Development of the Respiratory System
Lung development requires the coordinated growth and morphogenesis of multiple populations: the endodermal epithelium of the anterior foregut, splanchic mesoderm, mesothelium, vasculature and lymphatics, and nerves. Together they give rise to the respiratory system consisting of one trachea, four right lung lobes, and one left lung lobe. Each lobe contains a treelike system of conducting airways that end in millions of highly vascularized alveoli, where gas exchange takes place. The trachea and the two primary lung buds develop on the ventral side of the foregut. The lung buds then undergo extensive branching morphogenesis, which is highly stereotypical initially but becomes more variable. Molecular and genetic analyses have identified critical reciprocal interactions between the endoderm and the mesoderm and between the mesothelium and the mesoderm, involving multiple signaling pathways. From the earliest stages, there is proximal–distal patterning of the endoderm related to the developmental fate of the cells. Lineage tracing has shown that the distal tip cells are initially multipotent and give rise to descendants in both conducting airways and alveoli. Subsequently, tip cells become more developmentally restricted and give rise to only alveolar epithelial cell types. Lineage tracing and genetic analysis have shown that mesoderm cells give rise to airway smooth muscle and stromal components of the alveoli, whereas most of the blood vessels derived by angiogenesis from the pre-existing endothelium. Alveolar development is highly complex and continues for several weeks after birth with the formation of secondary septa, which increase surface area for gas exchange.
