Developmental Origins of COPD

慢性阻塞性肺病的发展起源

• 批准号: 10382431
• 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
• 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/10382431
• 关键词: 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; 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 diseases; Mediating; Mesenchymal; Mesenchyme; Modeling; Mus; Neonatal; Neutrophil Activation; Newborn Infant; Patients; Pharmacology; 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; 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.

摘要 最新数据表明，高达50%的慢性阻塞性肺疾病（COPD）是由衰竭引起的。 在成年早期达到最大的肺功能，而不是在以后的生活中肺功能加速下降。 由于肺功能轨迹在出生后不久就建立起来，婴儿期肺功能缺陷可能 在成年期持续存在并易患COPD。许多早产儿出生时肺处于囊状阶段 发展质量和这些婴儿的肺部炎症可导致支气管肺发育不良（BPD）， 以发育改变为特征的早产儿并发症，远端有扩张和较少的气隙 肺。沿着儿童期呼吸道疾病，BPD患者存在肺峰值降低的风险 在成年期功能正常，可能发展为COPD。为了了解异常的早期 肺发育长期异常的肺生长和功能，我们开发了一种转基因模型， 其中IKKβ是NF-κB的上游激活因子，可以在肺中以发育阶段特异性表达。 方式使用该模型，我们发现在囊状期（但不是肺泡期）的短暂炎症 阶段）减少了fibulin-5（一种关键的弹性蛋白组装成分）的表达，并导致弹性蛋白的改变。 纤维组织和扩张的终端气隙。值得注意的是，患有囊状期炎症的小鼠 显示出肺弹性纤维组织的持续异常，并发展为COPD样表型 患有肺气肿和牙槽附着丧失，从2月龄进展到24月龄。中性粒 在囊状期的消耗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下调小鼠肺成纤维细胞fibulin-5表达并改变囊状期 体外弹性蛋白组装，可能通过激活表皮生长因子受体信号传导。这些 研究结果支持中性粒细胞弹性蛋白酶下调fibulin-5的表达， 纤维组装在囊状阶段的肺，从而诱发慢性阻塞性肺病在成年期。具体的目标是 目的是：1）描述中性粒细胞损害囊状神经元中弹性纤维组装的机制， 阶段，2）确定间充质衍生的fibulin-5在弹性纤维组装过程中的作用和调节。 肺发育，以及3）研究肺中弹性纤维组装受损的长期影响。 总的来说，拟议的研究将确定炎症在关键发育窗口期的影响， 对新生儿和成人肺病的影响。慢性阻塞性肺疾病发生机制的探讨 将使未来的研究能够预防和/或治疗这种使人衰弱的疾病。