Embryology Learning Resources
Duke University Medical School
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Lung and Diaphragm Development

Suggested readings from Langman's Medical Embryology (11th. ed.):
Ch. 11, pp. 155-154
Ch. 13, pp. 201-207

Click here to launch the Simbryo Lung Development animation (and some really trippy music -you'll understand once the window opens...)

I. Development of the Respiratory Tract

  • the respiratory tract develops from foregut endoderm and associated mesoderm

A. Early development

  • the first sign of lung development is the appearance during the 4th week of gestation of the respiratory diverticulum, which is a ventral outgrowth of the foregut endoderm.
  • outgrowth and proliferation of the respiratory diverticulum depends on factors from the surrounding mesoderm, including retinoic acid signaling, which induces expression of TBX4 in the endoderm essential for differentiation of the trachea and lungs.

Disruption of the mesoderm, retinoic acid signaling, or TBX4 expression in the endoderm will interfere with this process and can cause defects in lung/trachea development.

  • as the respiratory diverticulum grows, longitudinal mesodermal folds called the tracheo-esophageal ridges form that eventually pinch off to separate the trachea from the esophagus.

Disruption of the formation of the tracheo-esophageal ridges can result in tracheo-esophageal fistulas. This is very often associated with a spectrum of mesodermal defects called the VATER association (Vertebral anomalies, Anal atresia, Tracheoesophageal fistula, Esophageal atresia, and Renal atresia), or, if Cardiac defects and Limb defects are also present, VACTERL.

Tracheoesophageal fistulas occur in about 1/3000 births and most are of the sort where the proximal esophagus ends blindly whereas the distal esophagus communicates with the trachea via a fistula. Complications arise both prenatally and postnatally:

  • PRENATALLY: polyhydramnios (too much amniotic fluid) due to an inability of the fetus to swallow the amniotic fluid (an important part of the recycling the fluid)
  • POSTNATALLY: infants cough and choke IMMEDIATELY upon feeding due to an inability to swallow; connection of lower esophagus to the trachea can allow gastric contents to get into lungs causing irritation and possibly pneumonitis (inflammation of the lungs).

An extreme example is tracheal atresia where the trachea fails to form entirely and the lungs bud directly from the esophagus.

B.  Development of the larynx

  • The epithelial lining and glands of the larynx are derived from endoderm, which proliferates and temporarily occludes the lumen of the larynx.  Growth and expansion of the wall of the larynx combined with apoptosis of some the epithelium leads to recanalization of the larynx by about 10 weeks.
  • The cartilage and muscles of the larynx arise from mesenchyme from the 4th and 6th pharyngeal arches.  Specifically, the cartilage is from neural crest-derived mesenchyme whereas the muscles of the larynx are from somitomeric mesenchyme and therefore innervated by branches of the vagus nerve associated with each arch (4th arch by the superior laryngeal branch, 6th arch by the recurrent laryngeal branch).

The process of recanalization can be disrupted resulting in laryngeal atresia (occlusion of the laryngeal lumen, also known as CHAOS, or Congenital High Airway Obstruction Syndrome) or laryngeal web (partial occlusion via a membranous web over the vocal cords).  Either of these can be repaired surgically.  However, the effects of laryngeal atresia are much more severe: air is trapped in the lungs causing dilation of the lower airways.

C.  Development of the trachea

  • tracheal epithelium and glands are derived from endoderm
  • tracheal smooth muscle, connective tissue, and cartilage are derived from visceral (or splanchnic) mesoderm.
  • as with the larynx, the endoderm overproliferates resulting in occlusion of the lumen followed by recanalization by about 10 weeks.

D. Segmental branching and development of the bronchial tree

  • by the end of the 4th week, the trachea divides into two primary bronchi (right and left)
  • a few days later, primary bronchi divides into secondary bronchi (3 on the right and 2 on the left, corresponding to the lobes of the lungs)
  • the secondary bronchi branch then into tertiary bronchi (10 on the right, 8 on the left), establishing the 18 bronchopulmonary segments of the lungs by the end of the 7th week.
  • by the end of the 6th month, approximately 14 additional generations of branching events have occurred and this continues up until about 8 years postnatally such that in all there are about 23 segmental branches in the adult lung

Branching morphogenesis is MESODERM and RETINOIC ACID-DEPENDENT (along with several other genetic factors such as TBX4 and FGF10, for example).  Early disruption of segmental branching can cause the loss, or agenesis, of entire bronchopulmonary segments, lobes, or even an entire lung.  Congenital lung cysts arise if the disruption is later in development such that the terminal bronchioles within a small portion of the lung are abnormally dilated.  These dilated pockets appear as empty "cysts" in a chest x-ray.

