Respiratory System Development

• The respiratory system is divided into the upper and lower respiratory tracts/systems.
• Development of the lower respiratory tract begins on day 22 and continues to form the trachea, lungs, bronchi, and alveoli.
• The process of the lower respiratory tract divides into five phases: embryonic, pseudoglandular, canalicular, saccular, and alveolar.

Respiratory System

• Upper respiratory tract consists of the nose, nasal cavity and paranasal sinuses, and pharynx.
• Lower respiratory tract consists of the larynx, trachea, bronchi, and lungs.

Development of Lower Respiratory Tract and Lungs

• The primordium is the ventral wall of the foregut, which develops into the laryngotracheal groove, and then into the laryngotracheal diverticulum.
• The respiratory system starts as median outgrowths known as the laryngotracheal groove, appearing in the floor of the caudal end of the anterior foregut, otherwise know as primordial pharynx.
• Primordium of the tracheobronchial tree develops caudal to the 4th pair of pharyngal pouches.
• The endodermal lining of the laryngotracheal groove forms the pulmonary epithelium and glands of the larynx, trachea, and bronchi.
• Connective tissue, cartilage, and smooth muscle develop from the splanchnic mesoderm surrounding the foregut
• The laryngotracheal groove protrudes at the end of the 4th week to form the laryngotracheal diverticulum.
• Laryngotracheal diverticulum elongates after investing with splanchnic mesenchyme.
• The distal ends of the laryngotracheal diverticulum enlarge to form a respiratory bud (lung bud).
• The right and left lung buds first appear as two lateral outpouchings of the foregut, on either side of the tracheal primordium.
• The laryngotracheal diverticulum separates from the primordium pharynx, maintaining communication through the primordial laryngeal inlet.
• Longitudinal tracheoesophageal folds develop in the diverticulum, approach each other, and fuse to form a partition known as the tracheoesophageal septum.
• At the end of the 5th week, the septum divides the cranial portion of the foregut into a ventral part: the laryngotracheal tube (primordium of the larynx, trachea, bronchi, and lungs); and a dorsal part: the primordium of the oropharynx and esophagus.
• A longitudinal tracheo-esophageal septum (esophagotracheal) develops and divides the diverticulum into a ventral and dorsal portion.
• The ventral portion primordium becomes the larynx and trachea; bronchi and lungs.
• The dorsal portion primordium becomes the oropharynx and esophagus.

Respiratory Primordium: Larynx

• The opening of the laryngotracheal diverticulum into the primitive foregut becomes the laryngeal orifice.
• The epithelium and glands are derived from the endoderm.
• Laryngeal muscles and the cartilages of the larynx, except for the epiglottis, develop from the mesoderm of the 4th & 6th pairs of pharyngeal arches.
• The laryngeal epithelium proliferates rapidly, resulting in temporary occlusion of the laryngeal lumen.
• Recanalization of the larynx normally occurs by the 10th week.
• Laryngeal ventricles, vocal folds, and vestibular folds are formed during recanalization.

Respiratory Primordium: Trachea

• The endodermal lining of the laryngotracheal tube distal to the larynx differentiates into the epithelium and glands of the trachea and pulmonary epithelium.
• The cartilages, connective tissue, and muscles of the trachea are derived from the mesoderm

Maturation of the Lung: Embryonic Phase

• The embryonic phase takes place between the third and sixth week of gestation.
• Lung development begins during the third week with the appearance of a respiratory diverticulum (lung bud) as an outgrowth from the ventral wall of the foregut.
• The lung bud expands in a ventral and caudal direction, invading the mesenchyme surrounding the foregut.
• The distal end of the lung bud bifurcates into the right and left primary bronchial buds; the proximal end forms the trachea and larynx.
• By the fifth week of gestation, the primary bronchial buds form three secondary bronchial buds on the right side and two on the left, foreshadowing the primordial lobes of the lungs.
• Each secondary bronchial bud gives rise to ten tertiary bronchi on the right side and eight on the left, demarcating the end of the embryonic phase.
• Tertiary bronchi become the bronchopulmonary segments of the adult lung.

Maturation of the Lung: Pseudoglandular Phase

• The pseudoglandular phase takes place during between the sixth and sixteenth week of gestation.
• The developing lungs resemble an exocrine gland.
• Respiratory tree undergoes twelve to fourteen more generations of branching, resulting in the formation of terminal bronchioles.
• Beginning around week 13, the lumens of the bronchi begin to expand in diameter.
• By 16 weeks, all major elements of the lung have been formed except those involved in gaseous exchange.
• Terminal bronchioles are formed, with no respiratory bronchioles or alveoli present
• Respiration is not possible at this stage.
• A fetus born during this period cannot survive.

Maturation of the Lung: Canalicular Phase

• The canalicular phase takes place during the sixteenth and twenty-eighth week of gestation.
• Lung tissue becomes highly vascular.
• Each terminal bronchiole further divides into respiratory bronchioles.
• The lumens of the respiratory bronchioles become enlarged, a result of the thinning of their epithelial walls.
• By about week 19 the respiratory bronchioles have formed; cells lining the respiratory structures begin to differentiate to form type I and type II pneumocytes.
• Once type II cells have differentiated, they begin to secrete small amounts of pulmonary surfactant.

