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. Branching is a key mechanism/process in lung development leading to alveolar saccules after about 23 branching generations (range of 18–30).


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: Introduction | Science Lecture | Lecture Movie | Med Lecture | Stage 13 | Stage 22 | Upper Respiratory Tract | Diaphragm | Histology | Postnatal | 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
Respiratory epithelium cell development.[2]

Some Recent Findings

  • Development and plasticity of alveolar type 1 cells[3] "Alveolar type 1 (AT1) cells cover >95% of the gas exchange surface and are extremely thin to facilitate passive gas diffusion. The development of these highly specialized cells and its coordination with the formation of the honeycomb-like alveolar structure are poorly understood. Using new marker-based stereology and single-cell imaging methods, we show that AT1 cells in the mouse lung form expansive thin cellular extensions via a non-proliferative two-step process while retaining cellular plasticity. In the flattening step, AT1 cells undergo molecular specification and remodel cell junctions while remaining connected to their epithelial neighbors. In the folding step, AT1 cells increase in size by more than 10-fold and undergo cellular morphogenesis that matches capillary and secondary septa formation, resulting in a single AT1 cell spanning multiple alveoli. Furthermore, AT1 cells are an unexpected source of VEGFA and their normal development is required for alveolar angiogenesis. Notably, a majority of AT1 cells proliferate upon ectopic SOX2 expression and undergo stage-dependent cell fate reprogramming."
  • Clonal Dynamics Reveal Two Distinct Populations of Basal Cells in Slow-Turnover Airway Epithelium[2] "We investigated the mouse tracheal epithelial lineage at homeostasis by using long-term clonal analysis and mathematical modeling. This pseudostratified epithelium contains basal cells and secretory and multiciliated luminal cells. Our analysis revealed that basal cells are heterogeneous, comprising approximately equal numbers of multipotent stem cells and committed precursors, which persist in the basal layer for 11 days before differentiating to luminal fate. We confirmed the molecular and functional differences within the basal population by using single-cell qRT-PCR and further lineage labeling. Additionally, we show that self-renewal of short-lived secretory cells is a feature of homeostasis. We have thus revealed early luminal commitment of cells that are morphologically indistinguishable from stem cells."
  • Notch3-Jagged signaling controls the pool of undifferentiated airway progenitors[4] "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."
More recent papers  
Mark Hill.jpg
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This table shows an automated computer PubMed search using the listed sub-heading term.

  • Therefore the list of references do not reflect any editorial selection of material based on content or relevance.
  • References appear in this list based upon the date of the actual page viewing.

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.

Links: References | Discussion Page | Pubmed Most Recent | Journal Searches


Search term: Lung Embryology

María Carmen Leiva, Raúl Ortiz, Rafael Contreras-Cáceres, Gloria Perazzoli, Iryna Mayevych, Juan Manuel López-Romero, Francisco Sarabia, Jose Manuel Baeyens, Consolación Melguizo, Jose Prados Tripalmitin nanoparticle formulations significantly enhance paclitaxel antitumor activity against breast and lung cancer cells in vitro. Sci Rep: 2017, 7(1);13506 PubMed 29044153

Lei Zhang, Xia Wang, Ruixue Wang, Xuelian Zheng, Na Li, Huannan Li, Xiaoren Cao, Bin Zhou, Yong Lin, Lan Yang Baicalin potentiates TRAIL‑induced apoptosis through p38 MAPK activation and intracellular reactive oxygen species production. Mol Med Rep: 2017; PubMed 28983599

Lucio Cagini, Stefania Balloni, Vienna Ludovini, Marco Andolfi, Alberto Matricardi, Rossella Potenza, Jacopo Vannucci, Annamaria Siggillino, Francesca Romana Tofanetti, Guido Bellezza, Maria Bodo, Francesco Puma, Lorella Marinucci Variations in gene expression of lung macromolecules after induction chemotherapy for lung cancer. Eur J Cardiothorac Surg: 2017; PubMed 28977471

