Development of the
Respiratory System
Thomas A. Marino, Ph.D.
Competencies: Upon completion of this
section of the course, you must be able to:
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•
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Define the segments of the primitive gut tube.
Describe the embryological movements of the
respiratory diverticulum as it develops into the
trachea, bronchi, and lungs.
Explain the origin of cells that develop into the
lung tissue.
Compare and contrast morphology of the lungs
during the four stages of lung development.
Describe the primitive body cavity and how it
becomes subdivided into pleural, pericardial
and peritoneal cavities.
Introduction
• Development of the lungs begins at 4
weeks.
• The epithelium of the respiratory system
develops from endoderm.
• The connective tissue, cartilage and
muscle develop from splanchnic
mesoderm.
Early Embryonic Morphology
• Early vertebrate body
plan
• At 26 days a small
opening in the foregut
appears.
• At 28 days it
evaginates to form a
laryngotracheal
diverticulum.
Separation of the
Laryngotracheal Diverticulm
• Longitudinal folds tracheoesophageal
ridges develop
• Form
tracheoesophageal
septum
Notochord
Noggin
Sox2
Esophagus
Nkx2-1
Lung Bud
FGF10
Wnt2
Bmp
RA
Significance
• Lack of
– Shh
– Retinoic acid
receptors
– FGF10
– Sox2
– Nkx2-1
– Bmp4
– Noggin
– Wnt
• Result
– Trachoesophageal
fistula
– Esophageal atresia
Tracheoesophageal septum
separates
• Trachea and lung buds ventral
• Esophagus - dorsal
Development of the Larynx
• Epithelium develops
from endoderm of
laryngotracheal tube.
• Connective tissue and
cartilage develops
from splanchnic
mesoderm.
• Cartilages develop
from neural crest cells.
Development of the Trachea
• Epithelium develops from
endoderm of laryngotracheal tube
• including glands
• Cartilage, connective
tissue and muscle from
splanchnic mesoderm
Splanchnic
Mesoderm
Endoderm
Cartilage
Smooth
muscle
Epithelial/Mesenchymal
Interactions
!
!
Endoderm
Mesoderm
In FGF10 deficient mice there are no
lung buds.
FGF2
FGF10
Development of the Lungs
• 4th week the lung bud
develops
• divides into two lung
buds
Development of the Lungs
• Two lung buds divide:
• The right one into three
main bronchi
• The left one into two
main bronchi
https://syllabus.med.unc.edu/
courseware/embryo_images/
unit-digest/digest_htms/
digest012a.htm
Development of the Lungs
• Bronchi continue to divide.
• By 6 months there have been 17 generations of
subdivisions.
• After birth there are an additional 6 divisions of
the bronchial tree.
• As growth occurs there is a caudal development
of the lungs.
• At birth the tracheal bifurcation is at the level of
the 4th thoracic vertebra.
Maturation of the Lungs
• There are 3 Stages of Lung Maturation
• 1. Pseudoglandular Period ( 5 - 16 weeks)
• 2. Canalicular Period (16 - 26 weeks)
• 3. Terminal Sac (Saccular) Period (26 weeks to
birth)
• There are 4(5) Stages of Lung Maturation
1. Embryonic ( 4 – 11 weeks)
2. Pseudoglandular Period ( 5 - 16 weeks)
3. Canalicular Period (16 - 26 weeks)
4. Saccular (Terminal Sac) Period (26 weeks to after birth)
5. Alveolar Period (late fetal period to childhood)
Maturation of the Lungs
• Pseudoglandular Period - 5 to16 weeks
• All elements of the lungs are developed except
those elements involved in gas exchange.
• Branching morphogenesis is prominent.
• Terminal Bronchioles present no respiratory
bronchioles
Branching morphogenesis
• Bud elongation
• Elongation stops
• Tip of the bud
widens
• Bifurcation
FGF10
FGF2
Factors involved
• Retinoic acid forms gradient with highest
levels proximally
– RA inhibits FGF10
• SHH promotes BMP4 which inhibits FGF10
• Wnt3b regulates BMPs which promote
proliferation of mesoderm.
• What BMPs are regulating is not precisely
known at the cellular level.
Maturation of the Lungs
• Canalicular Period - 16 - 26 weeks
• Overlap as cranial segments mature faster than
caudal ones.
• Lumen of bronchi and bronchioles become large
relative to tissues
• Bronchial tree branches become narrower.
• Respiratory bronchioles and alveolar ducts develop.
• Tissue becomes more vascular.
Maturation of the Lungs
• Canalicular Period
(16 - 26 weeks)
– Note the cuboidal
epithelium of the
airway.
– The blood vessels
are not close to the
epithelium
Maturation of the Lungs
• Terminal Sac Period
( 26 weeks - birth)
– Now the epithelium is
much thinner.
– The blood vessels
abut the epithelium
• What regulates the switch from
pseudoglandular to canalicular an to
terminal sac stage?
– Alveolar sacs begin to form
– Blood vessels become closely associated with
the alveolar cells.
