Developmental Origins of COPD

慢性阻塞性肺病的发展起源

• 批准号: 10184154
• 负责人: JOHN BENJAMIN
• 金额: $ 59.37万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 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/10184154
• 关键词: Adult; Age-Months; Alveolar; Area; Birth; Bronchopulmonary Dysplasia; Cause of Death; Cells; Childhood; Chronic; Chronic Obstructive Airway Disease; Chronic lung disease; Complication; Data; Development; Disease; Distal; Down-Regulation; Doxycycline; Elastic Fiber; Elastin; Epidermal Growth Factor Receptor; Epithelial; Epithelial Cells; Escherichia coli; Exposure to; FBLN5 gene; Failure; Fibroblasts; Future; Growth; Hyperoxia; Impairment; In Situ Hybridization; Infant; Inflammation; Inflammatory; Investigation; Lead; Leukocyte Elastase; Life; Lipopolysaccharides; Long-Term Effects; Longevity; Lung; Lung Inflammation; Lung diseases; Mediating; Mesenchymal; Mesenchyme; Modeling; Mus; Neonatal; Neutrophil Activation; Newborn Infant; Patients; Pharmacology; Phenotype; Population; Predisposition; Premature Infant; Pulmonary Emphysema; 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; exposure to cigarette smoke; genetic approach; infancy; lung development; mouse model; neonate; neutrophil; novel; pre-clinical; premature; prevent; pulmonary function; respiratory morbidity; scaffold; single-cell RNA sequencing; stem

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 新兴数据表明，由于失败而导致多达50％的慢性阻塞性肺疾病（COPD） 为了在成年初达到最大肺功能，而不是加速生命后期的肺功能下降。 由于肺功能轨迹是在出生后不久建立的，因此在婴儿期定义肺功能可能 在成年期间坚持并倾向于COPD。许多早产婴儿出生于肺病阶段 发展。这些婴儿的肺部感染会导致支气管肺发育不良（BPD），A 早产的并发症的特征是在不同 肺。与儿童期呼吸道发病率一起，BPD患者有肺峰值降低的风险 在成年年度运作，可能会发展COPD。了解早期连接异常的机制 肺发育到肺部生长和功能的长期异常，我们在 ikkβ是NF-κB的上游激活剂，可以在发育阶段的肺中表达 方式。使用此模型，我们发现在牙周阶段的瞬态感染（但不是肺泡 阶段）降低了Fibulin-5的表达，这是一种临界弹性蛋白组件成分，并导致弹性改变 纤维组织和扩张的终端空间。值得注意的是，带有圆锥形注射的小鼠 在肺弹性纤维组织中表现出持续的异常，并开发了类似COPD的表型 肺气肿和肺泡附着的丧失，从2到24个月大。中性粒细胞 寒冷阶段的耗竭挽救了这些小鼠的肺表型。此外，我们发现 中性粒细胞弹性蛋白酶通过小鼠肺成纤维细胞下调纤维蛋白-5的表达，并改变囊阶段 弹性蛋白组装离体，可能通过激活表皮生长因子受体信号传导。这些 发现支持了嗜中性粒细胞弹性蛋白酶下调纤维蛋白-5表达并改变弹性的假设 固定期肺中的纤维组件，因此在成年期间易于COPD。具体目标是 设计为：1）描述中性粒细胞损害固有纤维组件的机制 阶段，2）确定间充质衍生的纤维蛋白5在弹性纤维组件中的作用和调节 肺发育和3）研究肺中弹性纤维组件受损的长期影响。 拟议的研究集体确定炎症在关键发展窗口中的影响 在新生儿和成人肺部疾病上。对COPD的发展起源的机械理解 将赋予未来的调查，以预防和/或治疗这种使人衰弱的疾病。