SH Lecture - Respiratory System Development - Embryology 2/3/18, 1(31 pm

SH Lecture - Respiratory
System Development
Introduction

Current research suggests that

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

Lecture: 2017 | 2017 PDF |

2016 | 2016 PDF | 2015 | 2015
PDF | 2014 | Lecture 2014 PDF
| 2013 PDF | 2013 | 2012 | 2012
PDF (10 pages) | eMed Link to
Learning Activity - Respiratory
System Development

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:

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SH Lecture - Respiratory System Development - Embryology 2/3/18, 1(31 pm

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 [Collapse]

Hill, M.A. (2018). UNSW Embryology (18th

ed.) Retrieved March 2, 2018, from
https://embryology.med.unsw.edu.au
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 [Collapse]
Key Concepts
Moore, K.L., Persaud, T.V.N. & Torchia, M.G.
(2015). The developing human: clinically 1. upper and
oriented embryology (10th ed.). Philadelphia: lower
Saunders. respiratory
tract.
Chapter 10 Respiratory System 2. Embryonic
Chapter 8 Body Cavities and Diaphragm origin of
Chapter 9 Pharyngeal Apparatus, Face, respiratory
and Neck components
(tract, lungs,

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SH Lecture - Respiratory System Development - Embryology 2/3/18, 1(31 pm

Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R., diaphragm,

Francis-West, P.H. & Philippa H. (2015). muscles).
Larsen's human embryology (5th ed.). New 3. Key stages in
York; Edinburgh: Churchill Livingstone. respiratory
development.
Chapter 11 Development of the
4. Time course of
Respiratory System and Body Cavities
respiratory
development.
Histology and cell biology: An 5. Respiration at
introduction to pathology Chapter 13. birth.
Respiratory System
6. Postnatal
Developmental Biology 8e OnlineLung
development of
Branching Morphogenesis
Additional Before We Are Born (5th ed.) Moore and respiration.
Textbooks Persaud Chapter 13 p255-287 7. Developmental
Essentials of Human Embryology abnormalities.
Larson Chapter 9 p123-146
Human Embryology Fitzgerald and
Fitzgerald Chapter 19, 20 p119-123

2017 [www.lungmap.net LungMAP]:

The Molecular Atlas of Lung
Development Program.[1]
2017 Development of the lung.[2]
2017 Developmental pathways in lung
Review regeneration.[3]
article 2017 In utero alcohol effects on foetal,
neonatal and childhood lung disease.[4]
2014 Lung development: orchestrating
the generation and regeneration of a
complex organ.[5]

Respiratory Functional Unit

Alveolus

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

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SH Lecture - Respiratory System Development - Embryology 2/3/18, 1(31 pm

Alveolus histology Alveolus structure

Primary Lobule Secondary Lobule

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SH Lecture - Respiratory System Development - Embryology 2/3/18, 1(31 pm

region supplied by a region supplied by a terminal bronchiole

respiratory size - up to 2.5 cm across.
bronchiole connective tissue - bounded by fibrous
(interlobular) septa and containing internal
(interlobular) 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.

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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

Stage Human Features

lung buds originate as an outgrowth from
week 4
Embryonic the ventral wall of the foregut where lobar
to 5
division occurs
conducting epithelial tubes surrounded by
week 5
Pseudoglandular thick mesenchyme are formed, extensive
to 17
airway branching
bronchioles are produced, increasing
week 16 number of capillaries in close contact with
Canalicular
to 25 cuboidal epithelium and the beginning of
alveolar epithelium development
week 24
Saccular alveolar ducts and air sacs are developed
to 40
late fetal secondary septation occurs, marked increase
Alveolar to 8 of the number and size of capillaries and
years alveoli

Embryonic

Week 4 to 5 - lung buds originate as an outgrowth from the ventral wall of

the foregut where lobar division occurs.

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SH Lecture - Respiratory System Development - Embryology 2/3/18, 1(31 pm

Buccopharyngeal membrane (Week 4,

Stomodeum (Week 4, stage 11)
stage 11)

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(Week 5, stage 14)

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

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

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SH Lecture - Respiratory System Development - Embryology 2/3/18, 1(31 pm

2 peptides - gastrin-releasing peptide (GRP) and calcitonin gene

related peptide (CGRP)

Fetal
lung
histology

Week 8

(This is what a gland looks like.)

Canalicular stage

week 16 - 24
Lung morphology changes dramatically

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SH Lecture - Respiratory System Development - Embryology 2/3/18, 1(31 pm

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.
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

late fetal to 8
years.
Secondary
septum

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Expansion of gas
exchange alveoli,
vascular beds
(capillaries),
lymphatics and
innervation.
Postnatal lung,
with alveoli
forming.

