Respiratory Development

The respiratory system has several parts which develop independent of each other. The nose and nasal cavity develop from the head ectoderm and the neural crest mesenchyme, The pharynx develops from the endoderm of the primitive gut and surrounding mesenchyme, whereas the larynx, trachea and the lungs develop from the lung bud which is endodermal and from the surrounding mesenchyme.

Development of the Nose

The development of the nose comprises several processes which include the nasal placode formation, invagination of the nasal placodes forming the nasal pits, formation of the nasal sacs, and formation of the nasal septum.  

In the 4^th week or 5^th week of gestation neural crest cells migrate caudally towards the midface to induce the formation of two symmetrically positioned nasal placodes; the nasal placodes which are also called the olfactory placodes are thickenings of the head ectoderm which differentiate into the nasal epithelium. Proliferation of the neural crest mesenchymal cells at the margins of each of the nasal placodes produces a depression known as the nasal pit, which deepens and sink into the stomodeum to form the nasal sacs or the primary nasal cavity. A nasobuccal or oronasal membrane separates the nasal cavity from the underlying oral cavity. The nasal or olfactory pits deepen further communicate with the pharynx forming the primitive choanae or the posterior nasal apertures. Initially the nasal sacs are lined by a single layer of flattened cells, which proliferate forming two to three layers of undifferentiated spherical cells. In the 8^th week of gestation, the olfactory epithelium, which is a sensory epithelium, develops  in the cranial portion of the human nasal cavity. In the 9^th week of gestation, the pseudostratified ciliated columnar epithelium which characterizes the respiratory mucosa of the nose appears in the developing fetal nasal cavity; However, goblet cells and epithelial cells of  the nasal glands appear later in weeks 14^th to 16^th of embryonic development.

The nasal septum comprises an anterior cartilaginous component known as the septal cartilage and a posterior bony component known as the bony septum, which consists  of the vomer and the perpendicular plate of the ethmoid. The nasal septum is derived from the mesenchyme occupying the space between the two primary choanae. The developing septal primordium fuses with palatal shelves. The mesenchymal cells differentiate into chondroblasts that lay a matrix of hyaline cartilage, thus forming a cartilaginous septum. The bony septum (the perpendicular plate of the ethmoid and the vomer develop by endochondral ossification of the hyaline cartilage. The perichondrium and the periosteum develop from the surrounding mesenchymal cells.

The nasal conchae

The nasal pits divide each placode into medial and lateral nasal processes. The medial processes become the septum, philtrum, and premaxilla of the nose, whereas the lateral processes form the sides of the nose.

Fig. 11.1. The illustration on the left is of a front view of the head in the 5^th week of gestation showing the nasal placodes and the nasal pits and their relation to the oral cavity. The illustration in the middle is a coronal section of the nasal cavity showing the developing nasal septum and the developing nasal conchae. The illustration on the right is of a coronal section of nasal cavity showing the fully developed nasal septum and nasal conchae.

Development of the Nasopharynx

In the 4^th week of embryonic development, the cranial end of the foregut, which is endodermal in origin, expands and gives rise to pairs of lateral outpocketings known as the pharyngeal pouches numbered from 1 to 6. Several different glands and structures develop from these pouches; they include the thyroid gland, the parathyroid glands, the thymus, the tonsils, the tympanic cavity, the Eustachian tube, the oropharynx, and the nasopharynx. The endoderm of the nasopharynx differentiates to form the pseudostratified ciliated columnar epithelium with goblet cell. The underlying mesenchyme differentiates into the connective tissue elements and musculature of the nasopharyngeal wall. After complete development the nasopharynx is bound superiorly by the base of the skull, anteriorly: the nasal cavity, posteriorly by the posterior pharyngeal wall, inferiorly by the soft palate, and laterally by the medial pterygoid plates.

Development of the Larynx

The first indication of the development of the larynx is the development of the  laryngotracheal groove on the ventral wall (the floor) of the pharynx in the 4th week of embryonic development. In the same week, the  groove differentiates into the primitive laryngeal sulcus and the respiratory primordium where from the right and left lung buds develop. The laryngotracheal groove ultimately develops into the esophagotracheal septum that separates the respiratory system anteriorly from the esophagus posteriorly. The region of origin of the larynx lies between the 4th and 6th pharyngeal arches.  The laryngotracheal groove deepens, gradually its lateral edges approach each other and fuse forming a tube that descend. The tube is separated from the overlying esophagus by the tracheoesophageal septum. The fusion occurs in the caudocranial direction but is incomplete at the end of the tube resulting in a persistent communication between this laryngotracheal tube and the pharynx. From this point onwards the respiratory tract and gastrointestinal tract develop separately. The epithelium of the larynx is of endodermal origin whereas the laryngeal stroma and cartilages are from the mesenchyme of the 4th to 6th pharyngeal arches.