Leonel Armas-López, Joaquín Zúñiga, Oscar Arrieta, Federico Ávila-Moreno The Hedgehog-GLI pathway in embryonic development and cancer: implications for pulmonary oncology therapy. Oncotarget: 2017, 8(36);60684-60703 PubMed 28948003

Rokhsana Rasooli, Fatemeh Pourgholamhosein, Younes Kamali, Fatemeh Nabipour, Ali Mandegary Combination Therapy with Pirfenidone plus Prednisolone Ameliorates Paraquat-Induced Pulmonary Fibrosis. Inflammation: 2017; PubMed 28921394


Older papers  
  • Lung epithelial branching program antagonizes alveolar differentiation[5] "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[6] "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[7] "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[8] "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.[9] "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

  • 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

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

Bailey287.jpg

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.

Mechanisms

  • Initiation - Budding of foregut endoderm to generate the trachea.
  • Branching - A repeated mechanism of branching that is ongoing throughout development to form the conducting bronchioles then alveolar ducts.
  • Surface area increase - Expansion of the surface area in late development generating eventually the thin air–blood barrier for gas exchange in the acini.
  • Vascular development - Extension of a vascular capillary tree within the connective tissue and wall of the acini for gas exchange, and the lymphatic development for immunology of the lungs.
  • Surfactant development - allows lung inflation and decreases the work of breathing and also related to immunology of the lungs.
  • Musculoskeletal development - contributes the mechanical elements of ribs, intercostals and diaphragm required for breathing.

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

Stage Human Features
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
         

Embryonic

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
  • 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

respiratory histology week 8
Respiratory histology (week 8)
  • 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[10]

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

  • 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-sac-01.jpg

Alveolar sac structure

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 secondary septum

Respiratory secondary septum[11]

Respiratory Species Comparison

Mouse lung development
Mouse lung development[12]
Stages - 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
Links: Respiratory Development | Mouse | Rat | Rabbit

(Table modified from PMID 10852845[13])

Respiratory Species Comparison  
Stages - 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
Links: Respiratory Development | Mouse | Rat | Rabbit

(Table modified from PMID 10852845[13])

Mouse

Note that the model mouse respiratory system differs from human in size, distribution of cell types, and the time taken to develop.

Lung human and mouse Sox expression.jpg

Human and mouse Sox expression[14]

The following images are from a recent study of the development of bronchial branching in he mouse between E10 to E14.[15]

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

Mouse lung E12.5 to E18.5
Mouse whole lung E12.5.jpg Mouse whole lung E14.5.jpg Mouse lung E14.5 Sox9.jpg Mouse lung histology E18.5.jpg
E12.5 lungs E14.5 lungs E14.5 Sox9 E18.5 lungs
Reference[16]
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.[17]

Endocrine Lung

Neonatal Human Fetal Rabbit
Neonatal human pulmonary neuroendocrine cell EM01.jpg Fetal rabbit neuroepithelial body 01.jpg
Pulmonary neuroendocrine cell (EM)[18] Neuroepithelial body[18]

Pulmonary neuroendocrine cells (PNECs)

  • develop in late embryonic to early fetal period.[19][20]
  • 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).[21]
  • 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)


Links: Endocrine - Other Tissues | OMIM - GRP | OMIM - CGRP

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 [22])

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[23]

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 [24]

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 [24]

Molecular

Factor Links: hCG | BMP | Sonic hedgehog | HOX | FGF | Nanog | Nodal | Notch | FOX | PAX | Retinoic acid | SIX | Slit2/Robo1 | Sox | TBX | TGF-beta | VEGF | WNT | Hippo | NGF | Category:Molecular

TBX

Mouse respiratory Tbx4 and Tbx5.jpg Mouse- respiratory development 01.jpg
Mouse respiratory Tbx4 and Tbx5 model[25] Mouse respiratory development[26]]]
  • Nkx2-1 (Titf1) - ventral wall of the anterior foregut, identifies the future trachea.

