SH Lecture - Respiratory System Development

Embryology - 11 Dec 2023        Expand to Translate
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Introduction

Fetal Pharynx (week 12)

The lecture will introduce the development of the respiratory system and associated structures. The lecture will not cover adult anatomy, physiology of gas exchange, red blood cell function, cardiovascular development and will leave detailed histology to your associated practical class.

Current research suggests that both genetic and the developmental environment (fetal and postnatal) can influence the growth, differentiation and function of the respiratory system.

Lower respiratory tract	Respiratory tree

2019 Respiratory Development Lecture PDF

SH Links: Lymphatic Lecture | Lymphatics Practical Support | Respiratory Lecture | Respiratory Practical Support | Medicine

The respiratory system does not carry out its physiological function (of gas exchange) until after birth, though the respiratory tract, diaphragm and lungs do begin to form early in embryonic development and continue through fetal development, only functionally maturing just before birth. The lungs continue to grow postnatally through childhood and some research finding suggest that there remains potential for growth in the adult.

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.

The respiratory "system" usually includes descriptions of not only the functional development of the lungs, but also related musculoskeletal (diaphragm) and vascular (pulmonary) development.

Aim To understand the prenatal and postnatal developmental anatomy of human respiratory organs. Textbooks   Hill, M.A. (2020). UNSW Embryology (20th ed.) Retrieved December 11, 2023, from https://embryology.med.unsw.edu.au 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 - Respiratory  1902 The Nasal Cavities and Olfactory Structures | 1906 Lung | 1912 Upper Respiratory Tract | 1912 Respiratory | 1913 Prenatal and Neonatal Lung | 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 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 Chapter 8 Body Cavities and Diaphragm Chapter 9 Pharyngeal Apparatus, Face, and Neck 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 Additional Textbooks Paramothayan, S. (2018). Essential respiratory medicine. CHAPTER 2 Embryology, anatomy, and physiology of the lung Histology and cell biology: An introduction to pathology Chapter 13. Respiratory System Developmental Biology 8e OnlineLung Branching Morphogenesis 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 Review article 2017 [www.lungmap.net LungMAP]: The Molecular Atlas of Lung Development Program. 2017 Development of the lung. 2017 Developmental pathways in lung regeneration. 2017 In utero alcohol effects on foetal, neonatal and childhood lung disease. 2014 Lung development: orchestrating the generation and regeneration of a complex organ.

Key Concepts upper and lower respiratory tract. Embryonic origin of respiratory components (tract, lungs, diaphragm, muscles). Key stages in respiratory development. Time course of respiratory development. Respiration at birth. Postnatal development of respiration. Developmental abnormalities.

Respiratory Functional Unit

Alveolus

Alveolus (Latin alveolus = "little cavity", plural is alveoli)

Alveolus histology	Alveolus structure

Inter-Alveolar Septum

Septum containing Type I (AEC1) and type II (AEC2) alveolar epithelial cell, alveolar lumen (Alv), capillary lumen (Cap), capillary endothelial cell (Endo ). Lamellar bodies (LB) in type II cell. Arrowheads mark tight junctions between type II and type I cell. Collagen fibrils (col) are present in the interstitium. Transmission electron microscopy. Scale bar 2 µm

Primary Lobule region supplied by a respiratory bronchiole

Secondary Lobule region supplied by a terminal bronchiole size - up to 2.5 cm across. connective tissue - bounded by fibrous (interlobular) septa and containing finer internal septa. lobule contains a up to 12 acini and 30 - 50 primary lobules. blood supply - pulmonary artery branch blood drainage - pulmonary veins located at lobule periphery leave though the interlobular septa. lymphatics - arterial and interlobular septa associated (drain to subpleural plexus).

Developmental Overview

Germ Layers

• endoderm and splanchnic mesoderm form majority of conducting and alveoli.
• ectoderm will contribute the neural innervation.
• mesoderm also contributes the supporting musculoskeletal components.

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.

Development Stages

Note - the sequence is 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

Lung Stages - timing, airway and vascular development

Embryonic

Week 4 to 5 - lung buds originate as an outgrowth from the ventral wall of the foregut where lobar division occurs.

