DEVELOPMENT AND DIFFERENTIATION OF AIRWAY EPITHELIUM

在金黄地鼠的呼吸道发育过程中，糖原分解是两相的。这个 首先，糖原耗竭与内分泌细胞的出现相一致， 一天后，出现预裂细胞和存储前期细胞。第二 糖原耗竭与分泌功能成熟相一致。 细胞。这表明，从糖原获得的能量需要 在发育早期建立细胞谱系，并需要较晚的时间 用于膜和细胞器的生物合成，是发病所必需的 分泌细胞的功能。糖原分解的障碍是一个恒定的 在未控制的糖尿病妊娠后代的肺中发现 伴有轻度高血糖。这样的怀孕与 1)早期发育迟缓和先天畸形的发生率增加， (2)肺成熟延迟所致的呼吸窘迫综合征。自.以来 糖原分解似乎在功能上与两个不同的阶段有关 呼吸道发育(见上文)预计在糖尿病期间 妊娠高血糖时，胎儿呼吸道的早期发育会 受损，分泌细胞的成熟将被推迟。 相反，预计在低血糖怀孕期间， 胎儿呼吸道的早期发育将被加速，胎儿的成熟 与正常相比，分泌细胞将被加速。我们的主要目标是 胎儿支气管和细支气管发育的对比研究 和新生仓鼠在高血糖、低血糖和正血糖期间发育 怀孕。金黄地鼠早期可诱发轻度高血糖 由链脲佐菌素引起的妊娠和轻度低血糖 从一个小泵中持续输注胰岛素。糖尿病模型将是 旨在造成胎儿高血糖和高胰岛素血症，以及 降糖模型将被设计为创造胎儿低血糖和 低胰岛素血症(伴随着胎儿胰腺的发育)。这个 具体目标是通过1)监测肺内气道的发展 扫描时呼吸道三维管型的测量与分析 电子显微镜；2)有丝分裂指数和比例的量化 不同的上皮细胞类型；3)量化细胞分化 使用体视学方法；4)展示和绘制胰岛素受体图 对上皮细胞进行光镜和电子显微镜免疫标记； 5)免疫细胞化学评价分泌细胞成熟 细胞色素P-450还原酶和Clara细胞蛋白的表达。

Glycogenolysis is biphasic during airway development in hamsters. The first glycogen depletion coincides with the appearance of endocrine cells, followed one day later by preciliated and presecretory cells. The second glycogen depletion coincides with functional maturation of the secretory cells. This suggests that energy derived from glycogen is required to establish the cell lineages early during development, and later is required for biosynthesis of membranes and organelles necessary for the onset of secretory cell functions. Impairment of glycogenolysis is a constant finding in the lungs of offspring of uncontrolled diabetic pregnancies associated with mild hyperglycemia. Such pregnancies are associated with increased incidences of 1) early growth delay and congenital malformations, and 2) respiratory distress syndrome due to delayed lung maturation. Since glycogenolysis appears to be functionally linked to two distinct phases of airway development (see above) it is anticipated that during diabetic hyperglycemic pregnancies, the early growth of fetal airways will be impaired and that maturation of secretory cells will be delayed. Conversely, it is anticipated that during hypoglycemic pregnancies, the early growth of fetal airways will be accelerated and that maturation of secretory cells will be hastened, compared with normal. The major goal is to compare and contrast the development of bronchi and bronchioles in fetal and neonatal hamsters developing during hyper-, hypo- and euglycemic pregnancies. Mild hyperglycemia will be induced in hamsters early in pregnancy by streptozotocin, and mild hypoglycemia will be induced by continuous infusion of insulin from a minipump. The diabetic model will be designed to create fetal hyperglycemia and hyperinsulinemia, and the hypoglycemic model will be designed to create fetal hypoglycemia and hypoinsulinemia (following development of the fetal pancreas). The specific aims are to monitor intrapulmonary airway development by 1) measuring and analyzing three dimensional casts fo the airways in scanning electron micrographs; 2) quantifying mitotic indices and proportions of different epithelial cell types; 3) quantifying cellular differentiation using stereological methods; 4) demonstrating and mapping insulin receptors on epithelial cells using light and electron microscopic immunolabeling; and 5) evaluating secretory cell maturation by immunocytochemical demonstration of cytochrome P-450 reductase and Clara cell protein.