The lung arises from the floor of the primitive foregut as the laryngotracheal groove at approximately 4 to 6 weeks gestation in humans (Fig 1
). The proximal portion of this primitive structure gives rise to the larynx and trachea, which becomes separated from the esophagus, while progenitor cells located at the distal part of the primitive trachea give rise to the left and right main stem bronchi. Branching morphogenesis of the left and right bronchi forms specific lobar, segmental, and lobular branches. This process extends through the canalicular stage of lung development up to approximately 20 weeks gestation in humans. The first 16 of these 23 airway generations are stereo specific in humans, the remainder being fractal in geometry, but with a distinct proximal-distal pattern of diameter and epithelial differentiation that are genetically “hard wired.” Alveolarization begins at approximately 20 weeks in humans and continues at least up to 7 years of age, giving rise to an eventual alveolar gas diffusion surface 70 m2 in area by 1 μm in thickness. This enormous surface is closely apposed to an alveolar capillary network capable of accommodating a blood flow between 5 L/min at rest and 25 L/min at maximal oxygen consumption in the young and fit adult. The entire developmental process of the lung is orchestrated by finely integrated and mutually regulated networks of transcriptional factors, growth factors, matrix components, and physical forces.1–3 Factors that adversely impact the developing lung include human prematurity, oxygen exposure, early corticosteroid exposure, incorrect amounts of growth factor (platelet-derived growth factor, fibroblast growth factor [FGF], vascular endothelial growth factor, transforming growth factor [TGF]-β family, and Wnt) signaling, abnormal regulation, or injury of the pulmonary capillary vasculature. Individually and cumulatively, these all result in hypoplasia of the alveolar epithelial surface, with a resulting deficiency in gas transport, particularly during exercise. For example, survivors of human prematurity with bronchopulmonary dysplasia will desaturate on maximal exercise during childhood, and some are now entering young adulthood with increasingly severe gas diffusion problems.