弹性蛋白平衡紊乱在肺泡化阻滞中的作用：支气管肺发育不良发病关键机制

Bronchopulmonary dysplasia (BPD) is a chronic lung disease that develops in prematurely born infants who require supportive mechanical ventilation and oxygen therapy for respiratory distress. Described more than 40 years ago by Northway and coworkers, BPD was histopathologically characterized by airway epithelial metaplasia, peribronchial ?brosis, and vascular smooth muscle hypertrophy. However, advances in neonatal care, primarily the increased use of prenatal steroids and surfactant therapy, as well as improved ventilation strategies, have both increased the survival of very-low-birth-weight premature infants and changed the pathological picture of BPD to that of "new BPD", which is characterized more by disrupted alveolar and vascular growth, and less by ?broproliferative airway damage and parenchymal ?brosis. Our limited understanding of the pathogenic mechanisms at play, and the morbidity and mortality associated with BPD, underscore an urgent need both for further research in this area and for the development of improved clinical management options for affected patients..Disturbed elastin ?ber (as well as other matrix) structures in the lungs of patients with BPD have led some investigators to propose that elastin turnover is increased in affected patients, leading to aberrant remodeling of the extracellular matrix; others have suggested that elastic ?ber assembly is perturbed, promoting increased stability and resistance to proteolysis, leading to disorganized elastin ?ber formation in the developing lung. An improved understanding of the role played by the deposition and remodeling of the extracellular matrix in BPD, as well as the growth factor pathways regulating these processes, may improve our understanding of the pathogenesis of BPD, and expand the clinical management options for the treatment of this devastating disease. .There was differential expression of matrix proteins that regulate elastin synthesis and assembly and increased serine elastase activity in lung tissue of lambs with CLD. We speculated that these molecular and biochemical changes in the lungs might account for the aforementioned structural defects observed in this animal model of CLD. We therefore designed studies to test the hypothesis that prolonged cyclic stretch of the developing lung, with moderate hyperoxia, would adversely affect lung expression of genes and proteins that regulate alveolarization and elastin synthesis and assembly. We studied newborn mice, in which lung septation, angiogenesis, and matrix organization occur mainly after birth at term gestation. In addition, we describe the impact of the change on the amount and distribution of elastin in the lungs, and on apoptosis, which could contribute to the abnormal morphology of distal air spaces noted newborn mice with hyperoxia.

支气管肺发育不良(BPD)新概念主要特点是肺泡和血管生长扰乱，其组织学特征是无序的肺弹性蛋白形成过剩表达于受损的肺泡，表明BPD损伤了弹性纤维，影响了其生物合成与分解的平衡。肺部弹性纤维是肺泡提供弹性机械支持的结构支架，其与BPD发生的相互关系及分子和细胞机制尚未完全阐明。寻找高氧影响弹性蛋白发育组装成弹性纤维的关键因素是本领域探索重点。本研究以肺弹性蛋白发育特点为突破口，采用共聚焦及电镜技术研究肺弹性蛋白在肺泡发育期分布形式，排列状态特点；采用新生小鼠BPD模型，通过干预弹性蛋白分解、组装及转化生长因子(TGF-?)等途径探索BPD发病中高氧导致发育肺中弹性蛋白纤维形成紊乱的始动机制。体外肺成纤维细胞相应干预研究在弹性蛋白平衡中的影响因素与调控关系。希望其机制的阐明能够发展新的干预措施，以减轻无序的肺弹性蛋白形成过剩这一病理过程，打破弹性蛋白无序沉积的恶性进展，引导损伤的肺泡重建上皮化。

支气管肺发育不良(BPD)新概念主要特点是肺泡和血管生长扰乱，其组织学特征是无序的肺弹性蛋白形成过剩表达于受损的肺泡，表明BPD 损伤了弹性纤维，影响了其生物合成与分解的平衡。肺部弹性纤维是肺泡提供弹性机械支持的结构支架，其与BPD 发生的相互关系及分子和细胞机制尚未完全阐明。寻找高氧影响弹性蛋白发育组装成弹性纤维的关键因素是本领域探索重点。本研究以肺弹性蛋白发育特点为突破口，采用共聚焦及电镜技术研究肺弹性蛋白在肺泡发育期分布形式，排列状态特点；采用新生小鼠BPD 模型，通过干预弹性蛋白分解、组装及转化生长因子(TGF-β)等途径探索BPD 发病中高氧导致发育肺中弹性蛋白纤维形成紊乱的始动机制。体外肺成纤维细胞相应干预研究在弹性蛋白平衡中的影响因素与调控关系。希望其机制的阐明能够发展新的干预措施，以减轻无序的肺弹性蛋白形成过剩这一病理过程，打破弹性蛋白无序沉积的恶性进展，引导损伤的肺泡重建上皮化。