Respiratory System Development

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Introduction

Respiratory system overview (stage 13)

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. 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.[1] 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).


Respiratory Links: respiratory | Science Lecture | Lecture Movie | Med Lecture | Stage 13 | Stage 22 | upper respiratory tract | diaphragm | Histology | Postnatal | respiratory abnormalities | Respiratory Quiz | Respiratory terms | Category:Respiratory
Historic Embryology  
1902 The Nasal Cavities and Olfactory Structures | 1906 Lung | 1912 Upper Respiratory Tract | 1912 Respiratory | 1914 Phrenic Nerve | 1918 Respiratory images | 1921 Respiratory | 1922 Chick Pulmonary Vessels | 1934 Right Fetal Lung | 1936 Early Human Lung | 1937 Terminal Air Passages | 1938 Human Histology

Some Recent Findings

  • Notch3-Jagged signaling controls the pool of undifferentiated airway progenitors[2] "Basal cells are multipotent airway progenitors that generate distinct epithelial cell phenotypes crucial for homeostasis and repair of the conducting airways. Little is known about how these progenitor cells expand and transition to differentiation to form the pseudostratified airway epithelium in the developing and adult lung. Here, we show by genetic and pharmacological approaches that endogenous activation of Notch3 signaling selectively controls the pool of undifferentiated progenitors of upper airways available for differentiation. This mechanism depends on the availability of Jag1 and Jag2, and is key to generating a population of parabasal cells that later activates Notch1 and Notch2 for secretory-multiciliated cell fate selection." Notch
  • Alveolar progenitor and stem cells in lung development[1] "Alveoli are gas-exchange sacs lined by squamous alveolar type (AT) 1 cells and cuboidal, surfactant-secreting AT2 cells. Classical studies suggested that AT1 arise from AT2 cells, but recent studies propose other sources. Here we use molecular markers, lineage tracing and clonal analysis to map alveolar progenitors throughout the mouse lifespan. We show that, during development, AT1 and AT2 cells arise directly from a bipotent progenitor, whereas after birth new AT1 cells derive from rare, self-renewing, long-lived, mature AT2 cells that produce slowly expanding clonal foci of alveolar renewal."
  • Lung epithelial branching program antagonizes alveolar differentiation[3] "Mammalian organs, including the lung and kidney, often adopt a branched structure to achieve high efficiency and capacity of their physiological functions. Formation of a functional lung requires two developmental processes: branching morphogenesis, which builds a tree-like tubular network, and alveolar differentiation, which generates specialized epithelial cells for gas exchange. ...We thus propose that lung epithelial progenitors continuously balance between branching morphogenesis and alveolar differentiation, and such a balance is mediated by dual-function regulators, including Kras and Sox9. The resulting temporal delay of differentiation by the branching program may provide new insights to lung immaturity in preterm neonates and the increase in organ complexity during evolution."
  • Suppression of embryonic lung branching morphogenesis[4] "The role of HOM/C homeobox genes on rat embryonic lung branching morphogenesis was investigated using the lung bud explant culture system in an air/liquid interface. ...These results suggest a critical role for homeobox b3 and b4 genes in lung airway branching morphogenesis."
  • Retinoic acid-dependent network in the foregut controls formation of the mouse lung primordium[5] "The developmental abnormalities associated with disruption of signaling by retinoic acid (RA), the biologically active form of vitamin A, have been known for decades from studies in animal models and humans. These include defects in the respiratory system, such as lung hypoplasia and agenesis. ....The data in this study suggest that disruption of Wnt/Tgfbeta/Fgf10 interactions represents the molecular basis for the classically reported failure to form lung buds in vitamin A deficiency."

Clinical

  • Lung Function and Respiratory Symptoms at 11 Years in Extremely Preterm Children[6] "Following extremely preterm birth, impaired lung function and increased respiratory morbidity persist into middle childhood, especially those with bronchopulmonary dysplasia (BPD). Many of these children may not be receiving appropriate treatment."
  • Pediatric lung transplantation.[7] "Lung transplantation is an accepted therapy for selected pediatric patients with severe end-stage vascular or parenchymal lung disease. Collaboration between the patients' primary care physicians, the lung transplant team, patients, and patients' families is essential. The challenges of this treatment include the limited availability of suitable donor organs, the toxicity of immunosuppressive medications needed to prevent rejection, the prevention and treatment of obliterative bronchiolitis, and maximizing growth, development, and quality of life of the recipients. This article describes the current status of pediatric lung transplantation, indications for listing, evaluation of recipient and donor, updates on the operative procedure,graft dysfunction, and the risk factors, outcomes, and future directions."
More recent papers
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Search term: Lung Embryology

<pubmed limit=5>Lung Embryology</pubmed>

Textbooks

  • 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 The Respiratory Apparatus

Objectives

  • 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.


Development Overview

Human Embryonic Lung Development
Bailey287.jpg Bailey288.jpg Bailey289.jpg
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

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

Lung alveoli development cartoon.jpg

The sequence is most important rather than the actual timing, which is variable in the existing literature.

