L 15 Respiratory System development

• The endoderm is responsible for instructing and forming the notochord, heart, blood vessels, and mesodermal germ layer. It also constructs the lining of the digestive and respiratory tubes within the vertebrate body.

Digestive and Respiratory Tubes

• The digestive tube gives rise to buds that form the stomach, liver, gallbladder, pancreas, and intestine.
• The respiratory tube develops as an outgrowth of the digestive tube, ultimately forming the lungs.

Respiratory System Zones

• The respiratory system doesn't facilitate gas exchange until after birth and is divided into two zones: the conduction zone and the respiratory zone.
• The conduction zone (upper respiratory tract) includes the nose, nasal cavity, and pharynx, and serves as a continuous passage for air movement.
• The respiratory zone (lower respiratory tract), encompassing the larynx, trachea, bronchi, and lungs, is where gas exchange occurs.

Respiratory System Development

• Lung development starts at 4 weeks with a ventral outpocketing of the foregut endoderm.
• Initially, the digestive and respiratory tracts share a common cavity, which is later divided into thoracic and abdominal components.
• The lungs undergo 4 histological phases of development in utero, with morphogenesis continuing after birth and stabilization around age 8.
• Thyroid hormone, respiratory motions, and amniotic fluid play a role in lung maturation late in fetal development. Premature infants often have weak lungs due to the absence of this maturation process

Respiratory System Origins

• The respiratory system originates from the early pharynx, beginning as a median outgrowth (laryngotracheal groove) on the floor of the caudal end of the early pharynx.
• This development occurs caudal to the 4th pharyngeal pouch.
• By the end of week 4, the laryngotracheal groove protrudes to form the lung bud, also known as the laryngotracheal diverticulum or respiratory diverticulum.
• The ventral foregut, where the respiratory system develops, expresses the transcription factor Nkx 2.1, while the dorsal wall expresses Sox-2.
• Sox-2 expression is the default for the dorsal part of the foregut endoderm.
• Expression of Nkx-2.1 in the ventral half is stimulated by Wnt signaling from the mesodermal wall of the gut.
• BMP in the VENTRAL mesoderm suppresses Sox-2 signaling in the ventral half of the gut tube.
• Noggin signaling from the notochord suppresses BMP signaling in the dorsal half.

Key Players

• Nkx-2.1: ventral foregut
• Sox-2: dorsal wall of foregut
• Wnt: mesodermal wall of the gut
• BMP: ventral mesoderm
• Noggin: notochord

Respiratory Tube Specification

• The regional specificity of the mesodermal mesenchyme determines respiratory tube differentiation.
• In the neck region, the tube grows straight and becomes the trachea.
• In the thorax region, the tube branches and becomes the bronchi and lungs.

Larynx Formation

• During weeks 4-5 of gestation, rapid proliferation of the fourth and sixth pharyngeal arch mesenchyme around the site of origin of the respiratory bud converts the opening slit from the esophagus into a T-shaped glottis. The glottis is bounded by two lateral arytenoid swellings and a cranial epiglottis.
• Mesenchyme transforms into the thyroid, cricoid, and arytenoid cartilages, forming the larynx's skeletal supports, and the lumen of the larynx undergoes epithelial occlusion.
• During weeks 9-10, lateral folds and recesses form the structural basis for the vocal cords and adjacent laryngeal ventricles.
• Somitomere-derived musculature of the larynx is innervated by branches of the vagus nerves, with the fourth arch musculature innervated by the superior laryngeal nerve and the sixth arch musculature by the recurrent laryngeal nerve.

Trachea and Bronchial Tree

• A pair of bronchial buds appear, with the straight portion of the diverticulum forming the primordial trachea.
• The bronchial buds give rise to the primary bronchi, which then form additional lobes (3 right, 2 left) that become the secondary bronchi.
• Each secondary bronchial bud undergoes further branching during embryonic and fetal life, involving a combination of Hox gene expression.

Molecular Aspects of Respiratory Duct Elongation

• Retinoic acid and Tbx4/5, produced by the mesenchyme at the tip of the growing respiratory bud, stimulate FGF-10 production by the mesenchyme.
• FGF-10 stimulates cell proliferation in the epithelium at the head of the bud, causing it to grow towards the source of FGF-10. Apical epithelial proliferation is also promoted by Nkx-2.1 expression.

Branching Prelude

• Branching is initiated when apical epithelial cells of the elongating bud secrete BMP-4, which inhibits proliferation.
• BMP-4 prevents straight growth and facilitates branching.
• Shh, produced by epithelial cells, stimulates mesenchymal cell proliferation at the tip and inhibits FGF-10 formation.
• Mesenchymal cells produce TGT-beta1, which inhibits FGF-10 and promotes ECM protein synthesis, stabilizing the elongating respiratory duct.

Cleft Formation and Branching

• ECM molecules like fibronectin and collagen I, III, and IV stabilize the growing tip.
• FGF-10 secreted by mesenchyme lateral to the old apex initiates branching at two new signaling centers on either side of the original one.
• Tenascin is important for the stability of epithelial sheets along ducts.
• Hoxa-5 and Hoxa-6 are expressed early in the development of smaller bronchioles but not in gas exchange regions.
• Empimorphin is important for the formation of epithelial tubes, establishment of polarity, and cell arrangement. If blocked, branching becomes disorganized.
• Smooth muscle formation in the mesenchyme depends on Shh and BMP-4 signals from distal epithelial buds. FGF-9 controls the proliferation and differentiation of smooth muscle.

Embryonic Stage (Weeks 4-7)

• The lungs grow into and begin to fill the bilateral pleural cavities, major components of the thoracic body above the pericardium.

Pseudoglandular Stage (Weeks 8-16)

• Major formation and growth of the duct systems within the bronchopulmonary segments occurs, with the lung resembling a gland.
• The pulmonary arterial system begins to form, and elongating vessels run parallel to major developing ducts.

Canalicular Stage (Weeks 17-26)

• Respiratory bronchioles form, with a BMP-4 and Wnt gradient highest at the distal tips of branches to prevent distal cells from forming phenotypes characteristic of larger branches.
• There is intense growth of blood vessels and close association of capillaries.

Terminal Sac Stage (Weeks 26-Birth)

• Alveoli bud off and differentiate into type 1 and type 2 alveolar cells.
• Type I alveolar cells (pneumocytes) facilitate gas exchange after birth.
• Type II alveolar cells produce pulmonary surfactant to reduce surface tension and allow lung expansion during breathing.
• Type II cells form first, then differentiate into Type I cells. The respiratory tract in the fetus is filled with fluid. 90% of the alveoli form after birth.

Postnatal Stage

• 95% of alveoli develop postnatally, with a sufficient amount of alveoli present by age 8.

Tracheoesophageal Fistulas

• This malformation involves abnormal separation of the tracheal bud from the esophagus during early development.
• It manifests early after birth as choking or regurgitation of milk when feeding due to lack of correct transcription factor functioning.

Rare Malformations

• Tracheal agenesis, caused by defective separation between the esophagus and the respiratory diverticulum, and pulmonary agenesis, due to mutation of fibroblast growth factor 10 leading to null mutation of key molecules, are incompatible with life.