Upper Respiratory Tract

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

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SH Lecture - Respiratory System Development - Embryology 2/3/18, 1(31 pm

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

Adult upper respiratory tract conducting system

Additional Information - Histology [Expand]

Lower Respiratory Tract

week 4 early respiratory endodermal bud

week 4 later ventral endoderm growth

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lower respiratory tract

conducting system bronchi to lungs

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

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 Lung alveoli development cartoon
alveoli.

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Additional Information - Histology [Expand]

Fetal Lung Volume

Each human lung volume as determined by ultrasound and matched to

gestational age[6]

Pleural Cavity

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.

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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.

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

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1. septum transversum- central tendon

2. 3rd to 5th somite- musculature of diaphragm
3. ventral pleural sac- connective tissue
4. mesentry of oesophagus- connective tissue
around oesophasus and IVC
5. pleuroperitoneal membranes- connective
tissue around central tendon

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).
Adult Cervical Plexus (phrenic nerve shown
Bochdalek hernia - most lower right)
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

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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.

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

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in the left side of the heart increases (more blood returning from
pulmonary).

Postnatal

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

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

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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.

Respiratory Tract Abnormalities

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 Congenital diaphragmatic hernia
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
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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) 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

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SH Lecture - Respiratory System Development - Embryology 2/3/18, 1(31 pm

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. PMID 8176553
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)

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[4]
Maternal obesity[7]
Maternal diabetes[8]
Maternal smoking[9]
Chronic hypoxaemia[10]
Environmental chemicals[11]

Additional Information

Respiratory Quiz

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SH Lecture - Respiratory System Development - Embryology 2/3/18, 1(31 pm

Grays - Respiratory [Expand]

Images
Respiratory Histology [Expand]

References

1. ↑ Ardini-Poleske ME, Clark RF,

Ansong C, Carson JP, Corley
RA, Deutsch GH, Hagood JS,
Kaminski N, Mariani TJ, Potter
SS, Pryhuber GS, Warburton D, Whitsett JA, Palmer SM &
Ambalavanan N. (2017). LungMAP: The Molecular Atlas of Lung
Development Program. Am. J. Physiol. Lung Cell Mol. Physiol. , 313,
L733-L740. PMID: 28798251 DOI.
2. ↑ Schittny JC. (2017). Development of the lung. Cell Tissue Res. , 367,
427-444. PMID: 28144783 DOI.
3. ↑ Stabler CT & Morrisey EE. (2017). Developmental pathways in lung
regeneration. Cell Tissue Res. , 367, 677-685. PMID: 27957616 DOI.
4. ↑ 4.0 4.1 Gauthier TW & Brown LA. (2017). In utero alcohol effects on
foetal, neonatal and childhood lung disease. Paediatr Respir Rev , 21,
34-37. PMID: 27613232 DOI.
5. ↑ Herriges M & Morrisey EE. (2014). Lung development:
orchestrating the generation and regeneration of a complex organ.
Development , 141, 502-13. PMID: 24449833 DOI.
6. ↑ Peralta CF, Cavoretto P, Csapo B, Falcon O & Nicolaides KH.
(2006). Lung and heart volumes by three-dimensional ultrasound in
normal fetuses at 12-32 weeks' gestation. Ultrasound Obstet Gynecol ,
27, 128-33. PMID: 16388511 DOI.
7. ↑ McGillick EV, Lock MC, Orgeig S & Morrison JL. (2017). Maternal
obesity mediated predisposition to respiratory complications at birth
and in later life: understanding the implications of the obesogenic
intrauterine environment. Paediatr Respir Rev , 21, 11-18. PMID:
27818069 DOI.

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SH Lecture - Respiratory System Development - Embryology 2/3/18, 1(31 pm

8. ↑ Azad MB, Moyce BL, Guillemette L, Pascoe CD, Wicklow B,

McGavock JM, Halayko AJ & Dolinsky VW. (2017). Diabetes in
pregnancy and lung health in offspring: developmental origins of
respiratory disease. Paediatr Respir Rev , 21, 19-26. PMID: 27665512
DOI.
9. ↑ McEvoy CT & Spindel ER. (2017). Pulmonary Effects of Maternal
Smoking on the Fetus and Child: Effects on Lung Development,
Respiratory Morbidities, and Life Long Lung Health. Paediatr Respir
Rev , 21, 27-33. PMID: 27639458 DOI.
10. ↑ McGillick EV, Orgeig S, Giussani DA & Morrison JL. (2017). Chronic
hypoxaemia as a molecular regulator of fetal lung development:
implications for risk of respiratory complications at birth. Paediatr
Respir Rev , 21, 3-10. PMID: 27692868 DOI.
11. ↑ Miller MD & Marty MA. (2010). Impact of environmental chemicals
on lung development. Environ. Health Perspect. , 118, 1155-64. PMID:
20444669 DOI.

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