Stomodeum (Week 4, stage 11, GA week 6)	Buccopharyngeal membrane (Week 4, stage 11, GA week 6)

(Week 5, stage 14, GA week 7)

• week 4 - 5
• Endoderm - tubular ventral growth from foregut pharynx.
• Mesoderm - mesenchyme of lung buds.
• Intraembryonic coelom - pleural cavities elongated spaces connecting pericardial and peritoneal spaces.

Stage 13 - Trachea and Lung buds (MRI sagittal sections)

Week 4	Week 4-5 (Stage 12 to 13)	Week 5 (Stage 15 to 16)	Week 6 (Stage 16 to 17)

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 more distal structures are lined with cuboidal epithelium. 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) in airway epithelium. May stimulate mitosis to increase branching, secrete 2 peptides - gastrin-releasing peptide (GRP) and calcitonin gene related peptide (CGRP). Week 8

Fetal lung histology

(This is what a gland looks like.)

Pseudoglandular and Canalicular Stages
Canalicular phase of bronchus can be mixed with the pseudoglandular phase. Human Lung showing a mix of pseudoglandular and canalicular stages

Canalicular stage

week 16 - 24 Lung morphology changes dramatically differentiation of the pulmonary epithelium results in the first formation of the future air-blood tissue barrier. Surfactant synthesis and the canalization of the lung parenchyma by capillaries begins. 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.
• Alveolar Cells Type II (Type II pneumocytes)
  • begin to secrete surfactant, levels of secretion gradually increase to term.
  • allows alveoli to remain inflated
• Vascular tree - also grows in length and diameter during this time.

Alveolar stage

Secondary septum

late fetal to 8 years. Secondary septum Expansion of gas exchange alveoli, vascular beds (capillaries), lymphatics and innervation. Postnatal lung, with alveoli forming.

Upper Respiratory Tract

Foregut cartoon

Pharynx

Foregut Development - from the oral cavity the next portion of the foregut is initially a single gastrointestinal (oesophagus) and respiratory (trachea) common tube, the pharynx which lies behind the heart. Note that the respiratory tract will form from a ventral bud arising at this level.

part of foregut development (Oral cavity, Pharynx (esophagus, trachea), Respiratory tract, Stomach) anatomically the nose, nasal cavity and the pharynx pharynx forms a major arched cavity within the pharyngeal arches (MH - pharyngeal arches will be described in BGD head development lecture). palate - development for mammals, allows breathing while feeding. Note - Specialised olfactory epithelium for smell, a small region located in roof of nasal cavity.

Respiratory epithelium pseudo-stratified ciliated cells goblet cells basal cells Respiratory epithelium development

• 

  Nasal cavities

• 

  Larynx

• 

  Adult upper respiratory tract conducting system

Additional Information - Histology

This will be covered in detail in your associated SH Practical class. Olfactory Epithelium Olfactory Epithelium Respiratory Epithelium Respiratory Epithelium Olfactory epithelium Olfactory cells Sustentacular cells - located mainly in the superficial cell layer of the epithelium (difficult to distinguish from olfactory cells). Basal cells - identified by their location in the epithelium. Epithelium Cilia are not visible goblet cells are absent from the olfactory epithelium. Lamina Propria olfactory axon bundles (lightly stained, rounded areas) connected to olfactory cells. Bowman's glands - (small mucous glands, olfactory glands) function to moisturise the epithelium. Nasal Olfactory Histology: overview image | detail image | Smell Development | Histology | Histology Stains Respiratory epithelium goblet cells ciliated cells basal cells Lamina propria connective tissue cavernous sinusoids - large spaces (empty or filled with red blood cells) glandular tissue - mucous glands (green) and muco-serous glands (brownish-green) Bone Lamellae and osteocytes in lacunae. Haversian systems are rare or absent. Nasal Respiratory Histology: overview image | detail image | Histology | Histology Stains Respiratory Histology: Bronchiole | Alveolar Duct | Alveoli | EM Alveoli septum | Alveoli Elastin | Trachea 1 | Trachea 2 | labeled lung | unlabeled lung | Respiratory Bronchiole | Lung Reticular Fibres | Nasal Inferior Concha | Nasal Respiratory Epithelium | Olfactory Region overview | Olfactory Region Epithelium | Histology Stains

Lower Respiratory Tract

• 

  week 4 early respiratory endodermal bud

• 

  week 4 later ventral endoderm growth

• 

  lower respiratory tract

• 

  conducting system bronchi to lungs

Stage 13 (Week 4-5)	Stage 22 (Week 8)

Lung alveoli development cartoon

• lung buds ( endoderm epithelial tubes) grow/push into mesenchyme covered with pleural cells (lung border)
• generates a tree-like network by repeated:

1. elongation
2. terminal bifurcation
3. lateral budding

Growth initially of branched "conducting" system of bronchial tree, followed by later development of the "functional units" of the alveoli.

