Respiratory System Development

From Embryology

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.

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

  • Suppression of embryonic lung branching morphogenesis[1] "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[2] "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[3] "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.[4] "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."

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 1. 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

Historic drawings of embryonic lung development

Bailey287.jpg Bailey288.jpg Bailey289.jpg
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

Lung alveoli development cartoon.jpg
Mouse lung development[5]

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

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.

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).

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.[6]

Species Development of Fetal Lungs

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[7]

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 [8])

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[9]

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 [10]

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 [10]

Molecular

Mouse respiratory development[11]
Fibroblast growth factor signaling[11]
  • Opposing Fgf and Bmp activities regulate the specification of olfactory sensory and respiratory epithelial cell fates[12] " 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[13] "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[14] "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[15] "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. <pubmed>20535580</pubmed>
  2. <pubmed>20484817</pubmed>
  3. <pubmed>20378729</pubmed>
  4. <pubmed>20371042</pubmed>
  5. <pubmed>15005800</pubmed>| BMC Developmental Biology
  6. 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.
  7. <pubmed>10852845</pubmed>| PMC1637815 | Environ Health Perspect.
  8. <pubmed>12235057</pubmed>
  9. <pubmed>11867341</pubmed>
  10. 10.0 10.1 <pubmed>12430957</pubmed>
  11. 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
  12. <pubmed>20392740</pubmed>
  13. <pubmed> 20301217</pubmed>
  14. <pubmed> 20147383</pubmed>
  15. <pubmed> 20185795</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 29) 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