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This chapter focuses on the mechanisms that control the development of the respiratory system from specification of the progenitors of the primordial lung to the formation of the definitive alveoli. The respiratory system is characterized not only by its major diversity in cellular phenotypes, but also by its complex 3D architecture in both the airway and alveolar compartments designed to conduct air and facilitate gas exchange. Its network of conduits comprises the trachea and extrapulmonary and intrapulmonary airways formed by multiple generations of branching epithelial tubules.

Development of the respiratory system encompasses prenatal and postnatal life, but timing and duration of specific events can vary substantially among species. Lung development starts much earlier in humans than in mice and rats; alveolar formation initiates in the human lung by late gestation in contrast to the murine lung, in which it is a postnatal process (Fig. 4-1). As an organ of exceptional structural and functional complexity, the lung is formed by a contribution of all embryonic layers, including the endoderm (epithelium), mesoderm (mesenchyme), and ectoderm (innervation).

Figure 4-1

Timeline for the developmental stages of mouse and human lungs and diagram of representative stages. Mouse (E, embryonic or P, postnatal days); humans (w, gestation week; y, year).

Based essentially on histologic criteria, lung development has been traditionally described in four stages: (1) Pseudoglandular: corresponding to the initial period of formation of the bronchial tree, when the lung exhibits a gland-like morphology with epithelial tubules separated by a thick mesenchymal layer; (2) Canalicular: when airway branching is nearly finished and distinct columnar and cuboidal epithelial cells are seen in proximal (large) and distal (small) airways, respectively. The epithelial tubules are then separated by a thinner mesenchyme containing blood vessels; (3) Saccular: primitive saccules are seen at the distal end of bronchial tree with widening of the lumens and the appearance of flat-shaped type I (AT1) and cuboidal, surfactant-producing type II (AT2) cells. The intimate approximation of the type I cell to the vascular structures (primitive alveolo-capillary barrier) allows gas exchange during the immediate postnatal period; and (4) Alveolar: when these primitive saccules undergo secondary septation to form numerous smaller mature alveolar structures to increase the gas-exchange surface.1,2


The lung originates from the anterior portion of the gut tube (foregut), which also gives rise to organs, such as the thyroid, stomach, liver, and pancreas.3,4 Respiratory progenitors of the lung and trachea arise from the ventral foregut endoderm in mice at around embryonic day 9 (E9.0, mid-gestation) and in humans around the 4th week of gestation. These cells can be readily recognized even before a lung primordial bud forms by the expression of Nkx2-1 (Ttf1, thyroid transcription factor 1); this gene, however, is not ...

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