Development of the Bronchial Tree

Lung development involves 5 stages: embryonic, pseudoglandular, canalicular, saccular, and alveolar. The inner respiratory epithelium arises from the endoderm, and the cartilage, bronchial muscles, connective tissue, and vasculature all arise from the mesoderm. Starting in the embryonic stage at 4 weeks of development, the lung bud branches off the ventral side of the foregut, forming the esophagus posteriorly and the trachea anteriorly. In the pseudomembranous stage, the trachea undergoes multiple generations of branching, and in the canalicular stage, primitive alveolar structures and capillaries develop. Next, in the saccular stage, gas exchange becomes possible as the capillaries more closely associate with maturing alveoli, and type II pneumocytes have started secreting surfactant. In the alveolar stage, the alveoli continue to grow in number and size and continue to mature until a child is 8 years old.

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Overview

Lung development occurs in 5 stages:

  • Embryonic: development of the trachea and primary bronchial buds
  • Pseudoglandular: development of the bronchial tree down to the level of the terminal bronchioles
  • Canalicular: development of the respiratory bronchioles and primitive alveoli
  • Saccular: maturation of the alveoli and production of surfactant
  • Alveolar: increase in number of alveoli, capillaries, and continued maturation

In utero, the lungs are:

  • Unnecessary as breathing organs (they are dormant)
  • A primary source of amniotic fluid 
  • Filled with fluid and not inflated

Immediately following delivery:

  • Lungs expand for the first time with a baby’s 1st breath.
  • This 1st breath pushes amniotic fluid out of the airspaces and into the vasculature as lungs fill with air.
  • Surfactant ↓ surface tension in the alveoli and keeps air spaces open.
  • Adequate surfactant is often a primary factor in determining infant survival.

Mnemonic:

To quickly recall the chronology of the stages of lung development, remember “Every Pulmonologist Can See Alveoli”:

  • Embryonic
  • Pseudoglandular
  • Canalicular
  • Saccular
  • Alveolar

Embryonic Stage

Development of the bronchial tree begins in the embryonic stage, with budding of the embryonic gut tube to form the larynx, trachea, and lungs by the end of the stage.

Embryonic layers

Table: Comparison of the 5 stages of lung development and their clinical relevance
Tissue layerStructures formed in the bronchial tree
Endoderm
  • Respiratory epithelium
  • Glands of the respiratory tract
MesodermSplanchnopleuric layer
  • Visceral pleura
  • Connective tissue
  • Bronchial musculature
  • Cartilage
Somatopleuric layerParietal pleura
EctodermNone

Process of development at the embryonic stage

The bronchial tree develops off of the foregut of the embryonic gut tube.

  • Occurs 4–7 weeks after conception
  • Embryonic gut tube: 
    • Forms from the laterally folded endoderm layer 
    • Is surrounded by mesoderm
    • Has 3 sections:
      • Foregut
      • Midgut
      • Hindgut
  • Lung bud (respiratory diverticulum): 
    • Buds off of the ventral side of the foregut around week 4
    • Simultaneously grows out (ventrally) and down (caudally)
    • Includes both endoderm and surrounding splanchnopleuric mesoderm
  • Tracheoesophageal groove (or ridge):
    • As the lung bud grows out and down, the tracheoesophageal groove appears as lateral indentations between the new lung bud and the foregut.
    • The grooves/ridges move in medially, “pinching off” the lung bud, and forming the tracheoesophageal septum.
    • The tracheoesophageal septum creates two separate tubes:
      • Esophagus (posteriorly, from the original foregut)
      • Trachea (anteriorly, from the lung bud) 
  • Primary bronchial buds: The trachea bifurcates into the right and left bronchial buds.
  • Defects at this stage can cause:
    • Tracheoesophageal fistula (TEF): occurs when the tracheoesophageal grooves fail to fully close in the midline 
    • Esophageal atresia: portions of the esophagus fail to form; often coexists with TEF
    • Tracheal atresia: partial or complete absence of the trachea below the larynx (lethal): The lower respiratory tract is often connected to the GI tract.
    • Bronchopulmonary sequestration: abnormally formed nonfunctioning accessory lung tissue that is not connected to the rest of the bronchial tree
Embryonic development of the bronchial tree - intestinal epithelium

Embryonic development of the bronchial tree

Image by Lecturio.

