ABSTRACT
Lung development can be subdivided into five distinct stages (1,2). The early stages of lung development are embryonic and pseudoglandular. During the pseudoglandular period the primitive airway epithelium starts to differentiate and neuroendocrine, ciliated, and goblet cells appear while mesenchymal cells have begun to form cartilage and smooth muscle cells. In the subsequent canalicular period, the airway branching pattern is completed and the prospective gas-exchange region starts to develop. During this period respiratory bronchioli appear, interstitial tissue decreases, vascularization of peripheral mesenchyme increases, and distal cuboidal epithelium differentiates into type I and type II cells. In the saccular (terminal sac) period, the growth of the pulmonary parenchyma, the thinning of the connective tissue between the airspaces, and maturation of the surfactant system are the most important steps towards extrauterine life. During the alveolar period, which is a predominantly postnatal process in human and rodents, alveoli are formed through a septation process that greatly increases the gas exchange surface area and the capillaries will fuse to form a single layer (2). If we assume that repair after injury recapitulates some of the developmental pathways used during lung development, understanding the underlying molecular and cellular mechanisms might be relevant for the clinical management of end-
MD: MASSARO, JOB: 03313, PAGE:
stage lung diseases such as chronic obstructive pulmonary disease (emphysema and chronic bronchitis), pulmonary fibrosis, cystic fibrosis, lung cancer, as well as the newborn airway disease bronchopulmonary dysplasia (BPD). Regeneration of small airways in order to restore normal gas exchange function could be a valuable therapeutic option for these lung diseases. Besides lung transplantation, at present there is no way to regenerate functional lung units damaged by these processes. Restoration of functional lung requires regeneration of both the vascular and epithelial components organized with a proper alveolar architecture. Epithelial airways are rendered useless without adjacent capillaries, while supportive fibroblasts and mesenchyme are crucial to keep the lung structure together. It would be ideal if all appropriate types of cells should proliferate and differentiate to restructure the lung. Therefore, it is important to identify the angiogenesis and branchingmorphogenetic factors guiding small airway formation during normal development.
