MAMMALIAN LUNG DEVELOPMENT - POSSIBLE ROLE OF CELL-PROLIFERATION IN THE FORMATION OF SUPERNUMERARY TRACHEAL BUDS AND IN BRANCHING MORPHOGENESIS

During the development of the lung, branching morphogenesis of the epithelium requires the presence of bronchial mesenchyme. Although continuing morphogenesis is dependent on growth through proliferation, there is no direct evidence to suggest that the specific pattern of branching is a consequence of differential mitotic activity which is influenced by the appropriate mesenchymal tissue. The induction of supernumerary buds in the tracheal epithelium of the mouse by transplantations of bronchial mesenchyme provides a means for analyzing the role of cell proliferation in the formation of bronchial buds. The problem was addressed by examining the ability of the tracheal epithelium at different stages of development to respond to bud induction by bronchial mesenchyme. An attempt was made to correlate this with the labeling index and 3H-thymidine uptake in the trachea at the respective stages. The 11 and 12 day old tracheal epithelia initiate supernumerary buds in response to bronchial mesenchyme, although the initiation in 12 day old embryonic trachea occurred somewhat later than in the 11 day old explants. The 13 day old trachea failed to elicit buds after the tracheal mesenchyme was stripped following treatment with 3% trypsin-pancreatin. A decrease in cell proliferation in the tracheal epithelium (as revealed by autoradiography and scintillation counting following 5 h labeling with 3H-thymidine) from 11-13 days of development could contribute to these varying responses to bud induction. Further autoradiographic studies where the labeling index in the induced bud and the tracheal epithelium of the same explant were compared, revealed a continued high level of labeling in the branching bud and a concomitant decrease in labeling of the trachea. The bronchial mesenchyme apparently acts as a mitotic stimulator or provides conditions permissive to continued mitotic activity.