4: Anatomic and physiologic aspects of airways

OUTLINE

Structure, 59

Neural Control of Airways, 62

Function, 64

Airway Resistance, 64

Maximal Expiratory Effort, 65

In its transit from the nose or the mouth to the gas-exchanging region of the lung, air passes through the larynx and then along a series of progressively branching tubular structures from the trachea down to the smallest bronchioles. In preparation for a discussion of diseases affecting the airways, this chapter describes the structure of these airways and then considers how they function.

Structure

The trachea, bronchi, and bronchioles down to the level of the terminal bronchioles constitute the conducting airways. Their functions are to transport gas and protect the distal lung from inhaled contaminants, but they do not directly participate in gas exchange. Beyond the terminal bronchioles are the respiratory bronchioles. They mark the beginning of the respiratory zone of the lung, where gas exchange takes place. Respiratory bronchioles are considered part of the gas-exchanging region of lung because some alveoli are present along part of their walls. With successive generations of respiratory bronchioles, more alveoli appear along the walls up to the site of the alveolar ducts, which are entirely “alveolarized” (Fig. 4.1). The discussion in this chapter is limited to the conducting airways and those aspects of the more distal airways that affect air movement but not gas exchange. Alveolar structure is discussed further in Chapter 8.

FIGURE 4.2 Schematic diagram of components of airway wall. A, Level of

large airways (trachea and bronchi). B, Level of small airways (bronchioles). BC,

basal cell; BM, basement membrane; CA, cartilage; CC, ciliated columnar epithelial

cell; CL, club cell; GC, goblet cell; MG, mucous gland; SM, smooth muscle.

Source: (Adapted from Weibel, E. R., & Burri, P. H. (1973). Funktionelle Aspekte

der Lungenmorphologie. In W. A. Fuchs, & E. Voegeli (Eds.), Aktuelle Probleme

der Roentgendiagnostik (Vol. 2). Bern, Switzerland: Huber.)

The surface layer (mucosa) consists predominantly of pseudostratified columnar epithelial cells. It is termed “pseudostratified” because the mucosa appears to be several cells thick in the trachea and large bronchi, owing to the columnar shape and variable positions of the nuclei; however, each cell is actually resting on the basement membrane (see Fig. 4.2A). The cilia that line the airway lumen are responsible for protecting the deeper airways by propelling tracheobronchial secretions (and inhaled particles that become trapped within them) toward the pharynx. The cilia of airway epithelial cells have the characteristic ultrastructure seen in other ciliated cells: a central pair of microtubules and an outer ring of nine double microtubules (see Fig. 22.1). Small side arms called dynein arms, which contain the adenosine triphosphatase (ATPase) dynein, are found on the outer double microtubules. Proper configuration and function of dynein arms are necessary for normal ciliary functioning, and patients with cilia lacking fully functional dynein side arms have impaired ciliary action and thus develop recurrent bronchopulmonary infections.

Scattered between the ciliated epithelial cells are mucin-secreting epithelial cells called goblet cells that produce and discharge mucins into the airway lumen. Normally, goblet cells are more prevalent in the proximal airways. Their numbers decrease peripherally, and they are not present in terminal bronchioles. Mucins are very large glycoproteins, some of which are bound to airway epithelial cell membranes, whereas others are secreted into the airways. Secreted mucins can polymerize, physically expand greatly,

and bind with water, electrolytes, and other molecules to form a viscous mucous gel that is essential for normal ciliary motion and hence for airway clearance of inhaled particles and microorganisms. In humans, there are seven major airway mucins; the two most important appear to be MUC5AC, produced primarily by goblet cells, and MUC5B, produced primarily by cells in the submucosal glands (see later). In normal healthy airway secretions, MUC5AC is the most abundant mucin present.

The mucosal layer of large airways consists of pseudostratified ciliated columnar epithelial cells.

The surface epithelium appears to have other important functions that may be altered in certain clinical conditions. By virtue of tight junctions between epithelial cells at the luminal surface, the epithelium prevents access of inhaled foreign material to deeper levels of the airway wall. There is evidence that inflammation-induced disruption in this barrier function, which allows antigens to penetrate the epithelial surface, is important in asthma. Another important function of the epithelium involves active transport and regulation of ions, particularly chloride and bicarbonate, to maintain a favorable ionic environment in the mucous layer lining the airway wall. In cystic fibrosis, an abnormality in chloride transport by surface epithelial cells plays a crucial role in the pathogenesis of the disease (see Chapter 7).

Basal cells are interspersed deep within the epithelium, abutting the basement membrane. The function of basal cells is to differentiate into and replenish the more superficial cells of the mucosa, either the ciliated cells or the secretory goblet cells. In more distal airways and terminal bronchioles, club cells are found interspersed among the ciliated epithelial cells. Club cells, which act as progenitor cells for themselves and for ciliated cells, have several protective functions, including synthesis of immune molecules and small amounts of mucus and surfactant proteins, as well as metabolism of inhaled chemicals. Another important cell type found in the airway epithelium is the pulmonary neuroendocrine cell (Kulchitsky cell). These cells are part of the amine precursor uptake and decarboxylation system and are therefore capable of producing amine hormones (serotonin, dopamine, norepinephrine) and polypeptide products. In addition, pulmonary neuroendocrine cells have cytoplasmic processes that extend to the luminal surface. As a result, these cells may be involved in sensing the composition of inspired gas and have been postulated to play a role in regional control of ventilation and perfusion. The different cell types in the airway mucosa are significant not only because of their normal physiologic roles but also because of the way they respond to airway irritation and their potential for becoming neoplastic.