Pseudoglandular Stage

This stage generates most of the bronchial tree. It gets its name because histologically, the bronchi (which are lined with cuboidal cells at this stage) resemble glands as they branch into the surrounding mesoderm.

  • Occurs at weeks 5–16 after conception
  • At the beginning of this stage, around week 5, the lung bud and primary bronchial buds have formed.
  • During this stage, continued distal budding/branching of the bronchi forms a majority of the respiratory tree.
  • Secondary bronchial buds: 
    • Right bronchial bud trifurcates into 3 secondary lobar bronchial buds.
    • Left bronchial bud bifurcates into 2 secondary lobar bronchial buds.
  • Tertiary bronchial buds: continued division
    • Right lung: approximately 20 tertiary bronchi
    • Left lung: approximately 18 tertiary bronchi
  • Terminal bronchioles: extensive branching (approximately 20 divisions take place) down to the level of terminal bronchioles
    • Terminal bronchioles (with thick epithelial linings) develop.
    • Respiratory bronchioles do not develop until the next stage→  no gas exchange is possible → fetus cannot survive yet
  • Branching bronchioles invade the surrounding mesoderm.
  • Mesoderm is differentiating into: 
    • Pulmonary vasculature → pulmonary capillary network begins to form
    • Connective tissue
    • Bronchial muscles
    • Cartilage
  • Pneumocyte precursors begin to develop:
    • Undifferentiated cuboidal epithelial cells line the respiratory tree.
    • Produce amniotic fluid
  • The first breathing movement can be seen as early as 10 weeks of gestation. 
    • Breathing is controlled by the brainstem.
    • Breathing movements are paradoxical: the diaphragm contracts and the thorax moves inwardly, and vice versa.
  • By the end of this stage:
    • Formation of terminal bronchioles, an arterial system, cartilage, and smooth muscle
    • Pneumocyte precursors develop.
  • Defect at this stage: 
    • Bronchial atresia or stenosis
    • Bronchogenic cyst: anomalous budding of the foregut that does not communicate with the tracheobronchial tree
Representation of pulmonary histology in the pseudoglandular stage

Representation of pulmonary histology in the pseudoglandular stage:
1: Lung mesenchyme
2: Type II pneumocyte precursors
3: Capillaries

Image by Lecturio.

Canalicular Stage

During this stage, the respiratory units (also referred to as canaliculi) develop at the end of the terminal bronchioles.

  • Occurs 16–26 weeks after conception
  • Respiratory units begin to develop: 
    • Terminal bronchioles (small “conducting” airways) extend and branch into the respiratory bronchioles.
    • Respiratory bronchioles lead to 3–6 alveolar ducts (the first primitive alveolar structures).
    • Vascularization of the surrounding mesenchyme occurs → dense capillary networks begin to surround the alveolar ducts
    • Fusion of the capillary and respiratory epithelial basement membranes
  • Type II pneumocytes:
    • Thicker cuboidal cells (unable to exchange gas) 
    • Line most of the respiratory epithelium and alveoli
    • Begin producing surfactant around week 20
    • Continue to produce amniotic fluid
    • Minimal differentiation into flattened type I pneumocytes that are capable of gas exchange
  • Surfactant (abbreviation for “surface active agent”): 
    • Produced from glycogen
    • Consists of:
      • Lipids (made up mostly of phosphatidylcholine) 
      • Hydrophobic surfactant proteins B and C
      • Hydrophilic surfactant proteins
    • Stored in lamellar bodies
    • Covers the alveolar surface
    • ↓ Surface tension within the alveoli prevents collapse of the alveoli after birth.
  • By the end of the canalicular stage:
    • Some respiration is possible owing to creation of the gas-exchanging portions of the lung.
    • A large part of the amniotic fluid has been produced.
    • The maturity of the lungs is based on production of surfactant.
    • Infants born at the later stage can survive with intensive care. 
  • Defects at this stage: cause damage to the gas-exchange components and result in structural alterations of the pulmonary parenchyma
Representation of pulmonary histology in the canalicular stage

