Respiratory System Development
|Embryology - 28 Feb 2020 Expand to Translate|
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- 1 Introduction
- 2 Some Recent Findings
- 3 Textbooks
- 4 Objectives
- 5 Development Overview
- 6 Lung Development Stages
- 7 Respiratory Species Comparison
- 8 Embryonic Respiratory Development
- 9 Pseudoglandular Respiratory Development
- 10 Endocrine Lung
- 11 Lung Histology
- 12 Upper Respiratory Tract
- 13 Movies
- 14 Lung Cardiovascular
- 15 Molecular
- 16 References
- 17 Terms
- 18 Additional Images
- 19 External Links
- 20 Glossary Links
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:
- upper respiratory tract, consisting of the nose, nasal cavity and the pharynx
- 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. The two main respiratory cell types, squamous alveolar type 1 and alveolar type 2 (surfactant secreting), both arise from the same bi-potetial progenitor cell. The third main cell type are macrophages (dust cells) that arise from blood monocyte cells.
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).
Some Recent Findings
|More recent papers|
This table allows an automated computer search of the external PubMed database using the listed "Search term" text link.
Search term: Lung Embryology
<pubmed limit=5>Lung Embryology</pubmed>
- Moore, K.L., Persaud, T.V.N. & Torchia, M.G. (2015). The developing human: clinically oriented embryology (10th ed.). Philadelphia: Saunders. Chapter 10 Respiratory System
- Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R., Francis-West, P.H. & Philippa H. (2015). Larsen's human embryology (5th ed.). New York; Edinburgh: Churchill Livingstone. Chapter 11 Development of the Respiratory System and Body Cavities
- 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 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.
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
The sequence is most important rather than the actual timing, which is variable in the existing literature.
|Embryonic||week 4 to 5||lung buds originate as an outgrowth from the ventral wall of the foregut where lobar division occurs||extra pulmonary artery then lobular artery|
|Pseudoglandular||week 5 to 17||conducting epithelial tubes surrounded by thick mesenchyme are formed, extensive airway branching||Pre-acinar arteries|
|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||Intra-acinar arteries|
|Saccular||week 24 to 40||alveolar ducts and air sacs are developed||alveolar duct arteries|
|Alveolar||late fetal to 8 years||secondary septation occurs, marked increase of the number and size of capillaries and alveoli||alveolar capillaries|
|embryonic stage - pseudoglandular stage - canalicular stage - saccular stage - alveolar stage Links: Species Stage Comparison | respiratory|
|Human Embryonic Lung Development|
|CRL 4.3 mm, Week 4-5, Stage 12 to 13||CRL 8.5 mm, Week 5, Stage 15 to 16||CRL 10.5 mm, Week 6 Stage 16 to 17|
- Endoderm - tubular ventral growth from foregut pharynx.
- Mesoderm - mesenchyme of lung buds.
- Intraembryonic coelom - pleural cavities elongated spaces connecting pericardial and peritoneal spaces.
Human lung pseudoglandular stage
- 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.
Alveolar sac structure
Premature babies have difficulties associated with insufficient surfactant (end month 6 alveolar cells type 2 appear and begin to secrete surfactant).
Respiratory secondary septum
Respiratory Species Comparison
|Respiratory Stages - Species Comparison - Stages 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|
|Data modified from|
Note that the model mouse respiratory system differs from human in size, distribution of cell types, and the time taken to develop.
Human and mouse Sox expression
The following images are from a recent study of the development of bronchial branching in he mouse between E10 to E14.
Mesenchyme (red) and epithelium (blue) the study used knockout mice to show the role of Wnt signalling in branching morphogenesis.
|Mouse lung E12.5 to E18.5|
|E12.5 lungs||E14.5 lungs||E14.5 Sox9||E18.5 lungs|
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.
|Neonatal Human||Fetal Rabbit|
|Pulmonary neuroendocrine cell (EM)||Neuroepithelial body|
Pulmonary neuroendocrine cells (PNECs)
- develop in late embryonic to early fetal period.
- later in mid-fetal period clusters of these cells form neuroepithelial bodies (NEBs).
- first cell type to differentiate in the airway epithelium.
- differentiation regulated by proneural genes - mammalian homolog of the achaete-scute complex (Mash-1) and hairy and enhancer of split1 (Hes-1).
- located in the fetal lung at bronchiole branching points.
- may stimulate mitosis to increase branching.
- secrete 2 peptides - gastrin-releasing peptide (GRP) and calcitonin gene related peptide (CGRP)
|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 
|Factor Links: AMH | hCG | BMP | sonic hedgehog | bHLH | HOX | FGF | FOX | Hippo | LIM | Nanog | NGF | Nodal | Notch | PAX | retinoic acid | SIX | Slit2/Robo1 | SOX | TBX | TGF-beta | VEGF | WNT | Category:Molecular|
|Mouse respiratory Tbx4 and Tbx5 model||Mouse respiratory development]]|
- Nkx2-1 (Titf1) - ventral wall of the anterior foregut, identifies the future trachea.
- Sox2 is essential for the initiation of lung development from the endodermal gut tube,
- Sox9 is essential for maintaining the tips and associated branching.
Several different Sox types are required for different stages of respiratory development. Wnt/β-catenin signaling does not regulate Sox9 expression in the lung.
Human and mouse Sox expression
- Localized Fgf10 expression not required for lung branching but prevents epithelial differentiation "As the lung buds grow out, proximal epithelial cells become further and further displaced from the distal source of Fgf10 and differentiate into bronchial epithelial cells. Interestingly, our data presented here show that once epithelial cells are committed to the Sox2-positive airway epithelial cell fate, Fgf10 prevents ciliated cell differentiation and promotes basal cell differentiation."
- 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."
Bone morphogenic protein 4 (Bmp4) acts as in an autocrine signalling mechanism to limit bud outgrowth and is therefore involved in branching.
- 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."
- <pubmed>26119728</pubmed>| Cell Rep.
- <pubmed>24693478</pubmed>| Anat Cell Biol.
- <pubmed>25973420</pubmed>| Front Med (Lausanne).]]
- <pubmed>15005800</pubmed>| BMC Developmental Biology
- Pinkerton KE & Joad JP. (2000). The mammalian respiratory system and critical windows of exposure for children's health. Environ. Health Perspect. , 108 Suppl 3, 457-62. PMID: 10852845
- <pubmed>25114215</pubmed>PMC4151720 | Proc Natl Acad Sci U S A.
- 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.
- <pubmed>22876201</pubmed>| PLoS Genet.
- 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
- <pubmed> 20301217</pubmed>
- <pubmed> 20147383</pubmed>
- <pubmed> 20185795</pubmed>
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Upper Respiratory Tract
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Cite this page: Hill, M.A. (2020, February 28) Embryology Respiratory System Development. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Respiratory_System_Development
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