ALVEOLUS FORMATION--MORPHOMETRIC AND MOLECULAR STUDIES

描述（改编自申请人摘要）：长期目标是了解肺泡形成的调节，因此该信息可用于治疗目的。在缺乏诱导人类肺泡形成的药理学手段的情况下，肺移植仍然是对其中存在肺泡形成发育缺陷（例如支气管肺发育不良）或由于肺泡破坏而导致的肺泡缺陷（例如肺气肿）的疾病的唯一补救。为了确保和促进肺泡形成的分子诱导，除了已经在啮齿动物中通过用全反式维甲酸（RA）治疗实现的肺泡形成之外，需要对自发和RA诱导的肺泡形成的机制以及RA治疗对肺泡缺陷肺的程度和功能作用的基本理解。该建议基于以下工作：RA 1）诱导新生大鼠中肺泡的形成，并防止皮质类固醇激素对肺泡形成的抑制，2）增加断奶后大鼠中肺泡的形成，3）部分消除断奶后大鼠中肺泡形成的先前的糖皮质类固醇抑制，4）在自发性分隔失败的成年紧皮小鼠中引发分隔，和5）消除了先前通过滴注弹性蛋白酶而形成肺气肿的成年大鼠中人和实验性肺气肿的关键特征。这一提议也是基于许多其他人的工作，这些工作导致了这样一种概念，即脂质间质细胞，维生素A的肺储存部位，作为组织中心，通过释放类维生素A来发出肺泡形成的开始、停止和代谢调节间隔的信号，其他细胞对这些信号做出反应，并在基因表达中发生适当的变化。因此，对于大鼠和小鼠的工作，具体目标集中在a）解释参与调节肺泡形成的类维生素A受体，B）评估具有实验性或自发性分隔失败的大鼠和小鼠的O2扩散途径的解剖学组分对RA治疗的反应，和c）通过培养的脂质间质细胞调节类维生素A的释放以及这些细胞对共培养的肺微血管细胞的影响。拟开展的工作将：1）通过进一步阐明参与肺泡形成诱导和停止的类维生素A受体，提供重要的生物学和临床信息; 2）进一步阐明类维生素A在临床上可能有用的条件和程度; 3）进一步推进用于治疗目的的诱导肺泡形成的新范式。

DESCRIPTION (Adapted from the applicant's abstract): The long term goal is to understand the regulation of the formation of pulmonary alveoli so this information may be used for therapeutic purposes. In the absence of pharmacological means of inducing alveolus formation in humans, lung transplantation remains the only remediation for diseases in which there is a developmental deficit of alveolus formation, e.g. bronchopulmonary dysplasia or a deficit of alveoli due to their destruction, e.g. emphysema. To insure and facilitate a molecular induction of alveolus formation, beyond that already achieved in rodents by treatment with all-trans retinoic acid (RA), a fundamental understanding of the mechanism(s) of the spontaneous and RA-induced formation of alveoli, and the extent and functional effect of RA treatment on alveolar-deficient lungs, are required. This proposal is based on work showing RA 1) induces the formation of alveoli in newborn rats and prevents the inhibition of alveolus formation by a corticosteroid hormone, 2) increases alveolus formation in postweaning rats, 3) partially abrogates the prior glucocorticosteroid inhibition of alveolus formation in postweaning rats, 4) initiates septation in adult tight-skin mice in which there is failed spontaneous septation, and 5) abrogates key features of human and experimental emphysema in adult rats previously made emphysematous by the instillation of elastase. This proposal is also based on the work of many others that has led to the notion that lipid interstitial cells, lung storage sites for vitamin A, serve as organizing centers to signal the onset, cessation, and metabolically regulated spacing of alveolus formation by the release of retinoids, to which other cells respond with appropriate changes in gene expression. Therefore the specific aims, for work on rats and mice, focus on a) the explication of the retinoid receptors involved in regulating alveolus formation, b) an assessment of the response of the anatomical components of the O2 diffusion pathway to RA treatment of rats and mice that have experimental or spontaneous failed septation, and c) the regulation of release of retinoids by cultured lipid interstitial cells and the effect of these cells on co-cultured pulmonary microvascular cells. The proposed work will 1) provide important biological and clinical information by further explicating the retinoid receptors involved in the induction and cessation of alveolus formation, 2) further elucidate the conditions and the extent to which retinoids might be useful clinically, and 3) further advance the new paradigm of the induction of alveolus formation for therapeutic purposes.