Representation of pulmonary histology in the canalicular stage:
1: Type I pneumocyte
2: Type II pneumocyte
3: Capillaries
4: Lung mesenchyme
5: Alveolar duct

Image by Lecturio.

Saccular Stage

During this stage, the alveoli begin to mature, as type II pneumocytes (cuboidal cells) flatten into type I pneumocytes capable of gas exchange, creating the gas-exchange surface area. Surfactant production increases significantly.

  • Week 26 after conception through birth
  • Alveolar ducts expand into terminal sacs and begin to mature:
    • Type II pneumocytes (thick cuboidal cells incapable of gas exchange) → flatten into thin type I pneumocytes (capable of gas exchange)
    • Results in thin-walled terminal sacs (immature alveoli)
    • Type II pneumocytes ↑ production of surfactant: usually reach adequate levels around week 32
  • Capillary networks grow: 
    • Capillaries associate with the terminal sacs.
    • Basal membrane forms between the pneumocytes in the terminal sacs and the endothelial cells. 
  • Gas exchange becomes possible:
    • When maturing terminal sacs with thin type 1 pneumocytes associate with capillaries
    • Known as the blood–air barrier
  • By the end of the saccular phase:
    • All generations of the conducting and respiratory branches have been formed. 
    • Sacculi are thin, smooth-walled sacks capable of gas exchange.
    • Surfactant production is increasing.
  • Infants born > 32 weeks have a much ↑ chance of survival than those born at 24 weeks.
Representation of pulmonary histology in the saccular stage

Representation of pulmonary histology in the saccular stage:
1: Type I pneumocyte
2: Type II pneumocyte
3: Capillaries
4: Saccular space
5: Basal membrane of the air passage
6: Basal membrane of the capillaries
7: Endothelium of the capillaries

Image by Lecturio.

Alveolar Stage

During the alveolar stage, the respiratory units continue to grow in number and maturity.

  • From 32 weeks after conception through 8 years of life
  • Septation of terminal sacs → ↑ surface area and leads to further maturation of alveoli
  • Continued expansion of the capillary network
  • Alveoli continue to increase in number:
    • 50 million alveoli at birth 
    • Rapid ↑ in alveolar number in the 1st 6 months of life
    • Continued growth in number and size of alveoli until age 8
    • Approximately 300 million alveoli by age 8
Alveolar stage

Representation of pulmonary histology in the alveolar stage:
1: Respiratory bronchiole
2: Primary septum
3: Alveolar sac
4: Capillaries
5: Type II pneumocyte
6: Type I pneumocyte
7: Alveolar duct

Image by Lecturio.

