The overall objective is to obtain a comprehensive understanding about the nature of pulmonary small-granule paracrine/endocrine cells, their population dynamics, the basic mechanisms they employ for sensory reception and stimulus-coupled secretion, and targets of the neuropeptide-like and other substances released from the basal pole of these cells. Little is known about any of these essential characteristics. The cells are widely but thinly scattered along the airways up to the respiratory zone and occur singly of in clusters termed neuroepithelial bodies because many are invested by visceral sensory and autonomic fibers. These cells are functional in fetal and adult life and will develop in organ cultures of fetal lungs where they can be studied physiologically more readily than in vivo (1) The life span and turnover of small-granule cells will be analyzed by autoradiography on adult, intact fetal, and organ cultured lungs using continuous 3H-thymidine infusion which has been successfully used to label them. Results may improve current understanding of fluctuations in small-granule cell number after chronic hypoxia and other noxious stimuli and provide insight about the cell of origin for pulmonary endocrine tumors. (2) Studies on the functional organization of small-granule cells will define characteristics of receptor and secretory surfaces using electron-cytochemical localization of Na+-K+ ATPase, Ca++ ATPase and other membrane-associated enzymes and lectin markers. Intracellular membrane circulation and vesicular traffic will be investigated using tracers for fluid-phase and adsorptive endocytosis, acid phosphatase for identification of lysosomes, and acetylcholinesterase for labeling secretory granules. Electrochemical behavior of these cell in stimulation-secretion coupling will then be investigated in a series of experiments carried out in vitro and in vivo and evaluated by ultrastructural stereology. (3) Serial reconstruction electron microscopy together with cyto- and immunochemical techniques for transmitter and associated enzymes will be applied to unraveling innervation patterns of bronchia/neuroepithelial bodies; patterns observed in rodents will be compared to those of human and monkey lungs. Autoradiography of receptor-bound ligands will be performed in frozen sections of lung in experiments to mark receptor sites for neuropeptides and other secretory products of small-granule cells. If receptors are found on bronchial smooth muscle, this will establish the relationship between the two cells as effector and target; and inasmuch as these neuropeptides are inhibitory on the muscle, this would implicate the small-granule cells in its control. Disturbance of this regulatory system could underlie pathogenesis of asthma.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL019379-12
Application #
3335822
Study Section
Pathology A Study Section (PTHA)
Project Start
1976-06-01
Project End
1992-03-31
Budget Start
1989-04-01
Budget End
1990-03-31
Support Year
12
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Boston University
Department
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Ebina, M; Hoyt Jr, R F; McNelly, N A et al. (1997) Effects of hydrogen and bicarbonate ions on endocrine cells in fetal rat lung organ cultures. Am J Physiol 272:L178-86
Sorokin, S P; Hoyt Jr, R F; Shaffer, M J (1997) Ontogeny of neuroepithelial bodies: correlations with mitogenesis and innervation. Microsc Res Tech 37:43-61
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
Ebina, M; Hoyt Jr, R F; Sorokin, S P et al. (1993) Calcium and ionophore A23187 lower calcitonin gene-related peptide-like immunoreactivity in endocrine cells of organ cultured fetal rat lungs. Anat Rec 236:226-30
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
Hoyt Jr, R F; McNelly, N A; Sorokin, S P (1990) Dynamics of neuroepithelial body (NEB) formation in developing hamster lung: light microscopic autoradiography after 3H-thymidine labeling in vivo. Anat Rec 227:340-50
Hoyt Jr, R F; Sorokin, S P; McDowell, E M et al. (1986) Periodic acid-Schiff-lead hematoxylin as a marker for the endocrine phenotype in human lung tumors. Arch Pathol Lab Med 110:943-51
Sarikas, S N; Hoyt Jr, R F; Sorokin, S P (1985) Ontogeny of small-granule APUD cells in hamster lung: a morphological study. Anat Rec 213:396-409

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