E. Development of the lungs

  • lung tissue starts to form around the bronchial tree starting at about the 5th week and is generally broken into 4 stages:
    • Pseudoglandular period (5-17 weeks)
      • the developing lung at this point resembles a branched, compound gland of endodermal air-conducting tubules (hence the term "pseudoglandular")
      • at this point, there are NO ALVEOLI, so respiration is NOT POSSIBLE and premature infants born during this period cannot survive

    • Canalicular period (16-26 weeks)
      • Respiratory bronchioles and alveolar ducts with some terminal sacs start to appear by week 24 and the vascularization increases such that gas exchange is possible by the end of this stage.
      • Surfactant production by type II pneumocytes begins around week 20-22, but overall is not enough to prevent airway collapse (atelactstasis)
      • Premature infants born at this stage have a VERY POOR prognosis

    • Terminal sac period (24 weeks – birth)
      • The overall number of terminal sacs and degree of vascularization increases dramatically
      • Surfactant production also increases such that airway collapse is less likely
      • Premature infants born at the beginning of this stage can survive, but will likely need ventilation assistance and administration of exogenous surfactant
      • The degree of alveolar vascularization and surfactant levels are the key factors affecting survival
    • Alveolar period (week 29 to 8 years)
      • Terminal sacs develop into alveolar ducts and alveolar sacs with numerous alveoli.
      • Expansion of the alveolar tree continues up until age 8 postnatally.  In fact, a newborn has about 1/6 the number of alveoli compared to an adult.

Because of the fewer number of mature alveoli, the lungs of a newborn are much denser than those of an adult when viewed on a chest x-ray.

F.  Surfactant production

  • surfactant production is essential to reduce surface tension in the alveolar wall and thereby prevent collapse of the airway
  • surfactant consists of phosphatidylcholine and other phospholipids that are linked together and spread over the alveolar surface  via association with surfactant proteins, of which there are 4 general types:
    • Surfactant Protein A: actually not so important as a linker, but does have a role in eliciting uterine contraction (see below)
    • Surfactant Protein B: this is the primary protein involved in spreading the phospholipids over the alveolar surface, and a deficiency in Surfactant Protein B can lead to respiratory distress (see below)
    • Surfactant Protein C: a minor linker protein
    • Surfactant Protein D: also a minor linker protein, more involved in immune function

        Surfactant Protein A plays a role in eliciting uterine contractions by activating as a pro-inflammatory agent on macrophages present in the amniotic fluid.  These activated macrophages invade the uterine wall and begin releasing Interleukin-1β, which ultimately leads to localized prostaglandin production that stimulates the uterine smooth muscle to contract.

  • Respiratory Distress Syndrome (RDS) or Hyaline Membrane Disease occurs when there is inadequate surfactant function, either due to a deficiency in Surfactant Protein B or inadequate production of surfactant by type II pneumocytes.  As a result, the airways collapse and become inflamed, resulting in the deposition of a glassy, proteinaceous film, or "hyaline membrane" on the alveolar surface that impedes gas exchange.  In premature infants with RDS, the main problem is that the type II pneumocytes haven't developed enough.  However, another factor that can irreversibly reduce surfactant production by type II pneumocytes is prolonged intrauterine asphyxia/hypoxia (e.g. maternal smoking and/or compromised cardiorespiratory function in the mother or even mechanical obstruction of the uterine arteries such as an impinging tumor).


II. Growth of lungs into the body cavity and development of the diaphragm

  • lateral folding of the body wall encloses the foregut endoderm such that it is suspended within the intraembryonic coelom (or body cavity) by a "sling" of dorsal mesentery, which is mesoderm derived.
  • the inside of the body wall is covered by a parietal peritoneum, which is derived from somatic mesoderm.
  • the gut tube is covered by a visceral peritoneum, which is derived from splanchnic, or visceral, mesoderm.
  • as the lungs develop from the foregut endoderm, they essentially "punch" into the coelom around the lungs, which is therefore called the pleural cavity.  Against the body wall, the pleural cavity is lined by parietal pleura (akin to parietal peritoneum) whereas the lungs are covered by visceral pleura (akin to visceral peritoneum).

    A. Separation of the pleural and pericardial cavities

  • at about 5 weeks, two longitudinal folds of mesoderm called the pleuropericardial folds appear in between the developing lungs and heart.
  • The pleuropericardial folds grow from the lateral body wall toward the midline to separate the pericardial cavity (ventrally) from the pleural cavity (dorsally).
  • development of the mediastinum further divides the pleural cavity into left and right halves.