Additional Information - Histology

This will be covered in detail in your associated SH Practical class. Respiratory Trachea Mucosa - formed by epithelium and underlying lamina propria. respiratory epithelium - (pseudostratified columnar and ciliated) ciliated cells, goblet cells, brush cells, endocrine cells, surfactant-producing cells (Clara cells), serous cells, basal cells, basement membrane. lamina propria - loose connective tissue, many elastic fibres Submucosa - connective tissue and submucosal glands submucosal glands (both serous and mucous parts) Cartilage perichondrium tracheal cartilage - hyaline cartilage, 16 to 20 C-shaped cartilages. trachealis muscle - (smooth muscle) Not visible in this section, together with connective tissue fibres, join ends of the cartilages together. Hyaline Cartilage Development forms from mesenchymal cells. precursor cells become rounded and form densely packed cellular masses, chondrification centres. chondroblasts - (cartilage-forming cells) begin secreting the extracellular matrix components of cartilage. extracellular matrix - ground substance (hyaluronan, chondroitin sulfates and keratan sulfate) and tropocollagen (polymerises into fine collagen fibres, not visible). Trachea (overview HE) Trachea (overview VG) Trachea (detail layers) Trachea (detail glands) Bronchi Branching main bronchi -> lobar bronchi -> segmental bronchi (supply lung bronchopulmonary segments) -> bronchi -> bronchioles (smaller than 1 mm) -> respiratory bronchioles. Trachea branches into 2 main bronchi, with a histological structure similar to that of the trachea. branches are accompanied by branches of the pulmonary artery, nerves and lymph vessels surrounded by a layer of smooth muscle, which is located between the cartilage and epithelium. Bronchioles transition from bronchi to bronchioles the epithelium changes to a ciliated columnar epithelium. Smooth muscle present, glands and cartilage are absent. Respiratory Bronchioles first structures that belong to the respiratory portion of the respiratory system. wall out-pouchings form alveoli (site of gas exchange) end in alveolar ducts alveoli - duct or sac. Bronchiole Lung Elastin labeled lung Alveolar type I cells small alveolar cells or type I pneumocytes are extremely flattened (the cell may be as thin as 0.05 µm) form the bulk (95%) of the surface of the alveolar walls. The shape of the cells is very complex, and they may actually form part of the epithelium on both faces of the alveolar wall. Alveolar type II cells large alveolar cells or type II pneumocytes about as many type II cells as type I cells (cell shape accounts for small contribution to alveolar area). irregularly (sometimes cuboidal) shaped. form small bulges on the alveolar walls. contain are large number of granules called cytosomes (or multilamellar bodies) consist of precursors to pulmonary surfactant (mixture of phospholipids that keep surface tension in the alveoli low). Alveolar Duct Alveoli Alveoli Elastin Respiratory Histology: Bronchiole | Alveolar Duct | Alveoli | EM Alveoli septum | Alveoli Elastin | Trachea 1 | Trachea 2 | labeled lung | unlabeled lung | Respiratory Bronchiole | Lung Reticular Fibres | Nasal Inferior Concha | Nasal Respiratory Epithelium | Olfactory Region overview | Olfactory Region Epithelium | Histology Stains

Fetal Lung Volume

Each human lung volume as determined by ultrasound and matched to gestational age

Weeks (gestational) Volume (ml) 12 to 13 0.05 19 to 22 0.5 29 to 32 1.9

Pleural Cavity

pleura

pleura

• anatomical body cavity in which the lungs develop and lie.
• pleural cavity forms in the lateral plate mesoderm as part of the early single intraembryonic coelom.
• This cavity is initially continuous with pericardial and peritoneal cavities and form initially as two narrow canals.
  • later becomes separated by folding (pleuropericardial fold, pleuroperitoneal membrane) and the later formation of the diaphragm.

• 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 membrane - An early embryonic membrane that forms inferiorly at the septum transversum to separate peritoneal cavity from pleural cavity.

