DEVELOPMENTAL REGULATION OF LUNG ALVEOLUS FORMATION

肺泡是肺内气体交换的场所，形成一种 在所有研究的物种中，包括老鼠和人，都有相当的程度 发育调节的大球囊的细分(分隔) 它们构成了建筑上不成熟的气体交换区 阿龙。大鼠在出生后第4天至第14天左右出现肺间隔。如果 这一过程在此期间被地塞米松阻断。 (一种糖皮质激素)，它不会随后发生，从而导致 肺泡较少且气体交换表面积较小的大鼠 (Sa)比正常水平高。发展为支气管肺的早产儿 不典型增生(BPD)不能分离，肺泡较少，气体较小- 交换表面积高于无BPD的早产儿。的起因 这种分隔失败是未知的，但糖皮质激素可能 因为它们损害了大鼠和猴子的隔膜，并且是 常用于BPD的治疗。在这场竞争的核心 更新是两项具有重大临床意义的新发现 以肺泡太少为特征的疾病患者。我们 使用最先进的体视学程序来测量 肺的气体交换面积(Sa)、单个肺泡的体积 (V)和肺泡数(N)。我们发现，治疗 新生的大鼠服用维甲酸可以预防一半以上的 地塞米松对肺泡形成的抑制率为75%。 也许更重要的是，在未经治疗的大鼠中，维甲酸 导致肺泡数增加50%，而不会引起 肺容量增加。我们建议分两个阶段来研究这些新发现。 方法：[L]采用形态计量学、原位杂交、免疫定位等方法， 在超微结构水平上，为了定义细胞和 新生大鼠肺泡壁对黄曲霉毒素治疗的分子反应 维甲酸、地塞米松以及这些制剂的组合。 [2]进一步描述对处理的架构响应 维甲酸进行相同的测量(Sa，v，N)，使我们能够 进行初步的观察。我们相信我们能完成所有的工作 提出是因为[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 已经证明了我们可以在超微结构上进行免疫定位 水平，和[4]我们已经制定了一种方法，在现场进行 超微结构水平的杂交。

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.