Developmental Origins of COPD

摘要 新出现的数据表明，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肺功能，而不是在晚年加速肺功能下降。 由于肺功能轨迹是在出生后不久建立的，因此婴儿时期的肺功能缺陷可能 成年后坚持并易患慢性阻塞性肺疾病。许多早产儿出生时肺部处于囊状期。 关于发展的问题。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，远端空隙扩张和减少 阿龙。伴随着儿童时期的呼吸道疾病，bpd患者面临肺峰降低的风险。 在他们成年的时候，可能会发展成慢性阻塞性肺病。了解异常早期的联系机制 肺发育到肺生长和功能的长期异常，我们开发了一个转基因模型 哪个IKKβ，一种核因子-κB的上游激活物，可以在发育阶段特异性的肺中表达 举止。使用这个模型，我们发现球囊阶段(但不是肺泡)的一过性炎症 阶段)减少纤维蛋白-5的表达，这是一种关键的弹性蛋白组装成分，并导致弹性改变 纤维组织和扩张的终端空域。值得注意的是，患有球囊期炎症的小鼠 发现肺弹性纤维组织持续异常，并发展为COPD样表型 肺气肿和肺泡附着物丢失，从2个月到24个月的进展。中性粒细胞 囊状期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下调小鼠肺成纤维细胞纤维蛋白-5的表达并改变囊泡期 弹性蛋白在体外组装，可能通过激活表皮生长因子受体信号。这些 研究结果支持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 纤维聚集在囊状期的肺中，从而在成年时易患慢性阻塞性肺疾病。具体目标是 设计目的是：1)描述中性粒细胞损害球囊内弹性纤维聚集的机制 阶段，2)确定间充质来源的纤维蛋白-5在弹性纤维组装中的作用和调节 3)研究肺内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中的影响。 无论是新生儿还是成人肺部疾病。对慢性阻塞性肺疾病发病机制的认识 将使未来的研究能够预防和/或治疗这种令人衰弱的疾病。

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.