B.  Separation of the abdominal and thoracic cavities

  • with cranio-caudal folding, a block of connective called the septum transversum forms in between the heart and future liver
  • the septum transversum grows in a roughly transverse plane from front (ventral) to back (dorsal)
  • initially forms at about C1, but is displaced caudally with differential growth of the embryo
  • during weeks 5-6, the septum transversum is moving through the regions between C3, 4, and 5 and receives myoblasts that will eventually develop into the skeletal muscle of the diaphragm.  These myoblasts are innervated by the ventral rami of C3, 4, and 5 and "drag" this innervation with them as the developing diaphragm is displaced caudally, thus accounting for the course of the phrenic nerve.
  • the septum continues to grow dorsally until it meets the gut tube at about week 8 and then stops; differential growth of the embryo is such that the front (ventral) edge of the septum is at about T7 but the back (dorsal) edge is at about T12
  • at this point, there are still two open channels called the pericardioperitoneal canals on either side of the gut tube along the back of the body wall.  Closure of these canals is accomplished by the growth of two shelves called the pleuroperitoneal membranes from the lateral body toward the septum transversum.

Closure of the pericardioperitoneal canals is a complex process and disruptions are a frequent cause of congenital diaphragmatic hernias (CDH), in which abdominal contents herniate or protrude into the pleural cavity. The most common site of herniation is at the aortic or esophageal hiatus, but the overall effects are minor since the size of the defect is small.  CDH rarely occurs on the right side since the liver is in the way.  However, failure of the pericardioperitoneal canal to close on the left can lead to a large defect allowing the intestines to herniate into the left pleural cavity and interfere with development of the left lung, in some cases causing complete agenesis of the left lung.


Questions 1 and 2 refer to the following case:
A 35 year-old woman delivers an infant at 40 weeks of gestation (based on the last time of menstruation).  While in the neonatal care unit, the infant develops cyanosis and very rapid labored breathing and requires admission to the neonatal intensive care unit.  Imaging studies of the thoracic cavity show congestion in the lungs but they appear to be of normal size and there is no apparent abnormality in the diaphragm.  The woman reports no family history of lung disease and denies alcohol use, smoking, or taking medications during her pregnancy, and review of the mother’s medical records regarding prenatal care and ultrasound imaging is unremarkable.

1.  A biopsy of the infant's lung tissue would most likely show:

  1. an eosinophilic, hyaline "membrane" on the alveolar surfaces
  2. complete absence of type II pneumocytes
  3. significantly reduced branching of the bronchiolar tree compared to other infants of the same age
  4. bacterial infection and inflammation of the lung tissue (pneumonitis)



2. A possible cause of the infant's condition is:

  1. spontaneous mutation in the surfactant protein B gene
  2. presence of a tracheoesophageal fistula
  3. overproduction of mesoderm during gastrulation
  4. congenital diaphragmatic hernia and lung hypoplasia.



3. The period of lung development in which NO respiratory bronchioles or alveoli have yet formed is known as the:

  1. pseudoglandular period
  2. canalicular period
  3. terminal sac period
  4. alveolar period



4. The period of lung development in which surfactant production begins (but is not necessarily sufficient to prevent airway collapse) is known as the:

  1. pseudoglandular period
  2. canalicular period
  3. terminal sac period
  4. alveolar period


5. The skeletal muscle of the diaphragm is derived primarily from:

  1. myoblasts from thoracic somites 
  2. myoblasts from cervical somites
  3. vagal neural crest cells
  4. cervical neural crest cells
  5. thoracic neural crest cells



6. The smooth muscle in the wall of the respiratory tract is derived from:

  1. foregut endoderm
  2. splanchnic (visceral) mesoderm
  3. somatic mesoderm
  4. intermediate mesoderm
  5. neural crest



7. Congenital diaphragmatic hernias:

  1. arise due to a failure of the pleuropericardial folds to completely separate the pleural and pericardial cavities
  2. tend to occur more frequently on the right side of affected individuals
  3. can cause lung hypoplasia
  4. are due to a failure of neural crest cells to migrate and/or differentiate appropriately
  5. ALL of the above



For items 8 – 10 , select the one lettered option from the following list that is most closely associated with each numbered item below.  Options in the list may be used once, more than once, or not at all.
                a.  alveolar stage
                b.  canalicular stage
                c.  terminal sac stage
                d.  pseudoglandular stage
8. stage in lung development at which alveoli have not formed and survival is NOT possible

9. premature infants born at this stage have a relatively good prognosis although they will require respiratory support and treatment with exogenous surfactant

10. stage in lung development at which there is the most surfactant production



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Updated 10/11/11 - Velkey