As faculty of Weill Cornell Medicine, we are committed to providing

transparency for any and all external relationships prior to giving an

academic presentation.
I do not have a financial interest in commercial products or services
related to the subject of this lecture.
My research funding sources are NIH, QNRF.

- Stefan Worgall
Erich Wieschaus Christiane Nüsslein-Vollhard

2
 Stages of Lung Development
Each stage of lung development is regulated by transcription factors
TTF1 BMP4
FGF10 TGF b
Sonic hedgehog Sox 2 Fox F1 Micro RNAi

There are
5 stages
Of lung
development

3
Development of the Respiratory Diverticulum

comes out
of the
tube that
the gut
develops
from
endoderm
 Embryonic Stage of Lung
Development
26 days – 6 weeks
Respiratory diverticulum arises
from foregut endoderm
the diverticulum divides
they become the main bronchi
Three rounds of branching
Two lung primordia
Lung lobes
Bronchopulmonary segments

This stage of development forms

structure until the bronchopulmonary
the airway segments 5
 Pseudoglandular Stage of
Lung Development

6 -16 weeks
14 more generations of branching
Terminal bronchioles
All conducting airways formed

Mature Lung
structure
festatemYns
dense

PSEUDOGLANDULAR STAGE i
the end
forms up until
of the conducting airbags
the
branching
6
 Canalicular Stage of Lung
Development
16 -28 weeks
- Terminal bronchioles divides into two
(or more) respiratory bronchioles
- Respiratory vasculature develops
- Epithelium differentiates:
Proximal: Ciliated, secretory, neuroendocrine
Distal: Alveolar type I and II
tins i
produce form
Surfactant
7
 Saccular Stage of Lung
Development

28 -36 weeks can dogas

on excnong
- Respiratory bronchioles divide to
form terminal sacs (primitive alveoli)
- Can do gas exchange
precursor of
an alveolus

space for the sacs

8
 Alveolar Stage of Lung
Development
36 weeks – term / 2 years finishes in
childhood
- Terminal sacs differentiate in cranio-
caudal progression to form alveoli
(septation) more smaller alveoli
form TSA
- Alveolar formation is finished at 3-10 yr (?)
- From 20 to 70 million terminal sacs before birth to 300 to 400 million
alveoli in the mature lung (surface 75 m2 vs 3 m2)

between alveoli
bronchi
- Less pores of Kohn and channels of Lambert
there
araeuopwoefo.bg
EaYera9weEnwmatn8natJ 9
 these develop
later on after
birth 4 yrs

Complex Interactive Processes

Airway branching
Morphogenesis
Alveolarization
Angiogenesis /
vasculogenesis

Patrick J. Lynch, medical illustrator, CC BY 2.5,

https://commons.wikimedia.org/w/index.php?curid=1493050

10
Fetal Lung Fluid and Fetal Breathing
Fetal lungs are filled with fluid
- secreted from epithelial cells
- mucus from bronchial glands
- surfactant

Breathing movements stimulate

lung development

Lung fluid is mostly resorbed at

birth by blood and lymph
Capillaries
there are water channels that
Loss of fetal lung fluid leads to help with Pediatrics in Review, 2008, 29: e59

the reabsorption
pulmonary hypoplasia
of f wid
fluid in fetal lungs shmulates
lung development 11
 Clinically Relevant Lung
Developmental Problems
Too short
Too small

Other Things gone wrong

12
 Too Small
Pulmonary Agenesis / Hypoplasia
Rare branch mg does NIT occur
p right so there is ONLY
one wing
Pulmonary agenesis, tracheal agenesis
More common
a hole in the diaphragm
Reduced volume in pleural cavity so the intestines are
pushed into the thoracic
cavity to space for
- decreased space: Congenital diaphragmatic hernia weng
development
- decreased amniotic fluid (oligohydramnios) g
so the wings
EEfecamsedd
Renal agenesis (Potter sequence)
fluid in the
Leakage of amniotic fluid fetal wing is
required for
- decreased fetal breathing (CNS, neuromuscular) development
decreased movement of the fetal 13

lung leads to A development

 Too early
Neonatal Respiratory Distress Syndrome
Lack of surfactant
Secreted by alveolar type II cells in last 2 months of gestation
Surfactant is composed of
lipids proteins mutations
in the proteins may cause
problems in adults too

Surfactant decreases surface tension

(Young-LaPlace law: P=2T/r)

Alveoli are polygonal and

are suspended in a
connective tissue matrix)
14

parts of the babies lung will collapse

 all aureole Coucy se

Neonatal Respiratory Distress Syndrome

and Bronchopulmonary Dysplasia

Respiratory Distress Syndrome (RDS)

Surfactant deficiency

Bronchopulmonary dysplasia
(chronic disease following RDS)
Arrest of lung vascular and alveolar development
development of the wings stopped too early

15
 Modulation of Alveolar Development

Amnionitis Ventilation, Oxygen,

Inflammation Infection

Intrauterine Lung Extrauterine Lung Normal or

Development Development Injured Lung

Canalicular Stage
Saccular Stage

Alveolar Stage
Preterm Delivery
at 26 weeks

20 24 28 32 36 40
Weeks gestation
16
 Things gone wrong

Errors in branching morphogenesis lead to abnormal

number of lobes, segments

Esophageal atresia and tracheoesophageal fistula

Congenital Abnormalities of Lower Airways (CALA)

