Respiratory System Development
The respiratory system does not carry out its physiological function (of gas exchange) until after birth. The respiratory tract, diaphragm and lungs do form early in embryonic development. The respiratory tract is divided anatomically into 2 main parts: 1. upper respiratory tract, consisting of the nose, nasal cavity and the pharynx; 2. lower respiratory tract consisting of the larynx, trachea, bronchi and the lungs.
In the head/neck region, the pharynx forms a major arched cavity within the phrayngeal arches. The lungs go through 4 distinct histological phases of development and in late fetal development thyroid hormone, respiratory motions and amniotic fliud are thought to have a role in lung maturation.
Development of this system is not completed until the last weeks of Fetal development, just before birth. Therefore premature babies have difficulties associated with insufficient surfactant (end month 6 alveolar cells type 2 appear and begin to secrete surfactant).
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Some Recent Findings
- Human Embryology Larson Chapter 9 p229-260
- The Developing Human: Clinically Oriented Embryology (6th ed.) Moore and Persaud Chapter 12 p271-302
- Before We Are Born (5th ed.) Moore and Persaud Chapter 13 p255-287
- Essentials of Human Embryology Larson Chapter 9 p123-146
- Human Embryology Fitzgerald and Fitzgerald Chapter 19,20 p119-123
- Anatomy of the Human Body 1918 Henry Gray 1. The Respiratory Apparatus
- Describe the development of the respiratory system from the endodermal and mesodermal components.
- Describe the main steps in the development of the lungs.
- Describe the development of the diaphragm and thoracic cavities.
- List the respiratory changes before and after birth.
- Describe the developmental aberrations responsible for the following malformations: tracheo - oesophageal fistula (T.O.F); oesphageal atresia; diaphragmatic hernia; lobar emphysema.
Historic drawings of embryonic lung development
|Human embryo (CRL 4.3 mm, Week 4-5, Stage 12 to 13)||Human embryo (CRL 8.5 mm, Week 5, Stage 15 to 16)||Human embryo (CRL 10.5 mm, Week 6 Stage 16 to 17)|
Week 4 - laryngotracheal groove forms on floor foregut.
Week 5 - left and right lung buds push into the pericardioperitoneal canals (primordia of pleural cavity)
Week 6 - descent of heart and lungs into thorax. Pleuroperitoneal foramen closes.
Week 7 - enlargement of liver stops descent of heart and lungs.
Month 3-6 - lungs appear glandular, end month 6 alveolar cells type 2 appear and begin to secrete surfactant.
Month 7 - respiratory bronchioles proliferate and end in alveolar ducts and sacs.
Lung Development Stages
Human Lung Stages
|Embryonic||week 4 to 5||lung buds originate as an outgrowth from the ventral wall of the foregut where lobar division occurs|
|Pseudoglandular||week 5 to 17||conducting epithelial tubes surrounded by thick mesenchyme are formed, extensive airway branching|
|Canalicular||week 16 to 25||bronchioles are produced, increasing number of capillaries in close contact with cuboidal epithelium and the beginning of alveolar epithelium development|
|Saccular||week 24 to 40||alveolar ducts and air sacs are developed|
|Alveolar||late fetal to 8 years||secondary septation occurs, marked increase of the number and size of capillaries and alveoli|
The sequence is most important rather than the actual timing, which is variable in the existing literature.
- week 4 - 5 embryonic
- week 5 - 17 pseudoglandular
- week 16 - 25 canalicular
- week 24 - 40 terminal sac
- late fetal - 8 years alveolar
- Endoderm - tubular ventral growth from foregut pharynx.
- Mesoderm - mesenchyme of lung buds.
- Intraembryonic coelom - pleural cavities elongated spaces connecting pericardial and peritoneal spaces.
- week 5 - 17
- tubular branching of the human lung airways continues
- by 2 months all segmental bronchi are present.
- lungs have appearance of a glandlike structure.
- stage is critical for the formation of all conducting airways.
- lined with tall columnar epithelium, the more distal structures are lined with cuboidal epithelium.