SOX

  • 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.[16]

Lung human and mouse Sox expression.jpg

Human and mouse Sox expression[14]

FGF

Fibroblast growth factor signaling[26]
  • Localized Fgf10 expression not required for lung branching but prevents epithelial differentiation[27] "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[28] " 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."

BMP

Bone morphogenic protein 4 (Bmp4) acts as in an autocrine signalling mechanism to limit bud outgrowth and is therefore involved in branching.


Other

  • Heparan sulfate in lung morphogenesis[29] "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[30] "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[31] "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 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
  2. 2.0 2.1 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.
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
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  9. M Solomon, H Grasemann, S Keshavjee Pediatric lung transplantation. Pediatr. Clin. North Am.: 2010, 57(2);375-91, table of contents PubMed 20371042
  10. 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.
  11. 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).]]
  12. 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 PubMed 15005800 | BMC Developmental Biology
  13. 13.0 13.1 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 PubMed 10852845 | PMC1637815 | Environ Health Perspect.
  14. 14.0 14.1 Avinash Waghray, Jayaraj Rajagopal Tips from the embryonic lung. Elife: 2017, 6; PubMed 28806170
  15. Rachel S Kadzik, Ethan David Cohen, Michael P Morley, Kathleen M Stewart, Min Min Lu, Edward E Morrisey Wnt ligand/Frizzled 2 receptor signaling regulates tube shape and branch-point formation in the lung through control of epithelial cell shape. Proc. Natl. Acad. Sci. U.S.A.: 2014, 111(34);12444-9 PubMed 25114215 PMC4151720 | Proc Natl Acad Sci U S A.
  16. 16.0 16.1 Briana E Rockich, Steven M Hrycaj, Hung Ping Shih, Melinda S Nagy, Michael A H Ferguson, Janel L Kopp, Maike Sander, Deneen M Wellik, Jason R Spence Sox9 plays multiple roles in the lung epithelium during branching morphogenesis. Proc. Natl. Acad. Sci. U.S.A.: 2013, 110(47);E4456-64 PubMed 24191021
  17. 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.
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  19. E Cutz Neuroendocrine cells of the lung. An overview of morphologic characteristics and development. Exp. Lung Res.: 1982, 3(3-4);185-208 PubMed 6188605
  20. E Cutz, J E Gillan, A C Bryan Neuroendocrine cells in the developing human lung: morphologic and functional considerations. Pediatr. Pulmonol.: 1985, 1(3 Suppl);S21-9 PubMed 3906540
  21. Suzanne McGovern, Jie Pan, Guillermo Oliver, Ernest Cutz, Herman Yeger The role of hypoxia and neurogenic genes (Mash-1 and Prox-1) in the developmental programming and maturation of pulmonary neuroendocrine cells in fetal mouse lung. Lab. Invest.: 2010, 90(2);180-95 PubMed 20027181
  22. Pierre M Barker, Richard E Olver Invited review: Clearance of lung liquid during the perinatal period. J. Appl. Physiol.: 2002, 93(4);1542-8 PubMed 12235057
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  24. 24.0 24.1 Alison A Hislop Airway and blood vessel interaction during lung development. J. Anat.: 2002, 201(4);325-34 PubMed 12430957
  25. Ripla Arora, Ross J Metzger, Virginia E Papaioannou Multiple roles and interactions of Tbx4 and Tbx5 in development of the respiratory system. PLoS Genet.: 2012, 8(8);e1002866 PubMed 22876201 | PLoS Genet.
  26. 26.0 26.1 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
  27. Thomas Volckaert, Alice Campbell, Erik Dill, Changgong Li, Parviz Minoo, Stijn De Langhe Localized Fgf10 expression is not required for lung branching morphogenesis but prevents differentiation of epithelial progenitors. Development: 2013, 140(18);3731-42 PubMed 23924632
  28. 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 PubMed 20392740
  29. 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 PubMed 20301217
  30. 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
  31. 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 PubMed 20185795

