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.

摘要