In the 5th week of gestation, the development of the larynx becomes evident with the appearance of the mesenchymal-arytenoid swellings from the sixth branchial arches, just adjacent to the cranial end of the laryngotracheal tube. These swellings come closer to each other and the midline and abut the caudal end of the hypobranchial eminence thus converting the vertical laryngotracheal opening into a T-shaped aperture, thus forming the glottis. The arytenoid swellings develop into the arytenoid and corniculate cartilages and the primitive aryepiglottic folds.

The epiglottis develops in the 4^th  and 5^th weeks of embryonic development from the 4^th pharyngeal pouch and arch, specifically from a median swelling on the floor of the pharynx known as the epiglottic swelling which differentiates into the epiglottis.

Fig. 11.2. The illustration on the left shows the pharyngeal pouches and the origin of larynx (laryngeal inlet and arytenoid eminence) and the epiglottis (epiglottic swelling). The illustration on the left shows the relations of the developing larynx to the developing pharynx, trachea and esophagus.  

Development of the Trachea

In the 5^th week of gestation, the trachea develops from the respiratory diverticulum as a ventral outpocketing of the foregut; thus, the diverticulum is an endodermal outgrowth. It is a ventral outgrowth that elongates and becomes separated from the foregut by a septum called the tracheoesophageal septum. The proximal part of this primordium remain tubular and develops into the trachea, whereas its distal end distends into two bulbar structures called the lung buds. The epithelial lining of the trachea and the epithelium of the tracheal glands are foregut endodermal in origin, whereas the tracheal cartilaginous rings, the tracheal stroma and the tracheal smooth muscle fibers are all derived from the splanchnic mesoderm.

Fig. 11.3. The illustrations show the process of development of the trachea from the foregut.

Development of the Lungs

The lungs are made of bronchi, bronchioles, alveoli, connective tissue elements, blood vessels and nerves are surrounded by the pleura. All lining epithelia of theses passages in addition to pulmonary glandular epithelium are derived from the endoderm of foregut, which the hyaline cartilage of these passages along with all pulmonary connective tissue elements are splanchnic mesoderm origin.

The lungs and the extrapulmonary bronchi develop from a primordia known as the  lung respiratory diverticulum or the lung buds. The proximal part of the respiratory diverticulum the trachea, whereas its distal end expands and bifurcates a pair of buds often referred to as the bronchial buds because they differentiate and develop into the right main and left main bronchi. The endoderm of these buds differentiate into the pseudostratified columnar ciliated epithelium lining the primary or main bronchi; it also gives rise to the small compound seromucous bronchial glands. The flakes of bronchial hyaline cartilage, the bronchial smooth muscle fibers and the connective tissue elements of the bronchial wall are all derived from the splanchnic mesoderm.

Fig. 11.4.  The illustration relates the primordia of the trachea, bronchi and lungs to the endoderm of the foregut.

In the 5^th week of gestation, the primary bronchial buds give rise to two secondary bronchial buds on the left side, and three secondary buds on the right. Each secondary bronchial bud branches into ten tertiary bronchial buds. The developing lung is described to be in the pseudo glandular phase in the period between the 6^th and 16^th week of gestation. During this phase, the respiratory tree undergoes twelve cycles of branching giving rise to the terminal bronchioles.

Fig. 11.5. The illustrations show how branching of the bronchial buds yields different numbers of lobes in the right and left lungs.

The phase that follows is known as the canalicular phase and it spans over the 16^th to 20^th week of gestation. During this phase, the terminal bronchioles divide and yield the respiratory bronchioles which are characterized by the presence of solitary alveoli in their walls that are lined by a simple cuboidal epithelium. The lumena of the respiratory bronchioles become wider during this phase.

Fig. 11.6.  The illustration shows that the right has three lobes and the left lung has only two lobes. This resulted from the different branching patterns of the right and left bronchial buds during embryonic development.

The phase that follows the canicular phase is saccular phase that spans over the period extending from 28^th to 36^th week of gestation. During this phase, the respiratory bronchioles give rise to the alveolar ducts and the alveolar sacs. The final part of this phase is referred to as the alveolar phase which is characterized by maturation of the alveoli. The alveolar phase spans between the end of the fetal life and postnatally to early childhood.

Thus, the lung lobes develop from the primary bronchial buds during the embryonic stage of lung development. The right lung bud branches into three secondary buds, forming the three right pulmonary lobes, whereas the left lung bud branches only into two secondary buds, forming the two left pulmonary lobes. The lobar buds further subdivide to form the bronchopulmonary segments, which are fundamental functional units of the lungs, each supplied by a segmental bronchus. In turn, each bronchopulmonary segment subdivides into pulmonary lobules, each of which is supplied by a terminal bronchiole. The terminal bronchiole branches and give rise to respiratory bronchioles that are characterized the presence of solitary alveoli in their walls.

Fig. 11.7.  The illustration shows the pulmonary lobules which is also called the lung acinus as a group of alveolar sacs supplied by a single terminal bronchiole

During the early phase of their development, both lungs grow into the pericardioperitoneal canals of the body cavity which communicate freely with the peritoneal and pericardial cavities. When the pleuroperitoneal and pleuropericardial folds develop, they then separate the pericardioperitoneal canals from the peritoneal and pericardial cavities, thus resulting in the formation of the pleural cavity. The visceral pleura develops from the splanchnic mesoderm and covers the outer surfaces of the lungs, whereas the parietal pleura is derived from the somatic mesoderm and lines the chest wall.