Pleura

• serous membrane covers the surface of the lung and the spaces between the lobes.
• arranged as a closed invaginated sac.
• two layers (pulmonary, parietal) continuous with each other, the potential space between them is the pleural cavity.
• filled with pleural fluid produced by parietal pleura and reabsorbed by parietal pleural lymphatics.
• excess fluid - pleural effusion.

Diaphragm

Adult Diaphragm.

• Not respiratory tract but musculoskeletal development, there are 5 embryonic elements that contribute to the diaphragm.
• Innervation of the human diaphragm is by the phrenic nerves

septum transversum- central tendon 3rd to 5th somite- musculature of diaphragm ventral pleural sac- connective tissue mesentry of oesophagus- connective tissue around oesophasus and IVC pleuroperitoneal membranes- connective tissue around central tendon

Adult Cervical Plexus (phrenic nerve shown lower right)

• Phrenic Nerves - arising from the same segmental levels as the diaphragm skeletal muscles, segmental levels C3 to C5.
• The paired phrenic nerves are mixed nerves
  • motor neurons for the diaphragm
  • sensory nerves for other abdominal structures (mediastinum, pleura, liver, gall bladder).

Bochdalek hernia - most common on the posterior left side (85%). Failure of the pleuroperitoneal foramen (foramen of Bochdalek) to close allows viscera into thorax. Intestine, stomach or spleen can enter the pleural cavity, compressing the lung.

Pulmonary Circulation

• the pulmonary system not "functional" until after birth
• pulmonary arteries - 6th aortic arch arteries
• pulmonary veins - are incorporated into the left atrium wall
• bronchial arteries - branches from dorsal aorta

Pulmonary circulation

Fetal

Fetal Respiratory Movements

• Fetal respiratory movements (FRM) or Fetal breathing movements (FBM) are regular muscular contrations occurring in the third trimester.
• preparing the respiratory muscular system for neonatal function.
• may also have a role in late lung development.

Postnatal

The First Breath

The respiratory system does not carry out its physiological function (gas exchange) prenatally and remain entirely fluid-filled until birth. At birth, fluid in the upper respiratory tract is expired and fluid in the lung aveoli is rapidly absorbed this event has also been called "dewatering of the lung". The lung epithelia has to now rapidly change from its prenatal secretory function to that of fluid absorbtion. The exchange of lung fluid for air leads to: fall in pulmonary vascular resistance increase in pulmonary blood flow thinning of pulmonary arteries (stretching as lungs increase in size) blood fills the alveolar capillaries In the heart - pressure in the right side of the heart decreases and pressure in the left side of the heart increases (more blood returning from pulmonary).

Alveolar sac structure

Alveoli

At birth about 15% of adult alveoli number have formed 20 - 50 million to in the adult about 300 million. remaining subdivisions develop in the first few postnatal years

Human Alveoli Number

Respiratory Rate

• neonatal rate is higher (30-60 breaths/minute) than adult (12-20 breaths/minute).
  • tachypnea - (Greek, rapid breathing) an increased respiratory rate of greater than 60 breaths/minute in a quiet resting baby

Age	Rate (breaths/minute)
Infant (birth - 1 year)	30 - 60
Toddler (1 - 3 years)	24 - 40
Preschool (3 - 6 years)	22 - 34
School age (6 - 12 years)	18 - 30
Adolescent (12 - 18 years)	12 - 16

Rib Orientation

Infant rib - is virtually horizontal, allowing diaphragmatic breathing only. Adult rib - is oblique (both anterior and lateral views), allows for pump-handle and bucket handle types of inspiration.

Rib orientation

Respiratory Tract Abnormalities

Congenital diaphragmatic hernia

Lung Azygos Lobe

Preterm Birth

Respiratory System - Abnormalities

• Meconium Aspiration Syndrome - (MAS) Meconium is the gastrointestinal contents that accumulate in the intestines during the fetal period. 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. Damage to placental vessels meconium myonecrosis may also occur.

• Newborn Respiratory Distress Syndrome - (Hyaline Membrane Disease) membrane-like substance from damaged pulmonary cells, absence of surfactant, if prolonged can be irreversible, intrauterine asphyxia, prematurity and maternal diabetes medline plus | eMedicine

• Tracheoesophageal Fistula - Tracheo-Oesophageal Fistula, Oesophageal Atresia - Oesophageal Atresia with or without tracheo-oesophageal fistula Fistula - an abnormal communication between 2 structures (organs, vessels, cavities) that do not normally connect.

