simplified schema described earlier provides a practical framework for later discussions about pathophysiology and treatment of airway diseases. For example, inhaled anticholinergic medications such as ipratropium and tiotropium block the muscarinic cholinergic receptors, resulting in bronchodilation and decreased mucus production (see Chapter 6).

The role of the sympathetic (adrenergic) nervous system in controlling airway tone is much less clear because there is sparse if any adrenergic innervation of human airways. Despite the paucity of innervation by sympathetic nerves, there are adrenergic, primarily β2, receptors on bronchial smooth muscle that are stimulated by circulating catecholamines. When stimulated, β2-receptors activate adenylate cyclase, increasing the intracellular concentration of cyclic adenosine monophosphate (cAMP) and causing relaxation of bronchial smooth muscle. In contrast, stimulation of the less numerous α-adrenergic receptors results in a degree of bronchoconstriction. Receptor density of β2-adrenergic receptors is opposite that of cholinergic receptors; β2-adrenergic receptors are more dense in peripheral than in central airways. Inhaled β-adrenergic agonists cause bronchodilation and are a critical part of asthma and COPD treatment (see Chapter 6).

A search for innervation of the airways with a smooth muscle relaxant (bronchodilating) effect has demonstrated a third component of neural control, often called the nonadrenergic, noncholinergic inhibitory system. Similar to parasympathetic airway nerves, these nerve fibers run in the vagal trunk, but when stimulated they cause bronchial smooth muscle to relax, not constrict. Evidence suggests that important bronchodilator transmitters for these nerves are nitric oxide and vasoactive intestinal peptide.

Parasympathetic innervation provides bronchoconstrictor tone to the airways; nonadrenergic, noncholinergic inhibitory innervation provides bronchodilator tone. Adrenergic receptors are present on bronchial smooth muscle despite the absence of significant sympathetic innervation.

Thus far, only the neural output to (i.e., efferent control of) the airways has been discussed. In addition, there are airway receptors with sensory (afferent) nerve innervation. These receptors, which are located in the airway epithelial layer and are responsive to various chemical and mechanical stimuli, include myelinated cough (“irritant”) receptors and unmyelinated C fibers. Neural traffic is carried from these sensory endings in afferent fibers of the vagus nerve. This sensory information is not only communicated to the central nervous system via the afferent vagal fibers but also responsible for activation of local reflexes causing release of mediators called tachykinins from nerve endings in the airway wall. The tachykinins, which include substance P and neurokinin A, can cause bronchoconstriction, increased submucosal gland secretion, and increased vascular permeability (see Fig. 4.3). However, the magnitude of their importance in disease states such as asthma is not known with certainty.

Function

With each breath, air flows from the nose or mouth, through the bronchial tree, to the regions of the lung responsible for gas exchange. To generate this flow of air during inspiration, the pressure must be lower in the alveoli than at the nose or mouth because air flows from a region of higher pressure to one of lower pressure. The diaphragm and inspiratory muscles of the chest wall cause expansion of the chest and lungs, producing negative pressure in the pleural space and in the alveoli, thereby initiating airflow.

Flow in the airways can be considered analogous to the flow of current in an electrical system. However, rather than a voltage drop when electrons flow across a resistance, airways have a pressure difference between two points of airflow, and resistance to flow is provided primarily by the limited cross-sectional area of the airways themselves. The rate of airflow depends in part on the pressure

FIGURE 4.4 Contribution to resistance by airways at different levels of the

tracheobronchial tree. The greatest contribution to resistance is provided by

medium-sized bronchi (generations 3-5), whereas smaller airways (approximately

generation 9 and beyond) provide significantly less contribution to total resistance

because of their much larger total cross-sectional area.

Because resistance to airflow in the tracheobronchial tree depends on the total cross-sectional area of the airways, largeand medium-sized airways provide greater resistance than the more numerous small airways.

Maximal expiratory effort

The next important aspect of the physiology of airflow is the distinction between normal breathing and forced or maximal respiratory efforts. A great deal of information can be obtained by looking at flow during a forced expiration (i.e., breathing out from total lung capacity down to residual volume as hard and as fast as possible). In a discussion of this concept, it is useful to consider the flow-volume curve mentioned in Chapter 3 and shown again in Fig. 4.5. In this figure, a series of expiratory curves shows the kind of flow rates generated by progressively greater expiratory efforts. Curve A shows expiratory flow with a relatively low effort, whereas curve D shows flow with a maximal expiratory effort.

