The lung develops from the foregut. At the highness of the later larynx, the single tube splits into two buds for the esophagus and the lower respiratory tract, the “Lungenanlage” [1] (around gestational week 4). Out of this primitive bud, the larynx and the trachea develop, and the trachea finally separates into two bronchial buds. As in general, organogenesis recapitulates also the developmental stages of mammalian lung: a bronchial bud is also formed for a possible mediastinal lobe, as it is found in sheep, swine, and other mammalians. If this bud persists, a median mediastinal bronchial cyst can result [2]. Supernumerary buds are usually deleted by apoptotic mechanisms [3, 4]. Sometimes these buds can give rise to communications with the esophagus [5] or also to bronchogenic cysts [2, 6].

The bronchial buds give rise to several generations of bronchi, starting with the main bronchi, lobar bronchi, segmental bronchi, and so on. In the human lung, approximately 16 generations are formed around the seventh week. After that, bronchioli are formed with an additional of four generations, as membranous, and three generations of terminal respiratory bronchioli. These open into alveolar ducts on which alveoli are grouped.

For the bronchial and alveolar development, the mesenchyme derived from the mesoderm is essential. Each primitive bronchus is surrounded by splanchnopleuromesoderm. Without the connection to the mesoderm, no alveoli develop [7]. Some mediators have been identified, which are responsible for this cooperation between bronchial sprouting and mesenchyme development, such as epimorphin and fibroblast growth factor 7 (FGF7). If this is knocked out, no sprouting does occur [8, 9].

The different developmental stages of the lung are the embryonic stage, where the lung consists of branching tubules (gestational weeks 4–8). These tubules are lined by a single row of high columnar epithelium. In the pseudoglandular phase (weeks 8–16), the branching bronchial tree is embedded in a primitive immature mesenchyme; however, there are so many tubules that it mimics glandular structures (Figs. 1.1 and 1.2). Around the 13th week, the canalicular stage begins lasting until the 25th week. In this stage, the last generations of bronchioli are formed, the epithelium starts to differentiate into pneumocytes type I and II, capillaries are formed around the alveoli, and the bronchi are folded to form the first primitive lobules (Fig. 1.3). The bronchial epithelium also starts from few layers of cells, which expand during development and maturation. Columnar epithelia on H&E-stained section appear as clear cells due to abundant glycogen storage in the cytoplasm, and the nuclei are positioned at the apical cell portion (Fig. 1.4). During maturation, nuclei move toward the basal portion of the cell, and other structures and proteins replace glycogen granules. In the saccular or terminal sac stage (gestational weeks 24–36), the alveoli are formed, expanded, and capillarized, and surfactant synthesis is started. During the last 2 weeks (alveolar phase), alveoli are expanded, filled by amniotic fluid, secondary septation starts (proceeding still after birth), and respiration starts. In this phase, the fetus already can take up oxygen from the amniotic fluid and release carbon hydroxide. Even after birth bronchial generations and alveoli can be generated [9]. The newborn human has approximately 50 million alveoli at birth, which represents approximately one-sixth of the number of an adult.

The vascular structures arise in two different ways: the large arteries start from the sixth branchial arch and grow along the bronchial tree down to the periphery behind the ductus arteriosus. The veins develop later by sprouting from the left atrium into the mediastinum but in addition also from the sinus venosus. The veins reach the developing primitive lobules and surround them at the surface. Veins primarily form sinusoidal islands and coalesce into conducting structures following the interlobular septa [8, 9]. In contrast the capillaries develop from the mesoderm [10, 11].