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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL037640-02
Application #
3353474
Study Section
(SRC)
Project Start
1986-09-30
Project End
1992-03-31
Budget Start
1988-04-01
Budget End
1989-03-31
Support Year
2
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Type
Schools of Medicine
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201
McDowell, E M; Sorokin, S P; Hoyt Jr, R F (1994) Ontogeny of endocrine cells in the respiratory system of Syrian golden hamsters. I. Larynx and trachea. Cell Tissue Res 275:143-56
McDowell, E M; Hoyt Jr, R F; Sorokin, S P (1994) Ontogeny of endocrine cells in the respiratory system of Syrian golden hamsters. II. Intrapulmonary airways and alveoli. Cell Tissue Res 275:157-67
Hoyt Jr, R F; Sorokin, S P; McDowell, E M et al. (1993) Neuroepithelial bodies and growth of the airway epithelium in developing hamster lung. Anat Rec 236:15-22;discussion 22-4
Strum, J M; DeSanti, A M; McDowell, E M (1993) Patterns of cellular proliferation and airway branching in cultured fetal hamster lung explants. Tissue Cell 25:645-55
McDowell, E M (1993) Patterns of proliferation and differentiation during fetal development of the airway epithelium. Anat Rec 236:11-4, 172-3
Desanti, A M; McDowell, E M; Strum, J M (1992) Airway branching patterns and cytodifferentiation in cultured fetal hamster lung. Tissue Cell 24:853-68
Strum, J M; Compton, R S; Katyal, S L et al. (1992) The regulated expression of mRNA for Clara cell protein in the developing airways of the rat, as revealed by tissue in situ hybridization. Tissue Cell 24:461-71
Zhang, X M; McDowell, E M (1992) Vitamin A deficiency and inflammation: the pivotal role of secretory cells in the development of atrophic, hyperplastic and metaplastic change in the tracheal epithelium in vivo. Virchows Arch B Cell Pathol Incl Mol Pathol 61:375-87
Hoyt Jr, R F; McNelly, N A; McDowell, E M et al. (1991) Neuroepithelial bodies stimulate proliferation of airway epithelium in fetal hamster lung. Am J Physiol 260:L234-40
Ito, K; Ito, T; Strum, J M et al. (1991) Lectin histochemistry of developing submandibular glands of fetal Syrian golden hamsters. Anat Embryol (Berl) 183:135-41

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