Development of the Respiratory System

Thomas A. Marino, Ph.D.

Competencies: Upon completion of this section of the course, you must be able to:

• 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

Sox2 Esophagus

Nkx2-1 Lung Bud

FGF10 Wnt2 Bmp

Noggin

Notochord

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 laryngo- tracheal tube

• including glands

• Cartilage, connective tissue and muscle from splanchnic mesoderm

Endoderm

Splanchnic Mesoderm

Smooth muscleCartilage

Epithelial/Mesenchymal Interactions!!In FGF10 deficient mice there are no lung buds.

Endoderm Mesoderm

FGF10

FGF2

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

FGF10FGF2

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) • 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

Ciliated cells Goblet cells

Neuroendocrine cells

Alveolar cells

Type II 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: • 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 pre-

existing blood vessels • Vasculogenesis

– angioblasts develop into endothelial cells and new blood vessels form

• Vegf helps regulate this along with ephrinB2 and B4

T Peng et al. Nature 000, 1-4 (2013) doi:10.1038/nature12358

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.

Development of Body Cavities

Development of Horseshoe-Shaped 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 CirculationBrain and Spinal CordDorsal Aorta

Aortic Arches

Ventricle

Atria

Anterior Cardinal Vein

Posterior Cardinal Vein

Umbilical Vein

Umbilical Artery

Yolk Sac

Vitelline Artery & Vein

Common Cardinal Vein

BODY CAVITY Septum Transversum

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.