ALVEOLUS FORMATION--MORPHOMETRIC AND MOLECULAR STUDIES

描述(改编自申请人的摘要)：长期目标是了解肺泡形成的规律，以便这些信息可用于治疗目的。在人类缺乏诱导肺泡形成的药物手段的情况下，对于肺泡形成存在发育缺陷的疾病，如支气管肺发育不良或因其破坏而导致的肺泡发育不良，如肺气肿，肺移植仍然是唯一的治疗方法。为了确保和促进分子诱导肺泡的形成，除了用全反式维甲酸(RA)治疗在啮齿动物身上已经取得的效果之外，需要对自发和RA诱导的肺泡形成的机制(S)以及RA治疗对肺泡缺陷肺的范围和功能影响有一个基本的了解。这一建议基于的工作表明，RA 1)诱导新生大鼠肺泡的形成并防止皮质类固醇激素抑制肺泡的形成，2)增加断奶大鼠的肺泡形成，3)部分取消先前糖皮质激素对断奶大鼠肺泡形成的抑制，4)在自发性隔膜失败的成年紧密皮肤小鼠中启动隔膜，5)取消人类和实验性肺气肿的主要特征，以前通过注入弹性蛋白酶使成年大鼠肺气肿。这一建议也是基于许多其他人的工作，这些工作导致了这样的概念，即脂质间质细胞作为组织中心，通过释放维甲酸来通知肺泡形成的开始、停止和代谢调节的间距，其他细胞通过基因表达的适当变化对此做出反应。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维甲酸受体，b)评估O2扩散途径的解剖成分对实验性或自发性分离失败的大鼠和小鼠的RA治疗的反应，以及c)培养的脂质间质细胞对维甲酸释放的调节以及这些细胞对共培养的肺微血管细胞的影响。通过进一步阐明维甲酸受体参与肺泡形成的诱导和终止，将提供重要的生物学和临床信息，2)进一步阐明维甲酸可能在临床上有用的条件和程度，以及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.