DEVELOPMENTAL REGULATION OF LUNG ALVEOLUS FORMATION

肺泡形成的发育调节

• 批准号: 2519295
• 负责人: GLORIA D MASSARO
• 金额: $ 24.76万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-08-15 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2519295
• 关键词: albino rat; cell growth regulation; cell population study; combination chemotherapy; dexamethasone; electron microscopy; embryogenesis; histogenesis; in situ hybridization; lung alveolus; newborn animals; respiratory epithelium; respiratory gas transport; retinoate; retinoid binding proteins; statistics /biometry

Alveoli, the sites of gas-exchange in the lung, are formed to a substantial degree in all species studied, including rat and man, by the developmentally regulated subdivision (septation) of the large saccules that compose the gas-exchange region of the architecturally immature lung. Rat lungs septate from about the 4th to the 14th postnatal day. If the process is blocked during that period by treatment with dexamethasone (a glucocorticosteroid hormone), it does not occur subsequently resulting in rats that have fewer alveoli and a smaller gas-exchange surface area (Sa) than normal. Prematurely born infants who develop bronchopulmonary dysplasia (BPD) fail to septate and have fewer alveoli and a smaller gas- exchange surface area than premature infants without BPD. The cause of this failure to septate is unknown but glucocorticosteroid hormones may be involved because they impair septation in rats and monkeys, and are commonly used in the treatment of BPD. At the heart of this competitive renewal are two new discoveries of great clinical relevance to individuals with diseases characterized by having too few alveoli. We used state-of-the-art stereological procedures to measure the size of the lung's gas-exchange surface area (Sa), the volume of individual alveoli (v), and the number of alveoli (N). We discovered that treatment of newborn rats with retinoic acid prevents, by more than half, the dexamethasone induced 75% inhibition of the number of alveoli formed. And, perhaps more important, in otherwise untreated rats, retinoic acid causes a 50% increase in the number of alveoli without inducing an increase in lung volume. We propose to pursue these new findings in two ways: [l]Use morphometry, in situ hybridization, and immunolocalization, at the ultrastructural level, to define aspects of the cellular and molecular response of the alveolar wall to treatment of newborn rats with retinoic acid, dexamethasone, and a combination of these agents. [2]Further characterize the architectural response to treatment with retinoic acid making the same measurements (Sa, v, N) that allowed us to make the initial observations. We believe we can accomplish all the work proposed because [1]we have extensive experience in the stereology required to enumerate alveoli and particles, [2]we have all the reagents needed to perform the in situ hybridization and immunolocalization, [3]we have demonstrated we can perform immunolocalization at an ultrastructural level, and [4]we have worked out a method to perform in situ hybridization at the ultrastructural level.

肺泡是肺内气体交换的场所， 在所有研究的物种中，包括大鼠和人， 发育调节的大囊的细分（分隔） 构成了建筑上不成熟的气体交换区 肺。大鼠的肺从出生后第4天到第14天开始分裂。如果 在此期间用地塞米松治疗可阻断该过程 （一种糖皮质激素），它不会随后发生， 在肺泡较少和气体交换表面积较小的大鼠中， (Sa)较常年 发生支气管肺炎的早产儿 不典型增生（BPD）不能分隔，肺泡较少，气体较少， 交换表面积比早产儿无BPD。 事业 这种分隔失败是未知的，但糖皮质类固醇激素可能 因为它们会损害大鼠和猴子的分隔， 通常用于治疗BPD。在这场竞争的核心 更新是两个新发现的巨大临床相关性， 患有以肺泡过少为特征的疾病的个体。我们 使用最先进的体视学程序来测量 肺的气体交换表面积（Sa），单个肺泡的体积 (v)肺泡数（N）。我们发现， 维甲酸可以阻止新生大鼠超过一半的 地塞米松诱导形成的肺泡数量的75%抑制。 而且，也许更重要的是，在未经治疗的大鼠中， 导致肺泡数量增加50%， 肺容量增加。我们建议分两个阶段继续研究这些新发现。 方法：[1]采用形态计量学、原位杂交和免疫定位， 在超微结构水平，以定义细胞和 肺泡壁对新生大鼠用 视黄酸、地塞米松和这些药剂的组合。 [2]进一步描述建筑对处理的反应， 维甲酸进行相同的测量（Sa，v，N），使我们能够 进行初步观察。 我们相信我们可以完成所有的工作 因为[1]我们在体视学方面有丰富的经验， 需要计数肺泡和颗粒，[2]我们有所有的试剂 需要进行原位杂交和免疫定位，[3]我们 已经证明我们可以在超微结构上进行免疫定位， 水平，[4]我们已经制定了一种方法，以执行原位 在超微结构水平上的杂交。