• Anatomy of the mature respiratory system
• Principles of respiratory system development
• Developmental stages of the respiratory system

• The conducting portion
• The respiratory portion

The conducting portion

The conducting portion of the respiratory system consists of the following components:

• Nasal Cavity. Contains hairs to filter out particulate matter, and olfactory mucosa to provide a sense of smell.
• Pharynx. Acts as a resonant cavity for speech also serves as part of the alimentary tract.
• Larynx. Contains vocal folds which generate the voice. The larynx and all structures beyond can be isolated from the pharynx during swallowing.
• Trachea. Provides a flexible connection between the lungs and the more rigid structures of the upper respiratory tract.
• Bronchi. The trachea divides into 2 primary bronchi which lead into the left and right lungs. Secondary (etc) bronchii then ramify throughout the lungs.
• Bronchioles. The final conducting portions of the lungs, less than 1mm in diameter and devoid of cartilage, which undergo more branching divisions The final segments are called terminal bronchioles, which occur at about the 16th level of branching and lead into the respiratory portion of the lung.

The conducting portion of the respiratory tract is lined with a pseudostratified columnar epithelium. The upper reaches, from the trachea to the mid-sized bronchioles, consist of three main cell types;

• Ciliated cells. Possess motile cillia which extent into the lumen of the airway and sweep upwards in coordinated waves. Their action moves the mucous coat upwards along with trapped particles to be expelled.
• Goblet cells. Produce and secrete the mucous covering of the airways. This humidifies inhaled air and traps foreign particles, protecting the deeper portions of the lung.
• Basal cells. Do not extend into the lumen and are the stem cells for other cell types.

The respiratory portion

This consists of respiratory bronchioles, which lead to the alveolar components. Respiratory bronchioles are similar in construction to terminal bronchioles, except that the walls are periodically interrupted by alveoli which are capable of gas exchange. When the proportion of interspersed alveoli increases to the degree where they occupy the majority of the surface of the airway, the passages are termed alveolar ducts. Alveolar ducts end in clusters of alveoli termed alveolar sacs. The alveolus can be considered is the unit of gas exchange. It's walls are composed of two epithelial cell types;

• Type-I pneumonocytes are squamous pulmonary epithelial cells that form about 95% of the alveolar surface. They is an extremely thin and form part of the blood/air interface, the gasses diffusing through the cell.
• Type-II pneumocytes are cuboidal and generally located at the junctions between alveoli. They secrete phospholipid-rich pulmonary surfactant.

The respiratory system begins as a ventral outgrowth (laryngotracheal groove) from the wall of the foregut, close to the fourth and sixth pharyngeal pouches. The groove deepens and grows downwards to form a pouch-like evagination, fully open to the foregut. Two longitudinal folds of tissue (tracheo-oesophogeal folds) on either side of the groove grow together and fuse, forming a new tube (laryngeotracheal tube) distinct from the foregut. Communication with the foregut is maintained via a longitudinally oriented slit-like opening (laryngeal orifice). Proliferation of the underlying mesenchyme forms swellings around the laryngeal orifice (epiglotal swelling and arytenoid swellings) from which the epiglottis, glottis, laryngeal cartilages and musculature will develop. At the same time, the laryngeotracheal tube elongates downwards and penetrates the underlying splanchnopleuric mesoderm. A distinct swelling develops at the distal end and is termed the lung bud (respiratory diverticulum).

Approximately 28 days after fertilisation, the lung bud branches to form the left and right primary bronchial buds, which will ultimately develop into the left and right lungs. Branching is in part directed by the interaction of the epithelium with the underlying splanchnic mesoderm. By the fifth week, elongation, branching and budding of the two bronchial buds gives rise to three bronchial stems on the right and two on the left - these are the foundation for the lobular organisation of the mature lung.

Dichotomous branching continues for approximately ten weeks, establishing the conducting portion of the airways. Up to 24 orders of branches are generated, the final level being the prospective terminal bronchioles. New branches are being formed within a rapidly proliferating, homogeneous mesenchyme. Differentiation of the mesenchyme and epithelia begins in the more proximal regions of the airways and progresses distally, beginning during week 10 when mesenchymal cells condense around the larynx and trachea. These will form smooth muscle and supporting cartilages. The pulmonary arteries and veins develop in parallel with the conducting portion of the lungs and follow the same branching pattern.

Initially the airway lumina are very narrow, with a thick pseudostratified epithelial lining. From week 13 onward, the lumina enlarge and the epithelium thins to a more columnar structure. The pluripotent epithelial cells differentiate to cilliated cells and goblet cells, initially in the proximal regions of the developing lung and progressing distally.

