Lung Development, Airway Histology & Congenital Anomalies
From foregut bud to alveoli: timing, tissue, and the malformations that follow
Embryology: from lung bud to alveoli
Origin. Around week 4 the respiratory diverticulum (lung bud) grows from the ventral wall of the foregut. Foregut endoderm gives rise to the epithelium and glands of the larynx, trachea, bronchi and alveoli; the surrounding splanchnic mesoderm forms cartilage, smooth muscle, connective tissue and vessels. Tracheoesophageal folds fuse into a septum that separates the ventral trachea from the dorsal esophagus; incomplete separation produces tracheoesophageal fistula, most often esophageal atresia with a distal fistula. The bud divides into two main bronchi, then lobar (three right, two left) and segmental bronchi.
Five overlapping stages. Development proceeds from proximal to distal, each stage adding thinner-walled structures. A student mnemonic for the order: Every Puppy Can Sniff Apples.
| Stage | Approximate timing | Key events | Clinical significance |
|---|---|---|---|
| Embryonic | Weeks 4–7 | Lung bud, trachea, main, lobar and segmental bronchi | Tracheoesophageal fistula |
| Pseudoglandular | Weeks 5–17 | Branching to terminal bronchioles; gland-like histology | Conducting airways only; no gas exchange possible |
| Canalicular | Weeks 16–25 | Respiratory bronchioles and alveolar ducts; capillaries approach epithelium; type I and II pneumocytes differentiate | Gas exchange first possible; viability near 24 weeks |
| Saccular | Week 26 to birth | Thin-walled terminal sacs; flattened type I cells; rising surfactant | Survival improves as surfactant rises |
| Alveolar | ~Week 36 to ~8 years | Secondary septa create true alveoli; capillary bed matures | Only about one-sixth of adult alveoli present at birth |
Viability. Before the canalicular stage the lung is a branching tree of tubes without respiratory bronchioles or capillaries next to the epithelium. Once respiratory bronchioles, capillaries and pneumocytes appear, a preterm infant born around 24 weeks can survive with intensive support. Because most alveoli form after birth, prematurity and early lung injury can leave lasting alveolar simplification (bronchopulmonary dysplasia).
Growth factors. Normal growth needs adequate thoracic space, amniotic fluid, fetal lung fluid secreted by the epithelium, and fetal breathing movements that stretch the lung.
Congenital anomalies
Pulmonary hypoplasia. Oligohydramnios from bilateral renal agenesis, ARPKD, posterior urethral valves or prolonged rupture of membranes produces the Potter sequence: flat facies, limb deformities and pulmonary hypoplasia, which is the usual cause of death. Anything that crowds the chest can do the same.
Congenital diaphragmatic hernia. Failure of the pleuroperitoneal membrane to close leaves a posterolateral (Bochdalek) defect, about 85% on the left. Bowel in the chest compresses both developing lungs, worse on the hernia side, and the hypoplastic vascular bed causes pulmonary hypertension. Newborns have respiratory distress, a scaphoid abdomen, bowel sounds in the chest and a heart displaced to the right. The Morgagni hernia is anterior and retrosternal, usually right-sided and often found incidentally later in life.
| Feature | CPAM | Sequestration | Bronchogenic cyst |
|---|---|---|---|
| What it is | Multicystic overgrowth of terminal bronchiolar tissue | Nonfunctioning lung tissue | Closed cyst from abnormal foregut budding |
| Airway connection | Yes | No | No |
| Arterial supply | Pulmonary artery | Systemic, usually descending aorta | Local vessels |
| Typical site | One lobe | Lower lobes, often left | Middle mediastinum near the carina |
| Presentation | Fetal hydrops or neonatal distress; later infection, rare malignancy | Intralobar: recurrent pneumonia in childhood; extralobar: infancy, other anomalies | Airway compression (wheeze, stridor) or infection |
Sequestration subtypes. Intralobar sequestration lies within the normal visceral pleura and drains to pulmonary veins; extralobar sequestration has its own pleural covering, drains to systemic veins and often accompanies other anomalies such as CDH. Symptomatic lesions are resected.
Bronchogenic cyst. The wall contains respiratory epithelium, cartilage, smooth muscle and glands; cartilage separates it from an esophageal duplication cyst. Congenital lobar emphysema, by contrast, is overinflation of a lobe (often the left upper lobe) from deficient bronchial cartilage acting as a ball valve.
Airway histology
Conducting zone. The nose, pharynx, larynx, trachea, bronchi, bronchioles and terminal bronchioles move air, warm and humidify it, and trap particles on the mucociliary escalator, but exchange no gas. Their volume is the anatomic dead space, about 150 mL in adults. The respiratory zone — respiratory bronchioles, alveolar ducts and alveoli — is where exchange occurs.
| Level | Epithelium | Cartilage | Goblet cells | Smooth muscle | Cilia |
|---|---|---|---|---|---|
| Trachea and bronchi | Pseudostratified ciliated columnar | Yes | Yes | Yes | Yes |
| Bronchioles to terminal bronchioles | Ciliated columnar becoming cuboidal; club cells | No | No | Yes, prominent | Yes |
| Respiratory bronchioles | Cuboidal, interrupted by alveoli | No | No | Sparse | Cilia end here |
| Alveoli | Simple squamous type I cells with type II cells | No | No | No | No |
Bronchioles lack cartilage, so their patency depends on radial traction from surrounding lung — the reason they collapse in emphysema and constrict so effectively in asthma.
Alveolar cells and surfactant
Type I pneumocytes. Thin squamous cells that cover about 95% of the alveolar surface and form the gas-exchange barrier with capillary endothelium. They cannot divide.
Type II pneumocytes. Cuboidal cells clustered at alveolar corners that store surfactant in lamellar bodies. After injury they proliferate and differentiate to regenerate both type I and type II cells.
Surfactant. Mostly dipalmitoylphosphatidylcholine (DPPC, a lecithin) with surfactant proteins. By Laplace's law (P = 2T/r), small alveoli would empty into large ones; surfactant lowers surface tension more as alveoli shrink, preventing collapse and improving compliance.
Club cells. Nonciliated, dome-shaped cells of the bronchioles that secrete protective proteins and surfactant components, metabolize inhaled toxins with cytochrome P-450 and act as progenitors for bronchiolar epithelium.
Alveolar macrophages. They phagocytose particles and microbes. In pulmonary congestion from left heart failure, red cells leak into alveoli, and macrophages that digest them fill with hemosiderin — "heart failure cells," which stain blue with Prussian blue.
Fetal lung maturity
Timing. Type II cells begin making surfactant in midgestation, but production becomes adequate only near 35 weeks. An amniotic fluid lecithin:sphingomyelin (L/S) ratio above 2.0, especially with phosphatidylglycerol present, indicates mature lungs; a ratio below 1.5 predicts neonatal respiratory distress syndrome (NRDS).
Accelerators. Antenatal betamethasone or dexamethasone, given when preterm birth is likely between about 24 and 34 weeks, matures type II cells and increases surfactant; thyroid hormone also promotes maturation.
Delays. In maternal diabetes, glucose crosses the placenta and the fetus responds with β-cell hyperplasia and hyperinsulinemia, which delays surfactant production; infants of diabetic mothers develop NRDS despite being large. Cesarean delivery without labor misses the stress-induced cortisol surge. Surfactant deficiency causes diffuse atelectasis, hyaline membranes and a ground-glass chest film.