- week 16 - 24
- Lung morphology changes dramatically
- differentiation of the pulmonary epithelium results in the formation of the future air-blood tissue barrier.
- Surfactant synthesis and the canalization of the lung parenchyma by capillaries begin.
- future gas exchange regions can be distinguished from the future conducting airways of the lungs.
- week 24 to near term.
- most peripheral airways form widened airspaces, termed saccules.
- saccules widen and lengthen the airspace (by the addition of new generations).
- future gas exchange region expands significantly.
- Fibroblastic cells also undergo differentiation, they produce extracellular matrix, collagen, and elastin. May have a role in epithelial differentiation and control of surfactant secretion
- The vascular tree also grows in length and diameter during this time.
- near term through postnatal period.
- 1-3 years postnatally alveoli continue to form through a septation process increasing the gas exchange surface area.
- microvascular maturation occurs during this period.
- respiratory motions and amniotic fluid are thought to have a role in lung maturation.
Premature babies have difficulties associated with insufficient surfactant (end month 6 alveolar cells type 2 appear and begin to secrete surfactant).
Embryonic Respiratory Development
Pseudoglandular Respiratory Development
Pseudoglandular period identified in this paper (GA weeks 12 to 16)
Human lung at pseudoglandular stage showing E- and N-cadherin and β-catenin localization.
Species Development of Fetal Lungs
|Gestational age (days)|
|Human||280||< 42||52 - 112||112 - 168||168|
|Primate||168||< 42||57 - 80||80 - 140||140|
|Sheep||150||< 40||40 - 80||80 - 120||120|
|Rabbit||32||< 18||21 - 24||24 - 27||27|
|Rat||22||< 13||16 - 19||19 - 20||21|
Table modified from
|Fetal lung histology|
At birth the lung epithelium changes from a prenatal secretory to a postnatal absorptive function. Several factors have been identified as influencing this transport change including: epinephrine, oxygen, glucocorticoids, and thyroid hormones (for review see )
Upper Respiratory Tract
- part of foregut development
- anatomically the nose, nasal cavity and the pharynx
- the pharynx forms a major arched cavity within the pharyngeal arches
The animations below allow a comparison of early and late embryonic lung development. Compare the size and relative position of the respiratory structures and their anatomical relationship to the developing gastrointestinal tract.
| Early embryo (stage 13)
3 dimensional reconstruction based upon a serial reconstruction from individual Carnegie stage 13 embryo slice images.
| Late embryo (stage 22)
3 dimensional reconstruction based upon a serial reconstruction from individual embryo slice images Carnegie stage 22, 27 mm Human embryo, approximate day 56.
- pulmonary arteries and veins arise by vasculogenesis
- vasculogenesis in the mesenchyme surrounding the terminal buds during the pseudoglandular stage.
- vasculogenesis - describes the formation of new blood vessels from pluripotent precursor cells.
- angiogenesis in the canalicular and alveolar stages.
- angiogenesis - describes the formation of new vessels from pre-existing vessels.
See also review 
- vascularising the walls of the airways and the large pulmonary vessels providing giving oxygen and nutrients.
- extend within the bronchial tree to the periphery of the alveolar ducts.
- not found in the lungs until around 8 weeks of gestation.
- one or two small vessels extend from the dorsal aorta and run into the lung alongside the cartilage plates of the main bronchus.
- small bronchial veins within the airway wall drain into the pulmonary veins.
- large bronchial veins seen close to the hilum and drain into the cardinal veins and the right atrium.
See review 
- Opposing Fgf and Bmp activities regulate the specification of olfactory sensory and respiratory epithelial cell fates " In this study, we provide evidence that in both chick and mouse, Bmp signals promote respiratory epithelial character, whereas Fgf signals are required for the generation of sensory epithelial cells. Moreover, olfactory placodal cells can switch between sensory and respiratory epithelial cell fates in response to Fgf and Bmp activity, respectively. Our results provide evidence that Fgf activity suppresses and restricts the ability of Bmp signals to induce respiratory cell fate in the nasal epithelium."
