Respiratory System Development
|Embryology - 29 May 2017 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 Additional Images
- 18 External Links
- 19 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 shows an automated computer PubMed search using the listed sub-heading term.
References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability.
Wei Li, Xin Li, Shuhao Liu, Wende Yang, Fan Pan, Xiao-Yan Yang, Bin Du, Li Qin, Yunlong Pan Gold nanoparticles attenuate metastasis by tumor vasculature normalization and epithelial-mesenchymal transition inhibition. Int J Nanomedicine: 2017, 12;3509-3520 PubMed 28496326
Guangxin Zhong, Lu Chen, Ruihong Yin, Yan Qu, Yongxing Bao, Qiong Xiao, Zhaolin Zhang, Yaqian Shen, Cailing Li, Yun Xu, Zhigeng Zou, Hua Tian Chemokine (C‑C motif) ligand 21/C‑C chemokine receptor type 7 triggers migration and invasion of human lung cancer cells by epithelial‑mesenchymal transition via the extracellular signal‑regulated kinase signaling pathway. Mol Med Rep: 2017; PubMed 28487957
Tolga Acun, Natalie Doberstein, Jens K Habermann, Timo Gemoll, Christoph Thorns, Emin Oztas, Thomas Ried HLJ1 (DNAJB4) Gene Is a Novel Biomarker Candidate in Breast Cancer. OMICS: 2017, 21(5);257-265 PubMed 28481734
Fahim Haque, Yusuke Kaku, Sayoko Fujimura, Tomoko Ohmori, Robert S Adelstein, Ryuichi Nishinakamura Non-muscle Myosin II Deletion in the Developing Kidney Causes Ureter-bladder Misconnection and Apical Extrusion of the Nephric Duct Lineage Epithelia. Dev. Biol.: 2017; PubMed 28478097
Radoslaw Charkiewicz, Jacek Niklinski, Jürgen Claesen, Anetta Sulewska, Miroslaw Kozlowski, Anna Michalska-Falkowska, Joanna Reszec, Marcin Moniuszko, Wojciech Naumnik, Wieslawa Niklinska Gene Expression Signature Differentiates Histology But Not Progression Status of Early-Stage NSCLC. Transl Oncol: 2017, 10(3);450-458 PubMed 28456114
- 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.
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|
|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
|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
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.
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 
- 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 "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."
- 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."
- Tushar J Desai, Douglas G Brownfield, Mark A Krasnow Alveolar progenitor and stem cells in lung development, renewal and cancer. Nature: 2014, 507(7491);190-4 PubMed 24499815
- Julie K Watson, Steffen Rulands, Adam C Wilkinson, Aline Wuidart, Marielle Ousset, Alexandra Van Keymeulen, Berthold Göttgens, Cédric Blanpain, Benjamin D Simons, Emma L Rawlins Clonal Dynamics Reveal Two Distinct Populations of Basal Cells in Slow-Turnover Airway Epithelium. Cell Rep: 2015, 12(1);90-101 PubMed 26119728 | Cell Rep.
- Jun Yang, Belinda J Hernandez, Denise Martinez Alanis, Odemaris Narvaez, Lisandra Vila-Ellis, Haruhiko Akiyama, Scott E Evans, Edwin J Ostrin, Jichao Chen Development and plasticity of alveolar type 1 cells. Development: 2015; PubMed 26586225
- Munemasa Mori, John E Mahoney, Maria R Stupnikov, Jesus R Paez-Cortez, Aleksander D Szymaniak, Xaralabos Varelas, Dan B Herrick, James Schwob, Hong Zhang, Wellington V Cardoso Notch3-Jagged signaling controls the pool of undifferentiated airway progenitors. Development: 2015, 142(2);258-67 PubMed 25564622
- Daniel R Chang, Denise Martinez Alanis, Rachel K Miller, Hong Ji, Haruhiko Akiyama, Pierre D McCrea, Jichao Chen Lung epithelial branching program antagonizes alveolar differentiation. Proc. Natl. Acad. Sci. U.S.A.: 2013, 110(45);18042-51 PubMed 24058167
- 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 PubMed 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 PubMed 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 PubMed 20378729
- M Solomon, H Grasemann, S Keshavjee Pediatric lung transplantation. Pediatr. Clin. North Am.: 2010, 57(2);375-91, table of contents PubMed 20371042
- Shinichi Abe, Masahito Yamamoto, Taku Noguchi, Toshihito Yoshimoto, Hideaki Kinoshita, Satoru Matsunaga, Gen Murakami, Jose Francisco Rodríguez-Vázquez Fetal development of the minor lung segment. Anat Cell Biol: 2014, 47(1);12-7 PubMed 24693478 | Anat Cell Biol.
- Cho-Ming Chao, Elie El Agha, Caterina Tiozzo, Parviz Minoo, Saverio Bellusci A breath of fresh air on the mesenchyme: impact of impaired mesenchymal development on the pathogenesis of bronchopulmonary dysplasia. Front Med (Lausanne): 2015, 2;27 PubMed 25973420 | Front Med (Lausanne).]]
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- 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 PubMed 20147383
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