Reviews

Johannes C Schittny Development of the lung. Cell Tissue Res.: 2017, 367(3);427-444 PubMed 28144783

Michael Herriges, Edward E Morrisey Lung development: orchestrating the generation and regeneration of a complex organ. Development: 2014, 141(3);502-13 PubMed 24449833

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 PubMed 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 PubMed 20152174

Peter H Burri Structural aspects of postnatal lung development - alveolar formation and growth. Biol. Neonate: 2006, 89(4);313-22 PubMed 16770071

Mala R Chinoy Lung growth and development. Front. Biosci.: 2003, 8;d392-415 PubMed 12456356

P H Burri Fetal and postnatal development of the lung. Annu. Rev. Physiol.: 1984, 46;617-28 PubMed 6370120


Articles

Sonja I Mund, Marco Stampanoni, Johannes C Schittny Developmental alveolarization of the mouse lung. Dev. Dyn.: 2008, 237(8);2108-16 PubMed 18651668

Peter H Burri Structural aspects of postnatal lung development - alveolar formation and growth. Biol. Neonate: 2006, 89(4);313-22 PubMed 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 PubMed 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 PubMed 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 PubMed 10100986


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Terms

Respiratory Terms (expand to view) 
  • adenovirus - A Class I virus containing a single double-stranded DNA (dsDNA), which can cause infections in the upper respiratory tract in many animals. (More? Abnormal Development - Viral Infection)
  • alveolar duct - Anatomical short region lying between the end of the respiratory bronchioles and the final alveolar sacs. Term is also used in the mammary gland, to describe the smallest of the intralobular ducts into which the secretory alveoli open.
  • alveolar sac - alveolus, Latin alveolus = little cavity) Anatomical and functional end of the mammalian lung respiratory tree where gas exchange occurs. In humans, during lung development these are the last features to form from 7 months onwards.
  • alveolar - Term used in relation to the alveoli of the lungs. The final functional sac of the respiratory tree where gas exchange occurs between the alveolar space and the pulmonary capillaries.
  • alveolar stage - Term used to describe lung development, the final histological/developmental stage (Pseudoglandular, Fetal Canalicular, Terminal sac, Alveolar). This stage occurs from late fetal/neonate with alveoli formation, the final functional sac of the respiratory tree exists, where gas exchange occurs between the alveolar space and the pulmonary capillaries. (Lung stages: embryonic stage - pseudoglandular stage - canalicular stage - terminal sac stage - alveolar stage)
  • alveolus - (alveolar sacs, plural alveoli, Latin alveolus = little cavity) Anatomical and functional end of the mammalian lung respiratory tree where gas exchange occurs. In humans, during lung development these are the last features to form from 7 months onwards.
  • apgar - Non-invasive clinical test designed by Dr Virginia Apgar (1953) carried out immediately on newborn. The name is also an acronym for: Activity (Muscle Tone), Pulse, Grimace (Reflex Irritability), Appearance (Skin Color), Respiration. A score is given for each sign at one minute and five minutes after the birth. (More? Apgar test)
  • apnea - Respiratory term meaning the cessation of breathing.
  • assisted ventilation - Clinical term referring to newborn (perinatal) respiration assistance required immediately following delivery, the infant given minimal breaths for any duration with bag and mask or bag and endotracheal tube within the first several minutes from birth. Excludes free flow oxygen only and laryngoscopy for aspiration of meconium.
  • asthma - Flow limitation during tidal expiration in early life significantly associated with the development of physician-diagnosed asthma by the age of 2 years. Infants with abnormal lung function soon after birth may have a genetic predisposition to asthma or other airway abnormalities that predict the risk of subsequent lower respiratory tract illness. PMID 8176553
  • azygos lobe - Common condition (0.5% of population). The right lung upper lobe expands either side of the posterior cardinal. There is also some course variability of the phrenic nerve in the presence of an azygos lobe.