• Lobar Emphysema (Overinflated Lung) - There is an overinflated left upper lobe There is a collapsed lower lobe The left lung is herniating across the mediastinum

• Congenital Diaphragmatic Hernia - (1 in 3,000 live births) Failure of the pleuroperitoneal foramen (foramen of Bochdalek) to close (left side), allows viscera into thorax -iIntestine, stomach or spleen can enter the pleural cavity, compressing the lung. rare (Morgagni hernia) -an opening in the front of the diaphragm. Congenital Diaphragmatic Hernia | GeneReviews

• 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.

• 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).

• Hyaline Membrane Disease - (Newborn Respiratory Distress Syndrome) historic terminology, a membrane-like substance from damaged pulmonary cells.

• Bronchopulmonary Dysplasia - A chronic lung disease which can occur following premature birth and related lung injury. Most infants who develop BPD are born more than 10 weeks before their due dates, weigh less than 1,000 grams (about 2 pounds) at birth, and have breathing problems.

• 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.

• 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)

• Vascular development - During both the prenatal and postnatal development, impaired angiogenesis from a number of causes can decrease alveolarization of the lung. (decreased VEGF expression, increased oxygen tension, inflammatory cytokines, other adverse stimuli)

Environmental Factors

The lung is most sensitive to environmental effects given the long timecourse of development, including postnatal, multi-system origins, immune interactions, and our growing understanding of the effects of the prenatal environment on adult health (DOHAD). Below are some recent reviews of related topics.(not part of today's lecture presentation)

• Maternal alcohol
• Maternal obesity
• Maternal diabetes
• Maternal smoking
• Chronic hypoxaemia
• Environmental chemicals

