Conserved Mechanisms in the Formation of the Airways and Alveoli of the Lung.

Branching is an intrinsic property of respiratory epithelium that can be induced and modified by signals emerging from the mesenchyme. However, during stereotypic branching morphogenesis of the airway, the relatively thick upper respiratory epithelium extrudes through a mesenchymal orifice to form a new branch, whereas during alveologenesis the relatively thin lower respiratory epithelium extrudes to form sacs or bubbles. Thus, both branching morphogenesis of the upper airway and alveolarization in the lower airway seem to rely on the same fundamental physical process: epithelial extrusion through an orifice. Here I propose that it is the orientation and relative stiffness of the orifice boundary that determines the stereotypy of upper airway branching as well as the orientation of individual alveolar components of the gas exchange surface. The previously accepted dogma of the process of alveologenesis, largely based on 2D microscopy, is that alveoli arise by erection of finger-like interalveolar septae to form septal clefts that subdivide pre-existing saccules, a process for which the contractile properties of specialized alveolar myofibroblasts are necessary. Here I suggest that airway tip splitting and stereotypical side domain branching are actually conserved processes, but modified somewhat by evolution to achieve both airway tip splitting and side branching of the upper airway epithelium, as well as alveologenesis. Viewed in 3D it is clear that alveolar "septal tips" are in fact ring or purse string structures containing elastin and collagen that only appear as finger like projections in cross section. Therefore, I propose that airway branch orifices as well as alveolar mouth rings serve to delineate and stabilize the budding of both airway and alveolar epithelium, from the tips and sides of upper airways as well as from the sides and tips of alveolar ducts. Certainly, in the case of alveoli arising laterally and with radial symmetry from the sides of alveolar ducts, the mouth of each alveolus remains within the plane of the side of the ductal lumen. This suggests that the thin epithelium lining these lateral alveolar duct buds may extrude or "pop out" from the duct lumen through rings rather like soap or gum bubbles, whereas the thicker upper airway epithelium extrudes through a ring like toothpaste from a tube to form a new branch.