Maturation of the Lungs
• Terminal Sac Period (26 weeks to birth)
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Terminal sacs develop
Epithelium becomes very thin
Capillaries bulge into the alveoli
Type I alveolar cells develop
Capillary network develops rapidly
Formation of Alveoli
• PDGF
• Fgf
– Fgf2 and Fgf18 important for late alveolar
development
• Retinoic acid
– High and low levels can disrupt lung
development.
Multipotential cell
Bronchiolar cells
Non neuroendocrine
cells
Neuroendocrine
cells
Alveolar cells
Type II cells
??
??
Ciliated cells
Goblet cells
Type I cells
Maturation of the Lungs
• By 20 weeks Type II alveolar cells begin
producing surfactant.
• Surfactant permits expansion of terminal sacs.
• Fetus needs to weigh 1000 gm and be between
26 and 28 weeks before enough surfactant is
produced.
• Surfactant and enough capillaries are necessary.
Maturation of the Lungs
• Alveolar Period ( late fetal period to
childhood)
• Squamous epithelium forms.
• During this period respiratory bronchioles end as
terminal sacs.
• Terminal sacs become alveolar ducts.
• Alveoli form after birth.
• From 3rd to 8th year alveoli continue to develop.
Maturation of the Lungs
• Alveolar Period
– Now there are:
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Type I alveolar cells
Type II alveolar cells
Macrophages
Fibroblasts
Lungs at Birth
• At birth the lungs are filled with fluid.
• Fluid is replaced by air.
• Fluid cleared through:
• Mouth and nose
• Pulmonary capillaries
• Pulmonary arteries, veins and lymphatics
• After birth most growth is in the number of
respiratory bronchioles and alveoli and not an
increase in the size of alveoli.
Formation of blood vessels
• Angiogenesis
– Angiogenesis new blood vessels from preexisting blood vessels
• Vasculogenesis
– angioblasts develop into endothelial cells and
new blood vessels form
• Vegf helps regulate this along with
ephrinB2 and B4
The pulmonary vasculature develops in the absence of lung specification.
•
Cardiac outflow tract
and pulmonary
vasculature come from
cardiopulmonary
mesoderm progenitors
that lie in the posterior
splanchnic mesoderm.
!
•
Lung mesenchyme
develops separately
from these progenitors.
T Peng et al. Nature 000, 1-4 (2013) doi:10.1038/nature12358
Clonal analysis reveals that CPPs generate related lineages
within the cardiopulmonary system.
T Peng et al. Nature 000, 1-4 (2013) doi:10.1038/nature12358
Hedgehog signaling is required in CPPs to coordinate the
vascular connection between the heart and lung.
T Peng et al. Nature 000, 1-4 (2013) doi:10.1038/nature12358
Development of Body Cavities
Development of HorseshoeShaped Pericardial Cavity
Lateral body folding
occurs as well as head
folding.
Development of Body Cavities
• In the fourth week the
embryo has:
– large pericardial cavity
– left and right
pericardioperitoneal
canals
– large peritoneal cavity
Embryonic Circulation
Common Cardinal Vein
Dorsal Aorta
Brain and Spinal Cord
Posterior
Cardinal Vein
Anterior
Cardinal
Vein
Umbilical Artery
Umbilical Vein
Yolk
Sac
Aortic Arches
Ventricle
Atria
BODY CAVITY
Septum
Transversum
Vitelline Artery
& Vein
Division of Body Cavities
• Pericardioperitoneal
canal is dorsal to
septum transversum.
• pericardioperitoneal
canal is lateral to the
foregut.
Septum Transversum
Division of Body Cavities
• As lung bud grows a
membrane develops
between the lungs and the
heart.
• Ridge of tissue grows into
the pericardioperitoneal
canals.
• Ridges grow from the
lateral walls of each canal.
• Ridges called
PLEUROPERICARDIAL
FOLDS
Division of Body Cavities
• Pleuropericardial membranes separate
pericardial cavity from pleural cavities.
• Pleuropericardial membranes contain the
common cardinal veins which drain in the
primitive heart.
• The internal layer of the pleuropericardial
membrane becomes the fibrous
pericardium.
Division of Body Cavities
• Pleuropericardial
Membranes
Division of Body Cavities
• Pleuroperitoneal
membranes separate the
pleural cavity from the
peritoneal cavity.
• Attachment to the to the
dorsolateral abdominal
wall.
• Project into the
pericardioperitoneal
canal.
• Fuse with the:
• dorsal mesentary of the
esophagus
• septum transversum
• Lateral body wall
mesoderm
Pleuroperitoneal
membranes
Development of the Diaphragm
• The diaphragm
develops from:
• Septum transversum
• Pleuroperitoneal
membrane
• Dorsal mesentary of the
esophagus
• Lateral body walls
(cervical somite
myotomes).
Development of the Diaphragm
• At week 4 the septum transversum lies
opposite the 3rd, 4th, and 5th cervical
somites.
• Myoblasts from these somites migrate into
the diaphragm.
• Phrenic nerve comes from cervical nerves
3, 4, and 5.
Development of the Diaphragm
• As body grows diaphragm appears to
migrate caudally.
• By 6 weeks diaphragm lies opposite
thoracic somites.
• Phrenic nerve passes through the
pleuropericardial membrane.
• Phrenic nerve comes to lie in fibrous
pericardium.