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The lung is composed of numerous cell types and structures, all of which develop and grow at different rates. Understanding lung growth and development is critical for understanding normal pulmonary physiology as well as the developmental basis for the pathogenesis of pediatric respiratory disease. The primary function of lungs is gas exchange. Gas exchange occurs through development of lung parenchyma into millions of alveoli in close coordination with capillaries. Disruption of this developmental pathway can result in congenital lung lesions or impaired lung function.



Lung development traditionally has been divided into 5 stages (Fig. 495-1). Phases of lung development may overlap to some extent, and the gestational age ranges associated with each stage are rough estimates. The primitive endoderm is the initial site of lung development. Primitive endoderm is formed during gastrulation, at 3 weeks after conception in humans. This process is accomplished with the help of many nuclear transcription factors that regulate gene expression in the embryo. Some of the identified factors include forkhead box A2 (FOXA2), GATA binding protein 6 (GATA6), sex-determining region Y related HMG box (SOX17), and SOX2. Aberrations in these transcription factors will result in disruption of lung formation.

Figure 495-1

Stages of lung development.


Foregut Patterning

The embryonic stage is the first stage of lung development and begins with the formation of 2 primary lung buds, small saccular outgrowths of the ventral wall of foregut endoderm. The endodermal cells of the ventral wall of the foregut express the transcription factor NK2-homeobox 1 (Nkx2-1), which marks the site of formation of the primary lung buds. Just anterior to the lung buds, the foregut tube begins to separate into 2 structures: a dorsal esophagus and a ventral trachea. Regulators of gene expression such as retinoic acid and signaling peptides such as fibroblast growth factor (FGF) 10 facilitate this process. Disruption of this process can result in agenesis or hypoplasia of the larynx, trachea, or lungs. Several pathways have been described that play roles in dorsoventral axis patterning of the foregut endoderm. SOX2 expression is increased dorsally in the future esophagus, whereas Nkx2-1 expression is increased ventrally in the future trachea. This patterning depends on bone morphogenic proteins, FGF and Wnt, signaling peptides secreted from surrounding mesenchyme. Defects in this process may also lead to disruption of development of the foregut.

Development of the Central Tracheobronchial Tree

Epithelial cells of the lung bud invade the mesoderm to form tubules. Repetitive lateral and terminal dichotomous branching forms the proximal structures of the tracheobronchial tree. The region proximal to the bifurcation of the primary lung buds becomes the trachea and ...

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