05.26.09(b): development of the respiratory system and diaphragm

Author(s): Matthew Velkey, 2009

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Development of the Respiratory System and

Diaphragm

Matt Velkey

Spring 2009

The respiratory tract is derived from foregut endoderm and associated mesoderm

Lateral folding:

• Parietal (aka somatic) mesoderm lines embryonic body cavity (coelom)

• Visceral (aka splanchnic) mesoderm covers endodermal gut tube

• Gut tube suspended from body wall by dorsal mesentery

Cranio-caudal folding:

Langman’s Medical Embryology, 9th ed. 2004. (Both Images)

The respiratory tract is derived from foregut endoderm and associated mesoderm

From endoderm:

epithelial lining of trachea, larynx, bronchi, alveoli

From splanchnic mesoderm: cartilage, muscle, and connective tissue of tract and visceral pleura.

Human Embryology and Developmental Biology, 4th ed. 2009.

The lung buds form during the 4th week

• Initially appear as the respiratory diverticulum, which is a ventral outgrowth of foregut endoderm

• MESODERM dependent process: Retinoic acid produced by adjacent mesoderm induces expression of TBX4 in foregut endoderm. TBX4 induces growth and differentiation of the trachea and lungs.

Langman’s Medical Embryology, 10th ed

Splitting of foregut into esophagus and trachea

Tracheo-esophageal ridges: longitudinal ridges that eventually fuse to separate trachea from esophagus.

Langman’s Medical Embryology, 9th ed. 2004.

Tracheo-esophageal fistulas

• Incomplete separation and/or atresia of trachea and esophagus (B on right shows esophageal atresia)

• Defect likely in mesoderm and usually associated with other defects involving mesoderm (cardiovascular malformations, VATER / VACTERL, etc.)

VATER = Vertebral anomalies, Anal atresia, Tracheoesophageal fistula, Esophageal atresia, Renal atresia

VACTERL = VATER + Cardiac defects & Limb defects


Larsen’s Human Embryology, 4th edition. 2008.

Tracheoesophageal Fistulas / Esophageal Atresia

• Occur in approx 1/3000 births, most (90%) are that shown in (A) above.• Complications:

– PRENATAL: Polyhydramnios (due to inability to swallow amniotic fluid in utero)– POSTNATAL

Gastrointestinal: Infants cough and choke when swallowing because of accumulation of excessive saliva in mouth and upper respiratory tract. Milk is regurgitated immediately after feeding.

Respiratory: Gastric contents may also reflux into the trachea and lungs, causing choking and often leading to pneumonitis.

Surgical repair (neonatal or in utero) now result in 85% survival rates.


Tracheoesophageal fistula in a male fetus with Trisomy 18 at 17 weeks. The upper esophageal segment ends blindly (pointer).

Clinical Correlation:

Carlson. Human Embryology and Developmental Biology.

Tracheal atresia:

Lungs bud off esophagus


Carlson. Human Embryology and Developmental Biology.

Successive stages in the development of the larynx:The epithelial lining of the larynx is of endodermal origin. The

cartilages and muscles of the larynx arise from mesenchyme from the 4th and 6th pharyngeal arches

4 weeks

10 weeks

5 weeks

6 weeks Source Undetermined


Laryngeal Atresia

This rare anomoly results in obstruction of the upper airway - congenital high airway obstruction syndrome

(CHAOS). The atresia or stenosis causes lower airways to become dilated, lungs to enlarge and become echogenic

and the diaphragm becomes flattened or inverted. Can be detected by ultrasound.

Laryngeal Web

This uncommon anomaly results from incomplete recanalization of the larynx during the 10th week. A

membranous web forms at the level of the vocal cords, partially obstructing the airway

4 weeks

10 weeks

11 weeks 14 weeks - photomicrograph

Progressive changes in the development of the laryngotracheal tube:

Endodermal lining distal to the larynx differentiates into the epithelium and glands of the trachea and pulmonary epithelium. The cartilage, connective

tissue and muscles of the trachea derive from splanchnic mesenchyme.

Source Undetermined (All Images)

Growth of lungs into the body cavity

• Foregut endoderm surrounded by visceral (splanchnopleuric) mesoderm and suspended in body wall by dorsal mesentery

• As lungs grow, they expand into the body cavity

Larsen. Essentials of Human Embryology. 1998.

Larsen. Essentials of Human Embryology. 1998.