  • Bochdalek hernia - The most common form (80-85%) of the Congenital Diaphragmatic Hernia (CDH) types occurring mainly on the postero-lateral (left) side of the respiratory diaphragm. (More? Congenital Diaphragmatic Hernia)
  • bronchi - (Latin, bronchos = windpipe) Plural of bronchus, the two subdivisions of the trachea carrying air to the lungs. Embryologically form as an endodermal outpocket of the foregut which branch (bronchiole, subdivision of the bronchus) as they grow.
  • bronchiole - A smaller branch subdivision of the respiratory tract bronchus.
  • bronchopulmonary dysplasia - Clinical term for a heterogeneous lung disease seen in preterm (premature) infants and diagnosed within the first months of life. Condition was first described in 1967. (More? Preterm Birth)
  • canalicular stage - (fetal canalicular, canalicular phase) Term used to describe lung development, after early embryonic the second of the histological/developmental stages (pseudoglandular, fetal canalicular, terminal sac, alveolar). This stage occurs during the fetal period from week 16 to 24. During this stage there is lung bud mesenchymal angiogenesis and cellular differentiation into different stromal cell types (fibroblasts, myoblasts and chondrocytes). (Lung stages: embryonic stage - pseudoglandular stage - canalicular stage - terminal sac stage - alveolar stage)
  • carbon monoxide - (CO) A colourless and odorless gas formed mainly as a by-product of incomplete combustion of hydrocarbons and can cause cytotoxicity by tissue hypoxia. Carbon monoxide enters circulation though the respiratory system, binding to haemoglobin to form carboxy-haemoglobin (COHb), with fetal haemoglobin binding with a greater affinity.
  • CDH - Acronym for Congenital Diaphragmatic Hernia, a musculoskeletal abnormality of the respiratory diaphragm. The most common form being the B#Bochdalek herniaBochdalek hernia.
  • chronic lung disease - (CLD) Clinical term, a neonatal chronic lung disease can be caused by prolonged mechanical ventilation (MV) and oxygen-rich gas with premature infants.
  • Clara cells - Respiratory tract epithelial cells on the luminal surface of airways. These cells have a dome shaped cytoplasmic protrusion and no cilia and their function is secretory and xenobiotic. Clara cells can act as progenitor cell in small airways replacing injured terminally differentiated epithelial cells.
  • Clara cell secretory protein - (CCSP) A protective lung protein secreted from non-ciliated bronchiolar epithelial cells in the conducting airways of mammals. The protein increases in expression level post-natally and is thought to have antioxidant, immunomodulatory, and anticarcinogenic properties.
  • congenital diaphragmatic hernia - Abnormality due to failure of the pleuroperitoneal foramen (foramen of Bochdalek) to close (left side), allows viscera into thorax Intestine, stomach or spleen can enter the pleural cavity, compressing the lung. Rarer (Morgagni hernia) is an opening in the front of the diaphragm. Congenital Diaphragmatic Hernia | GeneReviews
  • congenital laryngeal webs - Laryngeal abnormality due to embryonic (week 10) incomplete recanalization of the laryngotracheal tube during the fetal period. Rare abnormality occuring mainly at the level of the vocal folds (glottis).
  • corticosteroid - An endocrine steroidal hormone produced by the adrenal cortex. Clinically, corticosteroids are also used for lung maturation of the premature neonate.
  • cystic fibrosis - Inherited disease of the mucus and sweat glands, causes mucus to be thick and sticky. Clogging the lungs, causing breathing problems and encouraging bacterial grow. (Covered elsewhere in the course)
  • diaphragm - A general term for a membranous sheet, used to describe the respiratory diaphragm. The muscular sheet separating chest from abdomen with several different embryonic origins. Regular contraction of the diaphragm is required in respiration. The diaphragm forms initially at the lower end of the pleuroperitoneal canal. (Embryonic origins: transverse septum (septum transversum) - tendon of the diaphragm, 3rd to 5th somite pairs - musculature of diaphragm, ventral pleural sac - connective tissue, mesentry of oesophagus - connective tissue around oesophasus and inferior vena cava, and pleuroperitoneal membranes - connective tissue around central tendon)
