Upper Airway Structure: Function, Regulation, and Development

Airway Embryology

Airway development in humans begins during the fourth week of gestation when the respiratory diverticulum, or lung bud, branches from the embryonic foregut. The esophagotracheal septum forms and separates the foregut into the esophagus dorsally and the trachea ventrally; thus, the developing airway is of foregut endodermal origin. Elongation of the respiratory diverticulum forms the trachea, whereas the main bronchi are formed by branching. Growth and elongation continue in the caudal direction under the influence of airway secretions and physical forces.

Maturation of the airway occurs first in the trachea and proceeds distally. Tracheal cartilage formation begins during the seventh week of gestation, but full maturation of the distal airway cartilage is not completed until after birth. Epithelial differentiation begins in the trachea during week 10 of gestation. Together with the phasic contractions of the fetal airway smooth muscle, which are present after gestational week 23, lung fluid secreted from the epithelial cells promotes the growth and development of the respiratory system.

Airway Structure

The airway tree is a branched conducting system whose major functions include the delivery, distribution, and conditioning of gas to the gas exchange units of the lung. The lower airway has three primary components: epithelium, cartilage, and smooth muscle. The epithelium lines the entire length of the airway. From the trachea to the large bronchioles, it is composed of a pseudostratified ciliated columnar epithelium called the respiratory epithelium. The designation pseudostratified applies because the respiratory epithelium is one cell layer thick and all cells attach to the basement membrane but not all cells extend out to the airway lumen, giving the histologic appearance of multiple cell layers. Beyond the large bronchioles, the airway epithelium undergoes a gradual transition to a simple ciliated columnar epithelium and, finally, a cuboidal epithelium. The airway epithelium is composed of approximately eight different cell types. The primary cell type in the epithelium is the columnar epithelial cell, which contains a layer of cilia on its apical surface. Other cell types present include mucus-secreting cells, brush cells, small granule cells, and basal cells.

Cartilage is present from the trachea to the bronchioles. In the trachea, cartilage exists as C-shaped rings that are open posteriorly. In the bronchi, the cartilage forms plates that encompass the entire airway circumference. At more distal airway generations, the cartilage plates become smaller and more discontinuous, gradually disappearing before the bronchioles. As with the airway cartilage, the architectural disposition of airway smooth muscle also varies with different configurations along progressive airway generations. In the trachea, the airway smooth muscle is confined to the trachealis muscle. The trachealis, along with fibroelastic tissue, bridges the gap between the tips of the C-shaped cartilage rings and forms the posterior wall of the trachea. By contrast, bronchial airway smooth muscle forms a complete circumferential layer that gradually diminishes and becomes discontinuous at lower generations.

A mucosal layer covers the inner surface of the trachea. The mucosa consists of an epithelial layer supported by a basement membrane. This basement membrane is part of a loose connective tissue layer called the lamina propria. The lamina propria is very cellular and contains lymphocytes and lymphatic tissue, plasma and mast cells, eosinophils, and fibroblasts. Also included within the mucosal layer are glands that send ducts to the epithelial surface.

Below the mucosa lies the submucosa. The submucosa is a connective tissue layer containing the distributing blood vessels, lymphatics, and mucus-secreting glands. The submucosa ends when it blends into the perichondrium of the cartilage rings. The outer layer of the trachea consists of adventitia, which binds the trachea to adjacent structures such as the esophagus, neck musculature, and mediastinal structures. The adventitia contains the large blood vessels and nerves supplying the components of the tracheal wall.

The primary innervation of the trachea is cholinergic from the vagus nerve. Vagal stimulation results in the contraction of airway smooth muscle. In addition, nonadrenergic, noncholinergic innervation controls both bronchoconstrictive and bronchodilatory actions through mediators such as nitric oxide, vasoactive intestinal peptide, neurokinins, and substance P. Little if any direct sympathetic innervation of the airway is present. Sympathetic control is provided primarily through circulating catecholamines.

More recent studies on structural maturation of airway smooth muscle at the cellular, ultrastructural, and protein expression levels have elucidated structural mechanisms for developmental changes in function. Although the individual lengths of isolated tracheal smooth muscle cells increased from prematurity to adulthood, a linear increase in cell length was not demonstrated during the neonatal period, precluding cell length changes as a mechanism for functional development. Similarly, developmental alterations in the electron-microscopic ultrastructure of the tracheal smooth muscle could not be identified as potential mechanisms. At the protein expression level, the expression of smooth muscle myosin SM1 and SM2 heavy chain isoforms increased across development. This increase correlates with the developmental increase in tracheal smooth muscle force development, providing a likely mechanism for the functional maturation of this airway smooth muscle.

In the developing rabbit trachea, clear patterns of expression or activation of matrix metalloproteinase (MMP)-2 and MMP-9, as well as their (tissue) inhibitors tissue inhibitor of metallinoproteinase (TIMP)-1 and TIMP-2, have been demonstrated during the progression of airway development. In the lung, differences in MMP activity have been associated with BPD and other chronic fibrotic lung diseases. Thus, it is implied that the progression of lung disease involves the alteration in MMP activity. As noted by Miller and colleagues, total MMP-2 quantity decreased steadily with increasing age in both the pregestational period and the postgestational period, whereas the active-to-latent ratio decreased only in the postgestational period. This change in the proteolytic potential of MMP-2 was compounded in the postgestational period by an age-dependent rise in TIMP-2 quantity. In that these arbitrary units of protein quantity are relative to a constant total protein load, the rise in TIMP-2 quantity affirms that the significant fall in MMP-2 levels is not likely to be the result of an increase in the quantity of inert, structural protein diluting the quantity of functional mediators of structural development. Of interest in this study is the lack of MMP-7 activity in the developing trachea, in contrast with the developing lung, where MMP-7 activity is present. These data support the assessment by other researchers that MMP-7 serves as a regulator for passage across the alveolar epithelium ^, and thus is not a mediator in the development of conducting airways. In this regard, MMP-7 may play a role in the differentiation between airway and lung development.