The endodermal cells that line the developing bronchial tree are multipotent cells that differentiate into several functional cell types that include the ciliated columnar cells, goblet cells, brush cells, small granule cells, Clara cells, type-1 pneumocytes and type-2 pneumocytes.

The ciliated columnar cells are principle cell type present in the epithelial lining of the nasopharynx, larynx, trachea and bronchia. Along with mucus blanket produced by the goblet cells and mucosal glands, the ciliated cells constitute a powerful defensive mechanism that protects the respiratory passages from harmful inhaled substance and microorganism. Brush cells, which are also known as tuft cells, are characterized by a tuft of microvilli (not cilia) in their free apical surface; they considered sensory receptor cells that detect harmful substances in the inhaled air. The bronchial small granule cells, which are also known as the neuroendocrine cells or the Kulchitsky cells are argyrophilic cells that are characterized by small dense core granules present in their basal parts; they are involved in local reflexes that regulate the airway tone. Clara cells, which are also known as club cells, are confined to the epithelium of bronchioles. They are non-ciliated cuboidal cells that secrete small amounts of surfactant and other specific proteins that reduces the surface tension of fluids covering the epithelial surface. Type-1 pneumocytes are thin squamous cells that line the pulmonary alveoli; they participate in the formation of the blood-air barrier and facilitates gaseous exchange between alveolar air and capillary blood. Type-2 are cuboidal cells present amongst type-1 pneumocytes; they produce surfactant that reduces alveolar surface tension preventing alveolar collapse. The respiratory epithelium also contains short basal cells that are considered to be progenitor cells.

Fig. 11.8.  The illustration shows the origin of primordia of the major parts of the respiratory system.

Fig. 11.9. The illustration shows the various types of functional cells that are present in the epithelium of the respiratory passages.

Although the initial primordia of the various parts of the respiratory system are either endodermal or ectodermal, yet the mesoderm and neural crest mesenchyme contributes quite significantly to the formation of every part of the respiratory system. Thus, whereas the epithelium and glands of the vestibular, the respiratory and olfactory regions of the nose are ectodermal in origin, yet nasal cartilage, bones and connective tissue elements neural crest mesenchymal in origin. Likewise, whereas the pharyngeal epithelium is ectodermal in origin, the pharyngeal musculature and the pharyngeal wall connective tissues are mesodermal in origin. Similarly, whereas the surface epithelium and the glandular epithelium of the larynx, trachea, bronchi, bronchioles and alveoli are endodermal, yet the musculature, the cartilages, and the connective tissue elements of the larynx, trachea, and lungs are derived from the splanchnic mesoderm.  

Fig. 11.10. The illustration classifies tissues of the various parts of the respiratory system in according to their primary germ origin.

Development of the Diaphragm

The diaphragm separates the chest cavity from the abdominal cavity plays a crucial role in respiration; it is mesodermal, and its development involves the formation of a dome-shaped muscle that separates the chest cavity from the abdominal cavity. The process of its development involves several steps that include the formation of the septum transversum which is mesenchymal in origin, development of the diaphragmatic musculature, development of the pleuroperitoneal folds, development the diaphragmatic crura, which are muscles that attach diaphragm to the lumbar vertebrae. Development of the septum transversum commences in the 4^th week of gestation and continues until the 8^th week. It emerges from the ventral body wall and grows dorsally until it opposes the pericardial sac.  

Fig. 11.11.  The illustration is a cross section the embryo showing the septum transversum (orange in colour) developing the ventral abdominal wall.

Congenital defects of the diaphragm include diaphragmatic eventration where the diaphragm is partially or completely absent, and diaphragmatic hernia where there is a hole in the diaphragm that allows passage of some of the abdominal organs from the abdomen into the thoracic cavity.

Congenital Anomalies of the Respiratory System

Congenital anomalies of the respiratory system are caused by genetic and environmental factors and could be structural or functional; they include the following:

• Arrhinia which is absence the nose resulting from complete failure of development of the nose.

• Nasal hypoplasia where the skin, cartilage, or bones of the nose are not fully developed.

• Nasal hyperplasia where the skin, cartilage, or bones of the nose are over developed.

• Deviated nasal septum that result from abnormal growth the nasal cartilage.

• Choanal atresia which causes lack of proper communication between the nasal cavity and the nasopharynx.

• Tracheal atresia where the trachea is completely blocked or absent.

• Tracheoesophageal fistula, which results from incomplete development of the esophagus and its malconnection to the trachea.

• Pulmonary agenesis where one or both lungs fail to develop.

• Congenital pulmonary airway malformation where abnormal tissues grow in the lung.

Congenital anomalies of the respiratory system may result in respiratory distress that causes difficulty in breathing and feeding difficulties.

Fig. 11.12.  Congenital arrhinia in a child.

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