- Heparan sulfate in lung morphogenesis "Heparan sulfate (HS) is a structurally complex polysaccharide located on the cell surface and in the extracellular matrix, where it participates in numerous biological processes through interactions with a vast number of regulatory proteins such as growth factors and morphogens. ...he potential contribution of HS to abnormalities of lung development has yet to be explored to any significant extent, which is somewhat surprising given the abnormal lung phenotype exhibited by mutant mice synthesizing abnormal HS."
- Signaling via Alk5 controls the ontogeny of lung Clara cells "Clara cells, together with ciliated and pulmonary neuroendocrine cells, make up the epithelium of the bronchioles along the conducting airways. Clara cells are also known as progenitor or stem cells during lung regeneration after injury. ...Using lung epithelial cells, we show that Alk5-regulated Hes1 expression is stimulated through Pten and the MEK/ERK and PI3K/AKT pathways. Thus, the signaling pathway by which TGFbeta/ALK5 regulates Clara cell differentiation may entail inhibition of Pten expression, which in turn activates ERK and AKT phosphorylation."
- Wt1 and retinoic acid signaling in the subcoelomic mesenchyme control the development of the pleuropericardial membranes and the sinus horns "Pericardium and sinus horn formation are coupled and depend on the expansion and correct temporal release of pleuropericardial membranes from the underlying subcoelomic mesenchyme. Wt1 and downstream Raldh2/retinoic acid signaling are crucial regulators of this process."
- ↑ Tatsuya Yoshimi, Fumiko Hashimoto, Shigeru Takahashi, Yuji Takahashi Suppression of embryonic lung branching morphogenesis by antisense oligonucleotides against HOM/C homeobox factors. In Vitro Cell. Dev. Biol. Anim.: 2010, 46(8);664-72 PMID:20535580
- ↑ Felicia Chen, Yuxia Cao, Jun Qian, Fengzhi Shao, Karen Niederreither, Wellington V Cardoso A retinoic acid-dependent network in the foregut controls formation of the mouse lung primordium. J. Clin. Invest.: 2010, 120(6);2040-8 PMID:20484817
- ↑ Joseph Fawke, Sooky Lum, Jane Kirkby, Enid Hennessy, Neil Marlow, Victoria Rowell, Sue Thomas, Janet Stocks Lung function and respiratory symptoms at 11 years in children born extremely preterm: the EPICure study. Am. J. Respir. Crit. Care Med.: 2010, 182(2);237-45 PMID:20378729
- ↑ M Solomon, H Grasemann, S Keshavjee Pediatric lung transplantation. Pediatr. Clin. North Am.: 2010, 57(2);375-91, table of contents PMID:20371042
- ↑ Hongwei Yu, Andy Wessels, Jianliang Chen, Aimee L Phelps, John Oatis, G Stephen Tint, Shailendra B Patel Late gestational lung hypoplasia in a mouse model of the Smith-Lemli-Opitz syndrome. BMC Dev. Biol.: 2004, 4();1 PMID:15005800 | BMC Developmental Biology
- ↑ Kaarteenaho R, Lappi-Blanco E, Lehtonen S. Epithelial N-cadherin and nuclear β-catenin are up-regulated during early development of human lung. BMC Dev Biol. 2010 Nov 16;10:113. PMID: 21080917 | PMC2995473 | BMC Dev Biol.
- ↑ K E Pinkerton, J P Joad The mammalian respiratory system and critical windows of exposure for children's health. Environ. Health Perspect.: 2000, 108 Suppl 3();457-62 PMID:10852845 | PMC1637815 | Environ Health Perspect.