Human Lung Stages
Lung Stage Human Features Vascular
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

Embryonic

  • Endoderm - tubular ventral growth from foregut pharynx.
  • Mesoderm - mesenchyme of lung buds.
  • Intraembryonic coelom - pleural cavities elongated spaces connecting pericardial and peritoneal spaces.

Pseudoglandular stage

  • 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.
Human right lung 7-8 weeks.jpg

Human lung pseudoglandular stage[8]

Canalicular 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.

Saccular stage

Alveolar sac structure
  • 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.

Alveolar stage

  • 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).

Respiratory Species Comparison

Mouse lung development[9]
Gestational age (days)
Species Term Embryonic Pseudoglandular Canalicular Saccular
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
Mouse 20 < 9 16 18 19

Table modified from[10]

Mouse

The following images are from a recent study of the development of bronchial branching in he mouse between E10 to E14.[11]

Mesenchyme (red) and epithelium (blue) the study used knockout mice to show the role of Wnt signalling in branching morphogenesis.

Mouse respiratory 36 to 60 somites.jpg

Mouse respiratory 44 to 60 somites.jpg

Links: Wnt | Mouse Development


Embryonic Respiratory Development

Lung development stage13-22.jpg

Pseudoglandular Respiratory Development

Human lung pseudoglandular.jpg

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.[12]


Lung Histology

Fetal lung histology.jpg
Fetal lung histology


Links: Respiratory System - Histology


Birth Changes

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 [13])

Upper Respiratory Tract

Adult upper respiratory tract conducting system
  • part of foregut development
  • anatomically the nose, nasal cavity and the pharynx
  • the pharynx forms a major arched cavity within the pharyngeal arches

Movies

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.

Stage13-GIT-icon.jpg
 ‎‎GIT Stage 13
Page | Play
Early embryo (stage 13)

3 dimensional reconstruction based upon a serial reconstruction from individual Carnegie stage 13 embryo slice images.

Stage22-GIT-icon.jpg
 ‎‎GIT Stage 22
Page | Play
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.

Lung Cardiovascular

Links: Cardiovascular System Development

Pulmonary Circulation

  • pulmonary arteries and veins arise by vasculogenesis[14]

Pulmonary Veins

  • 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 [15]

Bronchial Circulation

Bronchial Arteries

  • 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.

Bronchial Veins

  • 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 [15]

Molecular

Mouse respiratory Tbx4 and Tbx5 model[16]
Mouse respiratory development[17]
Fibroblast growth factor signaling[17]
  • Nkx2-1 (Titf1) - ventral wall of the anterior foregut, identifies the future trachea.
  • Localized Fgf10 expression not required for lung branching but prevents epithelial differentiation[18] "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[19] " 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[20] "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[21] "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[22] "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."


Links: Sox | StemBook - Specification and patterning of the respiratory system

References

  1. 1.0 1.1 <pubmed>24499815</pubmed>
  2. <pubmed>25564622</pubmed>
  3. <pubmed>24058167</pubmed>
  4. <pubmed>20535580</pubmed>
  5. <pubmed>20484817</pubmed>
  6. <pubmed>20378729</pubmed>
  7. <pubmed>20371042</pubmed>
  8. <pubmed>24693478</pubmed>| Anat Cell Biol.
  9. <pubmed>15005800</pubmed>| BMC Developmental Biology
  10. <pubmed>10852845</pubmed>| PMC1637815 | Environ Health Perspect.
  11. <pubmed>25114215</pubmed>PMC4151720 | Proc Natl Acad Sci U S A.
  12. 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.
  13. <pubmed>12235057</pubmed>
  14. <pubmed>11867341</pubmed>
  15. 15.0 15.1 <pubmed>12430957</pubmed>
  16. <pubmed>22876201</pubmed>| PLoS Genet.
  17. 17.0 17.1 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 Cite error: Invalid <ref> tag; name "PMID20614584" defined multiple times with different content
  18. <pubmed>23924632</pubmed>
  19. <pubmed>20392740</pubmed>
  20. <pubmed> 20301217</pubmed>
  21. <pubmed> 20147383</pubmed>
  22. <pubmed> 20185795</pubmed>


Reviews

<pubmed>20691848</pubmed> <pubmed>20152174</pubmed> <pubmed>16770071</pubmed> <pubmed>12456356</pubmed> <pubmed>6370120</pubmed>

Articles

<pubmed></pubmed> <pubmed></pubmed> <pubmed></pubmed> <pubmed>18651668</pubmed> <pubmed>16770071</pubmed> <pubmed>11867341</pubmed> <pubmed>10919986</pubmed> <pubmed>10100986</pubmed>

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Additional Images

Upper Respiratory Tract

Lower Respiratory Tract

Diaphragm

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Cite this page: Hill, M.A. (2020, March 30) Embryology Respiratory System Development. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Respiratory_System_Development

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© Dr Mark Hill 2020, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G