Respiratory 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? 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. alveolarization - (alveolarisation) The process of developmental differentiation of the functional unit of the lung.(embryonic stage - pseudoglandular stage - canalicular stage - saccular stage - alveolar stage) 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. (embryonic stage - pseudoglandular stage - canalicular stage - saccular 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. The acinus starts approximately 3 to 4 generations proximal of the bronchioalveolar duct junction and ends about 4 generations of alveolar ducts distal of the bronchioalveolar duct junction. angiogenesis - vascular growth by direct extension from pre-existing blood vessels. (see also vasculogenesis). 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. Asthma phenotypes have a number of different classifications; allergic asthma, intrinsic or nonallergic asthma, infectious asthma, and aspirin-exacerbated asthma, and environmental exposures (occupational agents, smoking, air pollution, cold dry air) (More? PMID 5439356) 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. Airway: trachea - bronchi - lobar bronchi - segmental bronchi - bronchioles - conducting bronchioles - terminal bronchioles - respiratory bronchioles - alveolar ducts. bronchiole - A smaller branch subdivision of the respiratory tract bronchus, lack supporting cartilage skeletons and have a diameter of about 1 mm. Epithelium is initially ciliated and graduates to simple columnar epithelium and lining no longer contain mucous-producing cells. bronchopulmonary dysplasia - (chronic lung disease in preterm infants) 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 American Lung Association) 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). (embryonic stage - pseudoglandular stage - canalicular stage - saccular 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 Bochdalek hernia. chorioamnionitis - (amnionitis, intra-amniotic infection) intrauterine bacterial infection/inflammation that can cause preterm birth and affect respiratory development directly as well as thought the underdeveloped brainstem, resulting in reduced respiratory drive. 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. connective tissue fibers - form a continuous alveolar support with axial, peripheral and septal fibers. 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. (More? 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 and neural system, and lungs mechanically and the amount of liquid within the developing lungs. 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. hypopharynx - connects the oropharynx to the oesophagus and the larynx, the region of pharynx below the hyoid bone. 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 - (embryonic stage) 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. (embryonic stage - pseudoglandular stage - canalicular stage - saccular stage - alveolar stage) 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. medullary respiratory centres - medulla oblongata collection of nuclei organised into ventral and dorsal respiratory groups. The ventral respiratory nuclei pre-Bötzinger complex (pBÖTC) required for respiratory rhythmogenesis. 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). newborn respiratory distress syndrome - (respiratory distress syndrome, RDS, hyaline membrane syndrome) - surfactant deficiency at birth more common in preterm birth. RDS Info 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) connecting the nasopharynx and laryngopharynx (hypopharynx). Region between the palate and the hyoid bone, anteriorly divided from the oral cavity by the tonsillar arch. 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. pleuroperitoneal membrane - An early embryonic membrane that forms inferiorly at the septum transversum to separate the peritoneal cavity from the pleural cavity. 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. (embryonic stage - pseudoglandular stage - canalicular stage - saccular stage - alveolar stage) pulmonary acini (singular - acinus) region of the lung supplied with air from one of the terminal bronchioles, anatomical and functional end of the mammalian lung respiratory tree where gas exchange occurs. Starts approximately 3 to 4 generations proximal of the bronchio-alveolar duct junction and ends about 4 generations of alveolar ducts distal of the bronchioalveolar duct junction. pulmonary arterial hypertension - (PAH) a progressive disease characterized by abnormalities of vascular tone and reactivity, vessel wall structure, growth, and thrombosis that in newborns, infants, and children can contribute to poor outcomes in cardiac, pulmonary, and systemic diseases. 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 bronchioles - may contain alveoli and have surface surfactant-producing Respiratory bronchioles can contain alveoli and surfactant-producing cells, and give rise to between 2 to 11 alveolar ducts. respiratory sinus arrhythmia - (RSA) Clinically used as an index of cardiac vagal activity, measured breath-by-breath by subtracting the minimum heart rate (HR) during expiration from the maximum HR during inspiration. 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 - (terminal sac stage) 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. Sacculation is a general anatomical term meaning to formed a series of sac-like expansions. (embryonic stage - pseudoglandular stage - canalicular stage - saccular stage - alveolar stage) secondary septa - (secondary septa) process in the lung alveolar stage of development (postnatally) where the double capillary network in the immature gas-exchange region fuses to form a single capillary layer. 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. Clinical surfactants used for surfactant replacement therapy are animal-derived preparations, commonly bovine (beractant, bovactant, BLES) or less common porcine (butantan, poractant-α and surfacen) PMID30728009. surfactant protein D - (SP-D) a multimeric collectin (collagen-containing C-type lectin) involved in innate immunity (anti-microbial) and expressed in pulmonary and non-pulmonary epithelia. PMID 29473039 surfactant replacement therapy - (surfactant 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 (newborn respiratory distress syndrome). 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 - (saccular stage, terminal sac phase, immature alveoli) Term used to describe the second last histological/developmental stage (pseudoglandular stage, Fetal Canalicular, saccular stage, 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. (embryonic stage - pseudoglandular stage - canalicular stage - saccular stage - alveolar stage) 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. Adult trachea is a ciliated pseudostratified columnar epithelium supported by C-shaped rings of hyaline cartilage. tracheoesophageal fistula - Abnormal connection between the trachea and oesophagus. Trisomy 21 - (Down syndrome) associated with significant cardiovascular and pulmonary mortality and morbidity of neonates, infants, and children. Infant lung histology may share features of decreased lung vascular and alveolar growth. (More? Trisomy 21 | PMID 25621156) 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). vasculogenesis - the formation of new blood vessels from angioblasts or endothelial progenitor cells (EPCs) that migrate, differentiate, and grow into tubes in response to signals from surrounding cells. (see also angiogenesis). VEGF - (vascular endothelial growth factor) a specific mitogen and survival factor required for endothelium growth and development also required in lung vasculature development and remodelling. ventilatory unit - region from a respiratory bronchiole extending to the supported alveolar ducts and alveoli. 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.

Additional Information

Additional Information - Content shown under this heading is not part of the material covered in this class. It is provided for those students who would like to know about some concepts or current research in topics related to the current class page.