  • endoderm - (Greek, endo = inside + derma = skin) One of the initial 3 germ cell layers (ectoderm, mesoderm, endoderm) formed by the process of gastrulation. The endoderm forms the epithelial lining glands and of the respiratory tract.
  • epaxial muscle - Anatomical term describing skeletal muscles which lie dorsal (posterior) to the vertebral column developing from the somite myotome. At the ribcage level the levatores costarum muscles involved with rib elevation during respiration.
  • epiglottis - (Greek, epi = above, upon) cartilaginous part of the larynx above the glottis, which in infancy directs food into the esophagus and not the trachea . Embryologically it develops in the foregut from the hypobranchial eminence, behind the undeveloped tongue, from which it separates at about 7 weeks. Postnatal anatomical development in humans involves a maturational descent in infancy (4 and 6 months of age). Contains lymphoid tissue (larynx-associated lymphoid tissue, LALT and Bronchus-associated lymphoid tissue, BALT).
  • Extracorporeal Membrane Oxygenation - (ECMO) an invasive therapy that has been investigated and utilized in newborn infants with cardiorespiratory failure.
  • fetal breathing movements - (FBM) Occur in the third trimester preparing both the skeletomuscular system and lungs mechanically for respiration.
  • fistula - An abnormal communication between 2 structures (organs, vessels, cavities) that do not normally connect, can occur between the trachea and oesophagus.
  • foregut - The first of the three part/division (foregut - midgut - hindgut) of the early forming gastrointestinal tract. The foregut runs from the buccopharyngeal membrane to the midgut and forms all the tract (esophagus and stomach) from the oral cavity to beneath the stomach. In addition, a ventral bifurcation of the foregut will also form the respiratory tract epithelium.
  • glottis - (Greek, = larynx) the boundary between pharynx to the larynx and consists of the vocal folds and their associated intervening space.
  • HIF-1 - A transcription factor that is one of the main regulators of homeostasis in human tissues exposed to hypoxia, due to inflammation and/or insufficient circulation.
  • hyaline membrane disease - (Newborn Respiratory Distress Syndrome) Abnormality due to a membrane-like substance from damaged pulmonary cells.
  • laryngeal cleft - (LC, laryngeal-tracheo-oesophageal cleft) A rare foregut abnormality allowing digestive tract and the airway to communicate causing chronic cough, aspiration and respiratory distress. The downward extension of the cleft determines the classification of the abnormality.
  • laryngeal webs - (congenital laryngeal webs) Laryngeal abnormality due to embryonic (week 10) incomplete recanalization of the laryngotracheal tube. Rare abnormality occuring mainly at the level of the vocal folds (glottis).
  • laryngotracheal groove - Early embryonic foregut developmental feature, forms on the anterior (ventral) wall of the pharynx and gives rise to larynx, trachea and entire respiratory tree. In humans, this feature is the first indication of respiratory development and appears during week 4.
  • larynx - Site of the the vocal folds in the neck. Embryologically develops from the foregut with the lining derived from endoderm and the cartilage from pharyngeal arch 4 and 6. Beginning as a simple foregut groove, the laryngotracheal groove which folds to form the laryngotracheal bud, then the larynx and trachea.
  • late-gestation lung protein 1 - (LGL1) A glycoprotein secreted by fetal lung mesenchyme and fetal kidney, involved in retinoic acid stimulated branching morphogenesis.
  • lipofibroblast - (lipid interstitial cell, pulmonary lipofibroblast) Cell involved in secondary septum formation during the alveolar stage of lung development (late fetal to postnatal). Cell is recognizable by a number of characteristic lipid droplets and contains cortical contractile filaments.
  • lobar emphysema - (overinflated lung) Abnormality of an overinflated left upper lobe There is a collapsed lower lobe The left lung is herniating across the mediastinum.