17
 Esophageal Atresia /
Tracheoesophageal Fistula
90 %

Theoesophagus is NIT developed

properly ANI there is a
connection between the
oesophagus the trachea18
 Esophageal Atresia /
Tracheoesophageal Fistula
Results from failure of the foregut to separate
completely into trachea and esophagus
Polyhydramnios
Part of VATER / VACTERL association forest
defects
associated
Vertebral defects, anal atresia, TE-fistula, renal or with the
fistula
radial defects / cardiovascular and limb defects)
Associated with tracheomalacia

19
 Congenital Pulmonary Airway
Malformations (CPAM)
Form of pulmonary dysplasia (hamartoma) something goes
f wrong development
may lead to multiple
cysts in the wing

Associated with renal and

cardiac abnormalities
Pleuropulmonary blastoma may develop in CCAM

20
 Pulmonary Sequestration
Piece of lung without connection to tracheobronchial tree
with systemic arterial blood supply
2 types
Intralobar (probably acquired)
Shared pleura
Pulmonary venous drainage
Extralobar (genetic)
piece of that
a
the wing
Extra pleura tissue is
NOT connected
Systemic venous drainage to the airways

Clinical: infection, hemoptysis

21
 Fetal Circulation

Oxygen and Low

nutrients come
from placenta Resistance

and not from the High

lungs and gut Resistance
The resistance switches immediately after 22
birth
 9 resistance
very smart
amountOf
that are
tffegbEood s smoctures
different between
the our circulation
developing fetal
lungs Umbilical vein

Ductus venosus

1
goes around
Foramen ovale
the liner
E Ductus arteriosus
Pum anens aorta
biffed fifty Umbilical arteries
causes it to
shut
PLACENTA closes due to the
changes in pressure
after birth
Langman’s Medical Embryology

23
 Umbilical vein
O2 sat 80%, pO2 35 mmHg

Aorta
O2 sat 70%, pO2 20 mmHg

Umbilical arteries
O2 sat 55%, pO2 15 mmHg

Langman’s Medical Embryology

24
After birth
the placenta is cut circulation through that system now
has A resistance

the wings are filled with air resistance d

d
more blood goes through
the palm artery

The ductus arteriosus shuts within a couple of hours

vasculature in the duct reacts to Oa 902 encourages

it to shut
the placenta makes prostaglandins which helps keep
the duct open when the placenta is out there
are no
longer prostaglandins in circulation
i it shuts
 Circulatory Changes After Birth

Cessation of placental blood

flow

Beginning of respiration

Blood flow through lung

increases

25
 What Remains

Foramen ovale Closure (20% probe patency)

Umbilical Vein Ligamentum teres hepatis

Ductus venosus Ligamentum venosum

Ductus arteriosus Ligamentum arteriosum

Umbilical arteries Medial umbilical ligaments

They are all fibrotic structures

that have me relevance 26
 Sometimes

Persistent Ductus
Arteriosus
PDA

May NOT close due to

a resistance in the lungs
in premature babies
IQ due to infection
27
Development of Thoracic Cavity and Diaphragm
5 weeks Superior Cross section Inferior Cross section

Lung buds develop and grow into pleuroperitoneal canals

Pleuropericardial folds (dorsal wall mesenchyme)
- Contain phrenic nerve and cardinal veins
- Develop into pleuropericardial membranes
- Fuse in the end to create pericardial and pleural cavities
Septum transversum separates (incompletely) thoracic and abdominal cavity
- Openings are pericardioperitoneal canals
Pleuroperitoneal folds develop
28
 Development of Thoracic Cavity and Diaphragm
4 months Superior Cross section Inferior Cross section

Pleuropericardial folds fuse to create pericardial and pleural cavities

Septum transversum, pleuroperitoneal membranes, esophageal mesentery

and body wall mesenchyme fuse to create diaphragm
- innervation: septum transversum C3-5 (N. phrenicus)
body wall mesenchyme (N. vagus) Jada'EFFIE
the diaphragm29
have different
innervation
Diaphragm

Larsen's Human Embryology, 4th ed

30
 Diaphragmatic Hernia

Failure of pleuroperitoneal membranes to close the

pericardioperitoneal canals
1 in 2-3000 births
Mostly on left side
Complicated by pulmonary hypoplasia
and hypertension
Fetal intervention: tracheal occlusion

31
 Origin of Lung and Diaphragm
Summary
The Lung is composite of tissues derived from
- Endoderm: Mucosal lining of bronchi, epithelial cells
of alveoli
- Mesoderm: Vasculature, muscle, cartilage, visceral pleura
The Diaphragm is composite of
- Septum transversum
- Mesentery of esophagus
- Pleuroperitoneal folds
- Body wall mesenchyme 32
 Chest Wall Mechanics

4 months 14 years

2 Bucket-handle effect
position of the ribs limits 33
the ability to move
the chest
 Respiratory System Compliance
Changes with Age
The chest wall is more
compliant in a baby A compliance
Chest wall of the system Chest wall
Lung
Lung
RS
RS
Volume

Newborn Adult

Pressure
 Lung Regeneration

Progenitor Tracheal basal cells

Bronchiolar secretory cells (Club cells)

Cells Alveolar Type II

Alveolar epithelial progenitor cells (AEP)

Stem cells?

Zacharias et al, Nature 2018