During a forced expiration, there are several determinants of airway diameter. First and most obvious is the inherent size of the airway, which depends on its level in the tracheobronchial tree and the tone of the airway smooth muscle. In disease, smooth muscle tone may be increased (as in asthma), or secretions in the airway may narrow the lumen (as in asthma or chronic bronchitis). Second is the potential collapsibility of the airway, which, in small airways, is affected by the amount of radial traction exerted by surrounding lung tissue on the airway walls. The trachea and larger bronchi are supported by cartilage, but small airways are surrounded by a supporting framework of alveolar walls that are constantly “pulling” or “tethering” the airways open. When lung parenchyma is destroyed, as in emphysema, the small airways lose some of this normal support and are more likely to collapse during a forced expiration (see Chapter 6). Third is the combination of external and internal pressures acting on the small airways. This balance of pressures is crucial in determining whether a particular airway remains open or closed during a forced expiration.

Airway diameter depends on the level of the airway in the tracheobronchial tree, airway smooth muscle tone, radial traction on the airway from surrounding lung tissue, and internal and external pressures on the airway.

The external pressure acting on an airway is determined by pleural pressure (Fig. 4.6). When pleural pressure is strongly positive, as with a forced expiration, the airway becomes compressed. It is only because of a counteracting pressure within the airways that they remain open in the face of a strongly positive external pressure. Two factors contribute to the internal airway pressure: (1) the elastic recoil of the lungs and (2) pleural pressure transmitted to the alveoli and airways. Fig. 4.6 shows that the alveolar wall is like a stretched balloon trying to expel its air. In the same way a balloon, in trying to collapse, exerts pressure on the air inside, the alveolar wall has its elastic recoil that exerts pressure on the gas within. This pressure results in flow from the alveoli through the airways. However, remember that flow through an airway is accompanied by a pressure drop along the airway. At a certain point along the airway, the pressure falls enough so that pressure within the airway becomes equal to the pressure outside the airway (i.e., pleural pressure). This point where the pressure inside the airway is the same as the pressure outside the airway is called the equal pressure point. Increased effort causes increased pleural pressure, which is exerted both on the alveolus and on the airway wall. The increased pressure on the alveoli (which would increase flow) is therefore matched by the increased external pressure on the airway. Thus, the driving pressure (i.e., the difference between alveolar pressure and the pressure at the equal pressure point) is determined only by the elastic recoil pressure of the lung. With additional effort, the increased alveolar driving pressure is exactly balanced by the increased external pressure on the airway, which promotes airway collapse (see Fig. 4.6). As a net result, the elastic recoil pressure, not the pleural pressure produced by a maximal expiratory effort, is the important determinant of maximal expiratory flow, at least in the effort-independent or latter part of a forced expiration. Subsequent chapters show that in diseases with altered elastic recoil, maximal expiratory flow rates are affected by this change in the effective driving pressure for airflow.

FIGURE 4.6 Schematic diagram of the equal pressure point concept during a

forced (maximal) expiration. Alveolus and its airway are shown inside the box,

which represents pleural space. Alveolar pressure (Palv) has two contributing components: pleural pressure (Ppl) and elastic recoil pressure of lung (Pel). In this diagram, Ppl = 20 cm H2O and Pel = 10 cm H2O, so Palv, the sum of Ppl and Pel, is 30 cm H2O.

At the equal pressure point, internal and external pressures on the airway are equal. The net driving pressure from the alveolus to the equal pressure point is the elastic recoil pressure of the lung.

The final question to be addressed here is the level at which this critical narrowing (i.e., the equal pressure point) occurs. The answer depends on lung volume. The equal pressure point does not remain at a constant position as an individual exhales to residual volume. At higher lung volumes, the elastic recoil pressure is greater (the alveoli are more stretched), and a longer distance separates the alveoli from the equal pressure point. At lung volumes above functional residual capacity, this critical point of narrowing is within relatively large airways, segmental bronchi or larger. At lower lung volumes, the elastic recoil pressure is lower, the distance from alveoli to the equal pressure point is smaller, and critical narrowing occurs in smaller, more peripheral airways. Because maximal airflow depends on elastic recoil and the resistance of the airways peripheral (“upstream”) to the equal pressure point, the resistance of the small airways is a larger component of the upstream resistance at small lung volumes and is therefore a greater determinant of maximal expiratory flow at lower volumes along the flow-volume curve.

The equal pressure point moves peripherally (toward smaller airways) as lung volume decreases during a forced expiration; hence, the resistance of small airways limits maximal expiratory flow more at low than at high lung volumes.

In summary, flow through the tracheobronchial tree reflects a combination of factors: airway size, support or radial traction exerted by the surrounding lung parenchyma, and driving pressure provided by the elastic recoil of the lung. Although pleural pressure contributes to the driving pressure for airflow, it also exerts a counterbalancing external pressure on the airway, promoting airway collapse. Later

discussion of specific disorders will show how these different factors are interrelated as determinants of

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