Clinical Relevance

Table: Comparison of the 5 stages of lung development and their clinical relevance
Developmental stageDescriptionClinical relevance
Embryonic period (weeks 4–7)
  • Respiratory diverticulum → lung buds + trachea
  • Bronchial buds: primary → secondary → tertiary bronchi
    Defects:
  • Tracheoesophageal fistula
  • Esophageal and/or tracheal atresia
  • Pulmonary sequestration
Pseudoglandular period (weeks 5–16)
  • Continued bronchiole branching → terminal bronchioles
  • Formation of capillaries
  • Development of type II pneumocyte precursors → produces amniotic fluid
  • Defects:
    • Bronchogenic cyst
    • Bronchial atresia
  • Lung tissue incapable of gas exchange
  • Infants born at this stage cannot survive.
Canalicular period (weeks 16–26)
  • Respiratory bronchioles → alveolar ducts → primitive alveoli
  • Prominent lung capillaries
  • Surfactant production
  • Airway diameter ↑
  • Defects:
    • Pulmonary hypoplasia
    • Respiratory distress syndrome
  • Respiration possible at 24 weeks
Saccular period (weeks 26–birth)
  • Alveolar ducts → terminal sacs
  • Gas-exchange surface area of the lungs expands.
  • Blood–air barrier fully develops.
  • Surfactant production ↑
  • Infants born at > 32 week have an ↑ survival rate.
Alveolar period (week 32–8 years)
  • Mature type II pneumocytes
  • Terminal sacs → alveoli
  • Following birth, alveoli ↑ in number:
    • At birth: 50 million
    • By age 8: 300 million
  • In utero: ↑ Vascular resistance due to aspiration of amniotic fluid
  • Postpartum: Inspiration of air leads to a drop in pulmonary vascular resistance.
  • Tracheoesophageal fistula: occurs when the esophagus is connected to the trachea by a fistular tract: A tracheoesophageal fistula is commonly associated with esophageal atresia, though multiple different anatomic variations are possible. Management requires surgical correction.
  • Pulmonary hypoplasia: incomplete development of the lungs, resulting in an abnormally low number or size of bronchopulmonary segments and/or alveoli: Pulmonary hypoplasia can be suspected on prenatal ultrasound with diagnosis at birth based on clinical findings and imaging and/or pulmonary testing. Management is focused on ventilatory support, and survival depends on the degree of lung underdevelopment.
  • Neonatal respiratory distress syndrome: disease due to a deficiency of surfactant in a preterm infant due to the immaturity of the lungs: This syndrome commonly occurs in infants < 28 weeks of gestational age. Diagnosis is usually clinical, with characteristic findings on chest X-ray. Management includes prevention of preterm labor, maternal steroids to promote fetal lung maturity while still in utero, giving surfactant, and providing respiratory support. 
  • Respiratory physiology: Human cells rely primarily on aerobic metabolism. Therefore, obtaining oxygen from the environment and bringing it to the tissues while excreting the byproduct of cellular respiration (carbon dioxide) in the most efficient manner is required for survival.

References

  1. Rehman S, Bacha D. (2020). Embryology, pulmonary. StatPearls. Retrieved March 9, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK544372/
  2. Sakonidou S, Dhaliwal J. (2020). The management of neonatal respiratory distress syndrome in preterm infants (European Consensus Guidelines—2013 update). Arch Dis Child Educ Pract Ed 100(5):257–259.
  3. Schittny JC. (2017). Development of the lung. Cell Tissue Res 367(3):427–444. 
  4. Davis RP, Mychaliska GB. (2013). Neonatal pulmonary physiology. Semin Pediatr Surg 22(4):179–184.
  5. DiFiore JW, Wilson JM. (1994). Lung development. Semin Pediatr Surg 3(4):221–232.
  6. Moss TJ. (2006). Respiratory consequences of preterm birth. Clin Exp Pharmacol Physiol 33(3):280–284.
  7. Martin R. (2020). Pathophysiology, clinical manifestations, and diagnosis of respiratory distress syndrome in the newborn. UpToDate. Retrieved March 8, 2021, from https://www.uptodate.com/contents/pathophysiology-clinical-manifestations-and-diagnosis-of-respiratory-distress-syndrome-in-the-newborn/print
  8. McGrath-Morrow S, Callaco, J. (2020). Complications and long-term pulmonary outcomes of bronchopulmonary dysplasia. UpToDate. Retrieved March 8, 2021, from https://www.uptodate.com/contents/complications-and-long-term-pulmonary-outcomes-of-bronchopulmonary-dysplasia
  9. Oermann C. (2020). Bronchopulmonary sequestration. UpToDate. Retrieved March 9, 2021, from https://www.uptodate.com/contents/bronchopulmonary-sequestration

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