DEVELOPMENT AND DIFFERENTIATION OF AIRWAY EPITHELIUM

仓鼠气道发育过程中糖原分解是双相的。 的 首先糖原耗尽与内分泌细胞的出现一致， 一天后，出现纤毛前细胞和分泌前细胞。 第二 糖原消耗与分泌型胶原的功能成熟一致。 细胞 这表明，来自糖原的能量是必需的， 在发育早期建立细胞谱系， 为生物合成膜和细胞器所必需的发病 分泌细胞功能。 糖原分解受损是一个常数 未受控制的糖尿病妊娠后代的肺部发现 与轻度高血糖症有关。 这样的怀孕与 1）早期生长迟缓和先天畸形的发生率增加， （2）肺成熟延迟引起的呼吸窘迫综合征。 以来 糖原分解似乎在功能上与两个不同的阶段有关， 气道发育（见上文），预计在糖尿病期间， 高血糖妊娠，胎儿气道的早期生长将 并且分泌细胞的成熟将被延迟。 相反，预计在低血糖妊娠期间， 胎儿气道的早期生长将加速， 分泌细胞会比正常的细胞更快。 主要目标是 比较胎儿支气管和细支气管的发育 和新生仓鼠在高血糖、低血糖和正常血糖期间发育 怀孕。 在仓鼠中， 妊娠的链脲佐菌素，和轻度低血糖将诱导 从微型泵持续输注胰岛素。 糖尿病模型将是 旨在造成胎儿高血糖和高胰岛素血症， 将设计低血糖模型以产生胎儿低血糖， 低胰岛素血症（胎儿胰腺发育后）。 的 具体目标是通过以下方式监测肺内气道的发展：1） 扫描气道三维模型的测量与分析 电子显微照片; 2）定量有丝分裂指数和比例 不同的上皮细胞类型; 3）量化细胞分化 应用体视学方法; 4）证明和绘制胰岛素受体 使用光镜和电子显微镜免疫标记对上皮细胞进行染色; 和5）通过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细胞蛋白的演示。

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.