The submucosal layer has two major components: bronchial mucous glands and bronchial smooth muscle. Mucus is a gel-like substance composed mostly of water (97%) and mucins. Other proteins including immunomodulators are also present, as well as electrolytes, lipids, and cellular debris. The mucous glands are located between bands of smooth muscle. The base of the glands is lined by mucous cells and serous cells and is connected to the airways by ducts lined by ciliated cells. The duct transports the secretions through the mucosa and discharges them into the airway lumen. As noted earlier, the primary mucin produced by mucous glands is MUC5B. In disease states such as chronic obstructive pulmonary disease and cystic fibrosis, where there is mucous gland hyperplasia and hypertrophy, MUC5B becomes more prominent than MUC5AC in bronchial secretions. However, whether the functions of MUC5AC and MUC5B are different is not yet understood. In addition, a common polymorphism in the MUC5B gene is associated with susceptibility to idiopathic pulmonary fibrosis (IPF), a disease of the lung parenchyma that is discussed in Chapter 11. Serous cells also line the mucous gland; these cells secrete proteoglycans and numerous antimicrobial substances involved in innate immunity (see Chapter 22). Airway smooth muscle is present from the trachea down to the level of the bronchioles and even the alveolar ducts. Disturbances in the quantity and function of the smooth muscle are important in disease,

particularly in the case of bronchial asthma.

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Bronchial secretions are produced by submucosal glands and goblet cells in the mucosa.

The fibrocartilaginous layer is important because of the structural support cartilage provides to the airways. The configuration of the cartilage varies significantly at different levels of the tracheobronchial tree, but the function at all levels is probably similar.

Airway structure changes considerably in the distal progression through the tracheobronchial tree.

We have thus far described the general structure of the airways, but structure varies considerably at different levels. Some of these differences are illustrated in Fig. 4.2. In the progression distally through the tracheobronchial tree, the following changes are normally seen:

1.The epithelial layer of cells becomes progressively thinner until there is a single layer of cuboidal cells at the level of the terminal bronchioles.

2.Goblet cells decrease in number until they disappear about at the level of the terminal bronchiole. Dome-shaped club cells appear in the smaller airways, where they contribute to mucus production and other functions.

3.Mucous glands, which are present in the trachea and large bronchi, are most numerous in the medium-sized bronchi. They become progressively fewer in number more distally and are absent from the bronchioles.

4.Smooth muscle changes in configuration at different levels of the tracheobronchial tree. In the trachea and large bronchi, smooth muscle is found as either bands or a spiral network, whereas in the smaller bronchi and bronchioles, a continuous layer of smooth muscle encircles the airway. As airway size decreases distally in the tracheobronchial tree, smooth muscle generally occupies a larger portion of the total thickness of the airway wall. The proportion of smooth muscle to airway wall thickness becomes maximal at the level of the terminal bronchiole.

5.Cartilage also changes in configuration. In the trachea, the cartilaginous rings are horseshoe shaped, with the posterior aspect of the trachea being free of cartilage. In the bronchi, plates of cartilage become smaller and less numerous distally until cartilage is absent in the bronchioles.

The preceding discussion describes many of the structural features of normal airways. However, a variety of changes occur with chronic exposure to an irritant such as cigarette smoke. Some of these changes, particularly in the epithelial cells, are important because of the potential for eventual malignancy (see Chapter 20). Other changes are apparent in the mucus-secreting structures (bronchial mucous glands and goblet cells) and are important features of chronic bronchitis. With chronic irritation, the mucous glands hypertrophy, and goblet cells become more numerous and are found more distally than usual, even in the terminal bronchioles. The implications of these changes in disease states are discussed in Chapter 6.

Neural control of airways

Innervation (neural control) of airways is an important aspect of airway structure, with particular clinical relevance in asthma (see Chapter 5). Neural control of airways affects contraction and relaxation of bronchial smooth muscle and the activity of bronchial mucous glands. An understanding of the innervation, receptors, and mediators involved in neural control of airway function is important both because of the potential role of neural control in the pathogenesis of asthma and because of the wellestablished role of pharmacotherapy in stimulating or blocking airway receptors. The following

discussion focuses on three components of the neural control of airways: the parasympathetic (cholinergic) system, the sympathetic (adrenergic) system, and the nonadrenergic, noncholinergic inhibitory system (Fig. 4.3).

FIGURE 4.3 Schematic diagram of neural control of airways. Parasympathetic

fibers innervating airway smooth muscle cells, submucosal glands, and goblet cells

are labeled 1; nonadrenergic, noncholinergic innervation of airway smooth muscle

cells is labeled 2; afferent innervation of airway epithelial cells is labeled 3; and

neural traffic along the pathway labeled 4 goes to the vagus nerve but also has

effects on airway smooth muscle cells, submucosal glands, and blood vessels via

local reflexes. ACh, acetylcholine; NKA, neurokinin A; NO, nitric oxide; SP,

substance P.

The parasympathetic nervous system provides the primary bronchoconstrictor tone to the airways via branches of the vagus nerve (cranial nerve X, also known as the pneumogastric nerve). Stimulation of these vagal branches causes contraction of smooth muscle in the airway wall; in addition, vagal fibers innervate bronchial mucous glands and goblet cells, resulting in increased secretions from both components of the mucus-secreting apparatus. The receptors on smooth muscle and the mucus-secreting apparatus are muscarinic cholinergic receptors; the neurotransmitter is acetylcholine. These cholinergic receptors are more dense in central than in peripheral airways. Identification of multiple subtypes of muscarinic receptors, elucidation of a variety of effects on both airway smooth muscle and on nerves supplying smooth muscle, and evidence of “cross-talk” among muscarinic and adrenergic receptors have

demonstrated that muscarinic receptor signaling is actually much more complicated. However, the

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