Maturation of the Lung: Saccular Phase

• The saccular phase takes place between the twenty-eighth and thirty-sixth week of gestation.
• The respiratory bronchioles give rise to a final generation of terminal branches.
• Many terminal sacs are developed.
• Their epithelium becomes very thin.
• Branches become invested in a dense network of capillaries, forming the terminal sacs (primitive alveoli) that are lined with type I and type II alveolar cells.
• Type I alveolar cells (type I pneumocyte) are branched cells.
• Type II alveolar cells act as the “caretaker” by responding to damage of the type I cells.
• Type II alveolar cells do this by dividing and acting as a progenitor cell for both type I and type II cells.

Maturation of the Lung: Alveolar

• A main milestone of respiratory development occurs around week 28, when sufficient alveolar precursors have matured so that a baby born prematurely at this time, can usually breathe on their own.
• The alveolar phase is characterized by the maturation of the alveoli, a process that takes place during fetal life to many years after birth.
• Mature alveoli do not form until after birth; 95% of alveoli develop postnatally.
• About 50 million alveoli, one sixth of the adult amount, are present in the lungs of a full-term newborn infant.
• From about 3-8 years, the number of alveoli keeps increasing, forming additional ..

Fetal Breathing

• Fetal movement and fetal tone develop between 7.5 and 9 weeks' menstrual age.
• Fetal breathing movements are detectable by at least 17-18 weeks gestation.
• The non-stress test is most reliable between 32 weeks and term.
• Fetal breathing movements involve muscle contractions that cause the inhalation of amniotic fluid and exhalation of the same fluid, with pulmonary surfactant and mucus.
• Fetal breathing movements are not continuous and may include periods of frequent movements and periods of no movements.
• Maternal factors can influence the frequency of breathing movements.
• Increased blood glucose i.e. hyperglycemia, can boost the number of breathing movements, while decreased blood glucose i.e. hypoglycemia reduces the number of fetal breaths.
• Tobacco use is known to lower fetal breathing rates.
• Fetal breathing may help tone the muscles in preparation for breathing movements once the fetus is born.
• Fetal breathing may help the alveoli to form and mature.
• Fetal breathing movements are considered a sign of robust health.

Birth

• Prior to birth, the lungs are filled with amniotic fluid, mucus, and surfactant.
• As the fetus is squeezed through the birth canal, the fetal thoracic cavity compresses expelling much of this fluid.
• Some fluid remains but is rapidly absorbed by the body shortly after birth.
• The first inhalation occurs within 10 seconds after birth and not only serves as the first inspiration, but also acts to inflate the lungs.
• Pulmonary surfactant is critical for inflation, reduces the surface tension of the alveoli.
• Preterm birth around 26 weeks frequently results in severe respiratory distress, though with current advances, some babies may survive; but prior to 26 weeks, sufficient pulmonary surfactant isn't produced sufficiently & the surfaces for gas exchange don't form, so survival is low.
• Lungs at birth are half filled with fluid that is derived from amniotic fluid, from the lungs & tracheal glands.
• Fluids in the lungs at birth are cleared by pressure on the fetal thorax during delivery, and by absorption into the pulmonary capillaries and lymphatics.
• Lung growth depends on adequate thoracic space, fetal breathing movements, and amniotic fluid volume.

Clinical Correlations: Respiratory Distress Syndrome (RDS)

• Primarily occurs in infants born prematurely.
• RDS results from insufficient pulmonary surfactant, which prevents proper lung inflation.
• Up to 50% of infants born between 26 and 28 weeks, and fewer than 30% of infants born between 30 and 31 weeks, develop RDS.
• A small amount of pulmonary surfactant begins to be produced at around 20 weeks, which is insufficient for inflation of the lungs; resulting in dyspnea and impaired gas exchange.
• Blood oxygen levels are low, while blood carbon dioxide levels and pH are high.
• The primary cause is premature birth, with other risk factors including gestational diabetes, cesarean delivery, second-born twins, and family history of RDS.
• RDS can lead to other serious disorders, e.g., septicemia (infection of the blood) or pulmonary hemorrhage, therefore, must be immediately recognized and treated to reduce risk of death/developing other disorders.

Clinical Correlations: Delivery, Tracheoesophageal Fistula (TEF), and Esophageal Atresia (EA)

• If an infant doesn't breathe on their own: treatment can include resuscitation and intubation that could require placing them on a ventilator to mechanically assist.
• If there is spontaneous breathing, the application of nasal continuous positive airway pressure (CPAP) may be required.
• Pulmonary surfactant is often administered.
• Death due to RDS has been reduced by 50% with pulmonary surfactant therapy.
• Other therapies could include the administration of: corticosteroids, supplemental oxygen, assisted ventilation, temperature regulation, nutritional support, & antibiotics to the premature infant.
• TEF: an abnormal connection between tracheal/esophageal lumens, occurring once in 3000-4000 infants and is more common in males.
• Most TEF cases (85%) are associated with EA, and result from incomplete division of the cranial part of the foregut into respiratory and esophageal parts during the 4th week of development.
• EA: A blind-ended closure of either the proximal and/or distal parts of the esophagus.