- ↑ Pierre M Barker, Richard E Olver Invited review: Clearance of lung liquid during the perinatal period. J. Appl. Physiol.: 2002, 93(4);1542-8 PMID:12235057
- ↑ Susan M Hall, Alison A Hislop, Sheila G Haworth Origin, differentiation, and maturation of human pulmonary veins. Am. J. Respir. Cell Mol. Biol.: 2002, 26(3);333-40 PMID:11867341
- ↑ 10.0 10.1 Alison A Hislop Airway and blood vessel interaction during lung development. J. Anat.: 2002, 201(4);325-34 PMID:12430957
- ↑ 11.0 11.1 Cardoso WV, Kotton DN. Specification and patterning of the respiratory system. StemBook [Internet]. Cambridge (MA): Harvard Stem Cell Institute; 2008 Jul 16. PMID20614584 | StemBook - Specification and patterning of the respiratory system
- ↑ Esther Maier, Jonas von Hofsten, Hanna Nord, Marie Fernandes, Hunki Paek, Jean M Hébert, Lena Gunhaga Opposing Fgf and Bmp activities regulate the specification of olfactory sensory and respiratory epithelial cell fates. Development: 2010, 137(10);1601-11 PMID:20392740
- ↑ Sophie M Thompson, Edwin C Jesudason, Jeremy E Turnbull, David G Fernig Heparan sulfate in lung morphogenesis: The elephant in the room. Birth Defects Res. C Embryo Today: 2010, 90(1);32-44 PMID:20301217
- ↑ Yiming Xing, Changgong Li, Aimin Li, Somyoth Sridurongrit, Caterina Tiozzo, Saverio Bellusci, Zea Borok, Vesa Kaartinen, Parviz Minoo Signaling via Alk5 controls the ontogeny of lung Clara cells. Development: 2010, 137(5);825-33 PMID:20147383
- ↑ Julia Norden, Thomas Grieskamp, Ekkehart Lausch, Bram van Wijk, Maurice J B van den Hoff, Christoph Englert, Marianne Petry, Mathilda T M Mommersteeg, Vincent M Christoffels, Karen Niederreither, Andreas Kispert Wt1 and retinoic acid signaling in the subcoelomic mesenchyme control the development of the pleuropericardial membranes and the sinus horns. Circ. Res.: 2010, 106(7);1212-20 PMID:20185795
David Warburton, Ahmed El-Hashash, Gianni Carraro, Caterina Tiozzo, Frederic Sala, Orquidea Rogers, Stijn De Langhe, Paul J Kemp, Daniela Riccardi, John Torday, Saverio Bellusci, Wei Shi, Sharon R Lubkin, Edwin Jesudason Lung organogenesis. Curr. Top. Dev. Biol.: 2010, 90();73-158 PMID:20691848
Edward E Morrisey, Brigid L M Hogan Preparing for the first breath: genetic and cellular mechanisms in lung development. Dev. Cell: 2010, 18(1);8-23 PMID:20152174
Peter H Burri Structural aspects of postnatal lung development - alveolar formation and growth. Biol. Neonate: 2006, 89(4);313-22 PMID:16770071
Mala R Chinoy Lung growth and development. Front. Biosci.: 2003, 8();d392-415 PMID:12456356
P H Burri Fetal and postnatal development of the lung. Annu. Rev. Physiol.: 1984, 46();617-28 PMID:6370120
Sonja I Mund, Marco Stampanoni, Johannes C Schittny Developmental alveolarization of the mouse lung. Dev. Dyn.: 2008, 237(8);2108-16 PMID:18651668
Peter H Burri Structural aspects of postnatal lung development - alveolar formation and growth. Biol. Neonate: 2006, 89(4);313-22 PMID:16770071
Susan M Hall, Alison A Hislop, Sheila G Haworth Origin, differentiation, and maturation of human pulmonary veins. Am. J. Respir. Cell Mol. Biol.: 2002, 26(3);333-40 PMID:11867341
S M Hall, A A Hislop, C M Pierce, S G Haworth Prenatal origins of human intrapulmonary arteries: formation and smooth muscle maturation. Am. J. Respir. Cell Mol. Biol.: 2000, 23(2);194-203 PMID:10919986
M P Sparrow, M Weichselbaum, P B McCray Development of the innervation and airway smooth muscle in human fetal lung. Am. J. Respir. Cell Mol. Biol.: 1999, 20(4);550-60 PMID:10100986
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Cite this page: Hill, M.A. (2013) Respiratory System Development. Retrieved December 5, 2013, from http://embryology.med.unsw.edu.au/embryology/index.php?title=Respiratory_System_Development
- Dr Mark Hill 2013, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G