Developing Rat Lung (3D view)
From transitional bronchiole to alveolus! <html5media height="500" width="856">File:Rat respiratory 01.mp4</html5media>
The flight starts by entering a transitional bronchiole. Domes of Club cell are visible on the surface of the bronchiole. Turning left an alveolar duct is entered. Various alveoli and the entrance of few alveolar ducts are visible. Shortly before the end of first alveolar duct, the fight turns left again and flies down another alveolar duct. After a short distance it ends in front of an alveolus which is subdivided by a low ridge representing a still forming new alveolar septum. Rat lung at postnatal day 36. Surface rendering of a sample scanned by SRXTM for Schittny et al. (Schittny et al. 2008) using the software Imaris 4.1 (Bitplane, Zürich, Switzerland). Because the magnification is changing during the flight a scale bar could not be easily shown. However, the entrance of the bronchiole has a diameter of ~100 µm (text from suppl. information) Schittny JC. (2018). How high resolution 3-dimensional imaging changes our understanding of postnatal lung development. Histochem. Cell Biol. , 150, 677-691. PMID: 30390117 DOI. Note - mouse and rat the acini and the ventilatory units are the same entity because they do not possess any respiratory bronchioles. The mouse model (C57BL/6J) completely lacks respiratory breathing movements seen in the human fetus.

Respiratory Quiz

Lung Development - Respiratory Health and Disease

Nikolić MZ, Sun D & Rawlins EL. (2018). Human lung development: recent progress and new challenges. Development , 145, . PMID: 30111617 DOI.

Arigliani M, Spinelli AM, Liguoro I & Cogo P. (2018). Nutrition and Lung Growth. Nutrients , 10, . PMID: 30021997 DOI.

Finke I, de Jongste JC, Smit HA, Wijga AH, Koppelman GH, Vonk J, Brunekreef B & Gehring U. (2018). Air pollution and airway resistance at age 8 years - the PIAMA birth cohort study. Environ Health , 17, 61. PMID: 30016982 DOI.

Stocks J, Hislop A & Sonnappa S. (2013). Early lung development: lifelong effect on respiratory health and disease. Lancet Respir Med , 1, 728-42. PMID: 24429276 DOI.

Merkus PJ. (2003). Effects of childhood respiratory diseases on the anatomical and functional development of the respiratory system. Paediatr Respir Rev , 4, 28-39. PMID: 12615030

adult lungs

Grays - Respiratory Images

947 The head and neck human embryo thirty-two days seen from the ventral surface. 948 Lung buds from a human embryo of about four weeks, showing commencing lobulations. 949 Lungs of a human embryo more advanced in development than week 4. 950 Cartilages of the larynx 950 epiglottis cartilage 950 thyroid cartilage 950 cricoid cartilage 950 arytenoid cartilage 951 Ligaments of the larynx (anterior view) 952 Ligaments of the larynx (posterior view) 953 Larynx and upper part of the trachea 954 955 Larynx entrance 956 957 958 959 960 961 Cartilages of larynx, trachea, and bronchi (front view) 962 Bronchi and bronchioles 963 964 965 966 Lateral view of thorax, showing the relations of the pleuræ and lungs to the chest wall. Pleura in blue; lungs in purple. 967 Transverse section through the upper margin of the second thoracic vertebra. 968 969 970 Front view of heart and lungs 971 Adult lungs 974 Lung secondary lobule 974 relabeled version 975 Lung primary lobule 975 relabeled version 976 Pig embryo lung

Respiratory Histology

Histology will be covered in more detail in your associated practical class. Fetal Histology Hyaline cartilage late canalicular unlabeled late canalicular Fetal Respiratory: late canalicular | unlabeled late canalicular | Hyaline cartilage | Respiratory Histology Adult Histology Olfactory Epithelium Olfactory Epithelium Respiratory Epithelium Respiratory Epithelium Trachea 1 Trachea 2 Bronchiole Lung Elastin labeled lung Alveolar Duct Alveoli Alveoli Elastin Respiratory Histology: Bronchiole | Alveolar Duct | Alveoli | EM Alveoli septum | Alveoli Elastin | Trachea 1 | Trachea 2 | labeled lung | unlabeled lung | Respiratory Bronchiole | Lung Reticular Fibres | Nasal Inferior Concha | Nasal Respiratory Epithelium | Olfactory Region overview | Olfactory Region Epithelium | Histology Stains

Glossary Links

Glossary: A | B | C | D | E | F | G | H | I | J | K | L | M | N | O | P | Q | R | S | T | U | V | W | X | Y | Z | Numbers | Symbols | Term Link

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Cite this page: Hill, M.A. (2023, December 11) Embryology SH Lecture - Respiratory System Development. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/SH_Lecture_-_Respiratory_System_Development

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© Dr Mark Hill 2023, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G