  • lung bud - term describing the primordia of lung development in the respiratory embryonic stage. Foregut endoderm branches into the surrounding visceral mesoderm, forming the trachea, which branches again into the bronchi and this process is repeated over and over again through development.
  • measles - (paramyxovirus) Measles (rubeola) is mainly a respiratory viral infection, clinically different from Rubella.
  • meconium aspiration syndrome - (MAS) Fetal stress in the third trimester, prior to/at/ or during parturition can lead to premature meconium discharge into the amniotic fluid and sunsequent ingestion by the fetus and damage to respiratory function.
  • mitochondria - Double membraned cell organelle located in the cytoplasm, a cell may contain 100's or more mitochondria, the number can relate to the metabolic activity of that cell. Functions in cell respiration, providing energy to the cell and also has a role in the process of apoptosis (programmed cell death).
  • nitrofen - A diphenyl ether herbicide teratogen used in rodent development to generate a range of developmental abnormalities, including congenital diaphragmatic hernia.
  • oropharynx - The second portion of the pharynx (throat) that is posterior to the oral cavity. The other pharynx regions are the nasopharynx and laryngopharynx (hypopharynx).
  • parathyroid hormone-related protein - (PTHrP) A protein named for its evolutionary and structural relationship to parathyroid hormone (PTH). A protein hormone produced by many fetal tissues and with a number of different functions including a possible autocrine role in lung development.
  • parietal pleura - Serous membrane which forms the outer lining of pleural cavity. mesoderm of the thoracic cavity body wall and derived from epithelia of pericardioperitoneal canals from intra-embryonic coelom. The inner pleural layer, visceral pleura, is splanchnic mesoderm in origin.
  • Pentalogy of Cantrell - A developmental abnormality of the anterior diaphragm, diaphragmatic pericardium, abdominal wall, cardiovascular and lower sternum.
  • Persistent Pulmonary Hypertension of the Newborn - (PPHN) A serious newborn condition due to due to the failure of closure one of the prenatal circulatory shunts, the ductus arteriosus. Occurs in about 1-2 newborns per 1000 live births and results in hypoxemia.
  • pharynx - (throat) embryo uppermost end of the combined gastrointestinal and respiratory tract beginning at the buccopharyngeal membrane and forms a major arched cavity within the phrayngeal arches. Also used as a respiratory term describing the initial segment of the upper respiratory tract divided anatomically into three regions: nasopharynx, oropharynx, and laryngopharynx (hypopharynx). Anatomically extends from the base of the skull to the level of the sixth cervical vertebra.
  • pleural cavity - Anatomical body cavity in which the lungs develop and lie. Forms in the lateral plate mesoderm as part of the early single intra-embryonic coelom, the pleural cavities are initially two narrow canals.
  • pleuropericardial fold - (pleuropericardial membrane) An early embryonic fold which restricts the communication between pleural cavity and pericardiac cavity, contains both the |cardinal vein and phrenic nerve.
  • pleuroperitoneal foramen - The developmental opening occurring in the intra-embryonic coelom before formation of the pleuroperitoneal membrane.
  • PLUNC - Acronym for Palate, LUng, Nasal epithelium Clone protein, related to the lipid transfer/lipopolysaccharide binding protein (LT/LBP) family. This protein is secreted by the airway conducting epithelia and acts as a surfactant that may interfere with biofilm formation by airway pathogens.
  • pseudoglandular stage - Term used to describe the second histological/developmental stage of lung development, after early embryonic. In humans this stage occurs during the early fetal period after about 20 generations of branching.
  • respiratory - Term used in relation to breathing (in and out) or associated with the lungs. Anatomically used to describe the lungs, air pathways and associated muscles. In cell biology used in relation to mitochondrial use of oxygen to produce energy and carbon dioxide waste.