Differentiation of pleural membranesThe lung buds “punch” into the visceral mesoderm. The mesoderm, which covers the outside of the lung, develops into the visceral pleura. The somatic mesoderm, covering the body wall from the inside, becomes the parietal pleura. The space between is the pleural cavity.


Pleuropericardial folds separate pleural and pericardial cavities.

5 weeks - pleuropericardial fold forms

8 weeks - lungs grow and expand into pleural cavity

6 weeks - pleuropericardial membrane reaches midline

7 weeks -further maturation of pericardium (expands pleural cavity

Moore and Persaud. The Developing Human.

Separating the abdominal and thoracic cavities: development of the septum transversum and diaphragm

As the embryo folds, a connective tissue structure, the septum transversum forms between the heart and body stalk.

Source Undetermined


Extension of the septum transversum partially divides abdominal and thoracic cavities•Grows in a roughly transverse plane from front to back•Angled downward such that front of septum is at about T7, back edge is at about T12

Carlson. Human Embryology and Developmental Biology, 4th ed. 2009.


• The septum transversum stops at the gut tube, leaving two open passageways on the left and right sides, aka the “pericardioperitoneal canals” (shown on the left)

• Closing off these canals requires growth from the dorsolateral body wall, aka the “pleuroperitoneal membranes” (shown on the right)

• Defects in this process cause CDH (congenital diaphragmatic hernias): abdominal contents herniate into pleural cavities and interfere with lung development.

Congenital Diaphragmatic Hernias

• Relatively common (1/2000 births)

• Hiatal hernias are most frequent, but effects are rather minor due to small size of defect

• Hernias due to failure of one or both pleurpericardial membranes to close off pericardioperitoneal canals have much more significant clinical impact because herniated abdominal contents interfere with lung development.

• 80-90% of hernias with clinical impact are on the left side. Large defects have high mortality due to extent of lung hypoplasia and dysfunction

Langman’s Medical Embryology, 9th ed. 2004. Figure 11.9

First three branching events are stereotyped:

After the initial bifurcation into two primary bronchi, two buds, or secondary bronchi, form on the left and three on the right predicting the five lobes of the adult human lung. Ten tertiary (segmental) bronchi form in the right lung and eight in the left lung - establishing the brochopulmonary segments of the adult human lung.

(10) Segmental bronchi (7-8)

Initial Patterning of the Lung:

Dissected embryonic mouse lung:

Right side cultured unperturbedafter dissection (i.e. covered by lung mesenchyme).

Left bronchial tip covered withtracheal mesenchyme.

Note no branching occurs atleft bronchial tip due totracheal mesenchyme inhibition.

Endodermal/Mesenchymal Interactions Important forBranching Morphogenesis

Source Undetermined

Signaling molecules known to be important for lung budding and branching morphogenesis

Development of the human lung

7 trachea; 1 Left main bronchus; 6 right main bronchus; others lobes

Source Undetermined

By the end of the sixth month, 17 generations of subdivisions have formed. Six more divisions occur during postnatal life for a total of 23 branching events in the adult human lung.

Branching continues to be regulated by epethelial-mesenchymal interactions (deriving from endodermal epithelial lung buds and the splanchnic mesoderm surrounding them).

During branching, the bronchial tree is assuming an increasingly caudal (posterior) position. At birth, the tracheal bifurcation is adjacent to the fourth thoracic vertebra (T4).

Stages of Maturation of the Lungs

Pseudoglandular Period (5-17 weeks):

By 17 weeks, all major elements have formed, except those involved with gas exchange (fetuses unable to survive if born at this stage).

Canalicular Period (16-25 weeks):

Bronchi, terminal bronchioles become larger, lung tissue becomes highly vascular. Alveolar ducts form by week 24. By end, some terminal sacs have formed so respiration is possible (small chance of survival at this stage).

Terminal Sac Period (24 weeks

to birth):

Many more terminal sacs develop, their epithelium becomes very thin and capillaries bulge into the developing alveoli. Blood-air barrier becomes well-developed. (By 26-28 wks, 1000 gr fetus has a sufficient # of sacs and surfactant to survive.)

Alveolar Period (late fetal period to age 8):

Alveoli-like structures are present by 32 weeks. Epithelial lining of sacs attenuate to extremely thin squamous epithelia, capable of gas exchange. 95% of characteristic, mature alveoli develop after birth.

Moore and Persaud. The Developing Human.

Canalicular Period: (16th-26th week)

Terminal Sac Period:(24th weeks to birth)Type I squamous cells

Alveolar Period:(late fetal thru childhood, Type II, surfactant-producing cells)

Development of lung tissue involved in air exchange


At birth:

Alveoli continue to mature after birth, become more muscular. Growth of lungs after birth due primarily to increase of respiratory bronchioles and alveoli. Only 1/6 of adult alveoli present at birth.

