Current concepts of epithelial cell kinetics in the airways are heavily based on studies done on the trachea and many studies have been done after cell proliferation has been induced by injury. These studies have ascribed a major proliferative role to the secretory cells and it has been suggested that basal cells have limited proliferative function and may play a major role in anchoring the columnar epithelium to the basal lamina. In this proposal, we propose to study the proliferative role of the bronchial epithelial cells in the uninjured hamster. Using tritiated thymidine and quantitative light microscopic, and where necessary, electronmicroscopic autoradiography, we plan to establish the progenitor relationship, turnover time, proliferative intensity and the contribution to cell renewal of eight different epithelial cell categories. We will identify those cell categories -which belong in the proliferative (P) and quiescent (Q) compartment and establish the identity of the stem cell. We propose to use our model of elastase-induced secretory cell metaplasia to quantitatively study large populations of secretory cells, and identify proliferative heterogeneity among the four subcategories of the secretory compartment. We hypothesize that secretory cells with many granules are quiescent, as is true for ciliated cells and unlike secretory cells with a few granules which , we hypothesize, play the role of dividing transit cells. We plan to validate this hypothesis and further determine if, following degranulation, secretory cells can regain their proliferative characteristics and transfer from the Q to the P compartment. Bronchogenic carcinoma is the most common malignancy in the male population and is nearly as common as breast carcinoma in the female population. Anti-neoplastic therapeutic chemotherapy is aimed at the proliferative compartment and in particular to the tissue stem cell. Our proposed studies will identify the currently disputable identity of the bronchial epithelial stem cell. They will also define the kinetic heterogeneity within the secretory cell compartment which may throw light on the pathogenesis of the persistent nature of elastase-induced secretory cell metaplasia.
| Breuer, R; Christensen, T G; Lucey, E C et al. (1993) Elastase causes secretory discharge in bronchi of hamsters with elastase-induced secretory cell metaplasia. Exp Lung Res 19:273-82 |
| Breuer, R; Christensen, T G; Wax, Y et al. (1993) Relationship of secretory granule content and proliferative intensity in the secretory compartment of the hamster bronchial epithelium. Am J Respir Cell Mol Biol 8:480-5 |
| Christensen, T G; Breuer, R; Haddad, C E et al. (1993) Quantitative ultrastructural analysis of the relationship between cell growth, shape change, and mucosecretory differentiation in cultured hamster tracheal epithelial cells exposed to retinoic acid. Am J Respir Cell Mol Biol 9:287-94 |