  • respiratory tree - Anatomical term to describe the components of the respiratory system (lungs) as they branch again and again ending in the functional units, the alveolar sacs (alveolus).
  • saccular stage - (sacculation is a general anatomical term meaning to formed a series of sac-like expansions). In lung development, the term refers to the process of lung epithelial cell differentiation, vascular remodeling and thinning of the mesenchyme. This process leads to enlargement of the diameter and surface area of the alveolar sacs. Distal epithelial cells form 2 populations: 1. cells flattens, thins, and spreads to form type I cells; 2. cells remain cuboidal, acquire surfactant filled lamellar bodies and differentiate into type II cells.
  • septum transversum - (transverse septum) A mesodermal region in the early embryo. Identified externally as the junctional site between amnion and yolk sacs, and internally (within the embryo) lying directly beneath the heart and at the foregut/midgut junction. This ventro-dorsal "plate" of mesoderm contributes several structures including: the central tendon of diaphragm and some of the liver.
  • stenosis - Term used to describe an abnormal narrowing, usually in relation to a tube for example: respiratory tract, blood vessel, gastrointestinal tract.
  • stomodeum - (stomadeum, stomatodeum) The primordial mouth region of the developing embryonic head.
  • surfactant - (surface active agent ; pulmonary surfactant) A mixture of lipids and proteins secreted by Type 2 alveolar cells between alveolar epithelium that reduces surface tension (detergent) at the air-liquid interface. The function is to prevent collapse of the lung at the end of expiration. In humans, these cells and their secretion develop towards the very end of the third trimester, just before birth.
  • surfactant replacement therapy - A clinical birth term referring to the endotracheal instillation of a surface-active suspension for treating surfactant deficiency due to either preterm birth or pulmonary injury resulting in respiratory distress.
  • tachypnea - (Greek, tachypnea = rapid breathing) Clinical term describing an increased respiratory rate of greater than 60 breaths/minute in a quiet resting baby.
  • terminal sac stage - (terminal sac phase, immature alveoli) Term used to describe the second last histological/developmental stage (Pseudoglandular, Fetal Canalicular, Terminal sac, Alveolar) of lung development. This stage occurs from late fetal week 24 to 36. During this stage branching and growth of the terminal sacs occurs, with cellular differentiation of the type -II pneumonocytes and type - I pneumonocytes The final functional sac of the respiratory tree occurs at the next neonatal period, where gas exchange occurs between the alveolar space and the pulmonary capillaries.
  • trachea - (windpipe) In the embryo, a ventral out-pocket of pharynx endoderm that branches in week 4 stage 13 into the right and left bronchi within the lung buds. The endoderm has associated mesoderm that later differentiates to form most structures outside the respiratory epithelium. In the adult, the trachea forms the functional connection between the pharynx and larynx to the lungs.
  • tracheoesophageal fistula - Abnormal connection between the trachea and oesophagus.
  • vagus - (Latin, vagus = wandering) cranial nerve X (CN X) A mixed nerve that leaves the head and neck to innervate respiratory tract (larynx, lungs), gastrointestinal tract (pharynx, esophagus, stomach), cardiac (heart) and abdominal viscera. This mixed nerve has sensory, motor and autonomic functions of viscera (glands, digestion, heart rate).
  • visceral pleura - Serous membrane which forms the inner lining of pleural cavity, both covering and attached to the lungs. Embryonically derived from the splanchnic mesoderm. The outer pleural layer, parietal pleura, is derived from mesoderm of the thoracic cavity body wall.
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Frazer JE. Development of the larynx. (1910) J Anat. 44: 156-191. PMID 17232839


Keibel F. and Mall FP. Manual of Human Embryology II. (1912) J. B. Lippincott Company, Philadelphia.

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