Lungs are fluid filled; fluid squeezed out and into lymphatics and blood vessels, expelled via trachea at delivery.

Surfactant remains on surface, lowers air/blood tension.

Surfactant proteins augment function of phospholipid surfactants

Four major surfactant proteins: A, B, C, and DSurfactant A: activates macrophages to elicit uterine contractions, also important in host defense

Surfactant B: organizes into tubular structures that are much more efficient at reducing surface tension (specific deficiency in Surfactant B can lead to respiratory distress)

Surfactant C: enhances function of surfactant phospholipids

Surfactant D: important in host defense.

Gilbert, Scott. Developmental Biology. 2006.

Clinical Correlations:

Respiratory Distress Syndrome/Hyaline Membrane Disease:

This disease affects 2% of live newborn infants, with prematurely born being most susceptible. 30% of all neonatal disease results from HMD or its complications.

Surfactant deficiency is the major cause of RDS or HMD. The lungs are underinflated and the alveoli contain a fluid of high protein content, probably derived from circulation substances and injured pulmonary epithelium.

In addition to prematurity, prolonged intrauterine asphyxia may produce irreversible changes in Type II alveolar cells, rendering them incapable of producing surfactant. Other factors may contribute to surfactant deficiency, but the genetics of surfactant production are not well-defined.

Prolonged, labored breathing damages alveolar epithelium, leading to protein deposition, or “hyaline” changes (shown in figure).

Clinical Correlations:

Congenital Lung Cysts: Cysts (filled with fluid or air) are thought to be formed by the dilation of terminal bronchi, probably due to irregularities in later development. If severe, cysts are visible on radiographs. Highly variable outcomes result from different cystic conditions.

Agenesis of the Lungs:Can occur bilaterally or unilaterally. Unilateral lung agenesis is compatible with live as remaining side hyperexpands and compensates.

Lung Hypoplasia:Often caused by congenital diaphragmatic hernias or congenital heart disease. Characterized by reduced lung volume. Extreme hypoplasia is inconsistent with life.

Langman’s Medical Embryology, 9th ed. 2004. (Both Images)Slide5: Human Embryology and Developmental Biology, 4th ed. 2009.Slide 6: Langman’s Medical Embryology, 10th edSlide 7: Langman’s Medical Embryology, 9th ed. 2004.Slide 8: Fig 11-4 from Schoenwolf et al. (2009). Larsen’s Human Embryology, 4th ed; Fig 13.3 from from Sadler (2006). Langman’s

Medical Embryology, 10th ed.Slide 9: Langman’s Medical Embryology, 10th ed. 2006.Slide 10: Carlson. Human Embryology and Developmental Biology. Slide 11: Carlson. Human Embryology and Developmental Biology. Slide 12: Source UndeterminedSlide 14: Source Undetermined (All Images)Slide 15: Larsen. Essentials of Human Embryology. 1998. Slide 16: Langman’s Medical Embryology, 9th ed. 2004Slide 17: Moore and Persaud. The Developing Human. Slide 18: Source UndeterminedSlide 19: Human Embryology and Developmental Biology, 4th ed. 2009.Slide 20: Schoenwolf et al: Larsen’s Human Embryology, 4th Edition. Copyright 2008 Churchill Livingston, an imprint of Elsevier, Inc.;

Schoenwolf et al: Larsen’s Human Embryology, 4th Edition. Copyright 2008 Churchill Livingston, an imprint of Elsevier, Inc.Slide 21: Moore and Persaud. The Developing Human. Slide 22: Carlson: Human Embryology and Developemental Biology, 4th Edition. Copyright 2009 by Mosby, an imprint of Elsevier, Inc. Slide 23: Source UndeterminedSlide 24: Carlson: Human Embryology and Developemental Biology, 4th Edition. Copyright 2009 by Mosby, an imprint of Elsevier, Inc. Slide 25: Source UndeterminedSlide 27: Moore and Persaud. The Developing Human. Slide 28: Langman’s Medical Embryology, 9th ed. 2004. Slide 30: Gilbert, Scott. Developmental Biology. 2006.Slide 31: Carlson: Human Embryology and Developemental Biology, 4th Edition. Copyright 2009 by Mosby, an imprint of Elsevier, Inc.

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05.26.09(b): development of the respiratory system and diaphragm

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