From weeks 16 to 24, the primordia of the respiratory portions of the lungs are formed. The terminal bronchioles divide to form two respiratory bronchioles which in turn branch to form 3 to 6 primitive alveolar ducts, ending in terminal sacs. At the same time, extensive angiogenesis within the peripheral mesenchyme leads to vascularisation of the developing respiratory structures. The cuboidal intermediate cells of the lower airways differentiate to form cilliated cells and clara cells. Peripheral mesenchymal cells differentiate to form the visceral pleura, the remaining mesenchymal cells gain the characteristics of stromal fibroblasts.

By week 26, the terminal sacs have started to dilate, and will eventually differentiate into alveolar complexes. The stroma thins, bringing the growing capillary network into close association with the immature alveoli. The cuboidal cells of the terminal sac epithelium differentiate into alveolar type-II cells which secrete low levels of surfactant. Where cells with type-II phenotype juxtapose a capillary, they differentiate to type-I cells, which flatten and can provide a functional though inefficient blood/air barrier if the infant is born prematurely.

During subsequent weeks there is a rapid expansion of the respiratory portion of the lung. Terminal saccules dilate and branch to form further generations of terminal saccules, vascularised septa form within growing terminal sacs and Type-I cells continue to flatten and spread, increasing the surface area available for gas exchange. The parenchyma of the lung continues to thin, and fibroblasts lay down the collagen and elastin fiber components of the stroma. The composition of pulmonary surfactant is developmentally regulated. By week 30, there is a significant rise in the amount of surfactant secreted from the type-II cells. By week 36, the stroma of the lung has thinned to the extent that capillaries may protrude into the prospective alveolar airspaces.

The final stages of maturation of the respiratory system occur after 36 weeks gestation and continues into adulthood. At around 36 weeks, the first mature alveoli appear, characterised by thin walled interalveolar septa with a single layered capillary network. The diameter of the capillaries is sufficiently large that they may span the alveolar walls and interact with the airspaces on both sides. New alveoli are generated by a process of septal subdivision of existing immature alveoli. There is a growth spurt soon after birth, though new alveoli continue to form at a high rate for up to 3 years. As the alveoli mature and the walls thin, there is a decrease in the relative proportion of stroma to total lung volume which contributes significantly to growth for 1 to 2 years after birth. By 3 years, the overall morphology of the lung has been established and subsequent expansion occurs through a proportional growth of all lung components until adulthood.

• Embryonic phase (3-7 weeks) Initial budding and branching of the lung buds from the primitive foregut. Ends with the development of the presumptive broncho-pulmonary segements.
• Pseudoglandular phase (7-16) weeks Further branching of the duct system (up to 21 further orders) generates the presumptive conducting portion of the respiratory system up to the level of the terminal bronchioles. At this time the future airways are narrow with little lumens and a pseudostratified squamous epithelium. They are embedded within a rapidly proliferating mesenchyme. The structure has a glandular appearance.
• Canalicular phase (16-24) weeks The onset of this phase is marked by extensive angiogenisis within the mesenchyme that surrounds the more distal reaches of the embryonic respiratory system to form a dense capillary network. The diameter of the airways increases with a consequent decrease in epithelial thickness to a more cuboidal structure. The terminal bronchioles branch to form several orders of respiratory bronchioles. Differentiation of the mesenchyme progresses down the developing respiratory tree, giving rise to chondrocytes, fibroblasts and myoblasts.
• Terminal sac phase (24-36) weeks Branching and growth of the terminal sacs or primitive alveolar ducts. Continued thinning of the stroma brings the capillaries into apposition with the prospective alveoli. Functional type-II pneumonocytes differentiate via several intermediate stages from pluripotent epithelial cells in the prospective alveoli. Type I pneumonocytes differentiate from cells with a type-II like phenotype. These cells then flatten, increasing the epithelial surface area by dilation of the saccules, giving rise to immature alveoli. By 26 weeks, a rudimentary though functional blood/gas barrier has formed. Maturation of the alveoli continues by further enlargement of the terminal sacs, deposition of elastin foci and development of vascularised septae around these foci. The stroma continues to thin until the capillaries protrude into the alveolar spaces.
• Alveolar phase (36 weeks - term/adult) Maturation of the lung indicated by the appearance of fully mature alveoli begins at 36 weeks, though new alveoli will continue to form for approximately three years. A decrease in the relative proportion of parenchyma to total lung volume still contributes significantly to growth for 1 to 2 years after birth, thereafter all components grow proportionately until adulthood.

Date of last revision: 26 June 1997 - 09:22:25