早产儿出生时肺部处于囊状阶段，并且在成年后易患慢性阻塞性肺病。这些婴儿的肺部炎症可导致支气管肺发育不良（BPD），这是一种疾病。早产并发症，其特征是远端空腔扩张和减少除了儿童时期的呼吸道疾病外，BPD 患者还面临肺峰值降低的风险。成年后可能会出现慢性阻塞性肺病 (COPD)，了解早期异常的机制。肺发育到肺生长和功能的长期异常，我们开发了一种转基因模型其中 IKKβ 是 NF-κB 的上游激活剂，可以在肺部以发育阶段特异性表达使用该模型，我们发现囊状阶段有短暂的炎症（但不是肺泡阶段）。阶段）减少了关键弹性蛋白组装成分 fibulin-5 的表达，并导致弹性纤维组织和扩张的末端空腔值得注意的是，处于囊状炎症阶段的小鼠。肺弹性纤维组织持续异常并形成慢性阻塞性肺病样表型 2 至 24 个月时出现肺气肿和肺泡附件缺失。囊状阶段的耗竭挽救了这些小鼠的肺表型。中性粒细胞弹性蛋白酶下调小鼠肺成纤维细胞 fibulin-5 的表达并改变囊状阶段弹性蛋白可能通过激活表皮生长因子受体信号传导进行离体组装。研究结果支持中性粒细胞弹性蛋白酶下调 fibulin-5 表达并改变弹性的假设肺囊状阶段的纤维聚集，从而在成年后易患慢性阻塞性肺病。旨在：1）描绘中性粒细胞损害球囊弹性纤维组件的机制阶段，2）确定间充质来源的fibulin-5在弹性纤维组装过程中的作用和调节肺部发育，3) 研究肺部弹性纤维组装受损的长期影响。总的来说，拟议的研究将确定关键发育窗口期间炎症的影响对新生儿和成人肺部疾病的机制了解 COPD 的发育起源。将使未来的研究能够预防和/或治疗这种使人衰弱的疾病。