Respiratory physiology

Conducting zone

The conducting zone includes the nose, nasopharynx, larynx, trachea, bronchi, bronchioles, and terminal bronchioles. These structures function to bring air into and out of the respiratory zone for gas exchange and to warm, humidify, and filter the air before it reaches the critical gas exchange region.

The progressively bifurcating airways are referred to by their generation number. The trachea, which is the zeroth generation, is the main conducting airway. The trachea divides into the right and left mainstem bronchi (the first generation), which divide into two smaller bronchi, which divide again. Ultimately, there are 23 such divisions into increasingly smaller airways, culminating in the airways of the 23rd generation.

Cartilage is present in the walls of the zeroth to 10th generations of conducting airways; it functions, structurally, to keep those airways open. Starting with the 11th generation, cartilage disappears; to remain open, those airways with no cartilage depend on the presence of a favorable transmural pressure (discussed below).

The conducting airways are lined with mucus-secreting and ciliated cells that function to remove inhaled particles. Although large particles usually are filtered out in the nose, small particles may enter the airways, where they are captured by mucus, which is then swept upward by the rhythmic beating of the cilia.

The walls of the conducting airways contain smooth muscle. This smooth muscle has both sympathetic and parasympathetic innervations, which have opposite effects on airway diameter: (1) Sympathetic adrenergic neurons activate β ₂ receptors on bronchial smooth muscle, which leads to relaxation and dilation of the airways. In addition, and what is more important, these β ₂ receptors are activated by circulating epinephrine released from the adrenal medulla and by β ₂ -adrenergic agonists such as isoproterenol. (2) Parasympathetic cholinergic neurons activate muscarinic receptors, which leads to contraction and constriction of the airways.

Changes in diameter of the conducting airways result in changes in their resistance, which produce changes in air flow. Thus the effects of the autonomic nervous system on airway diameter have predictable effects on airway resistance and air flow. The most notable effects are those of β ₂ -adrenergic agonists (e.g., epinephrine, isoproterenol, albuterol), which are used to dilate the airways in the treatment of asthma.

Respiratory zone

The respiratory zone includes the structures that are lined with alveoli and therefore participate in gas exchange: the respiratory bronchioles, alveolar ducts, and alveolar sacs. The respiratory bronchioles are transitional structures. Like the conducting airways, they have cilia and smooth muscle, but they also are considered part of the gas exchange region because alveoli occasionally bud off their walls. The alveolar ducts are completely lined with alveoli, but they contain no cilia and little smooth muscle. The alveolar ducts terminate in alveolar sacs, which also are lined with alveoli.

The alveoli are pouchlike evaginations of the walls of the respiratory bronchioles, the alveolar ducts, and the alveolar sacs. Each lung has a total of approximately 300 million alveoli. The diameter of each alveolus is approximately 200 micrometers (μm). Exchange of oxygen (O ₂ ) and carbon dioxide (CO ₂ ) between alveolar gas and pulmonary capillary blood can occur rapidly and efficiently across the alveoli because alveolar walls are thin and have a large surface area for diffusion.

The alveolar walls are rimmed with elastic fibers and lined with epithelial cells called type I and type II pneumocytes (or alveolar cells). Type II pneumocytes synthesize pulmonary surfactant (necessary for reduction of surface tension of alveoli) and have regenerative capacity for the type I and type II pneumocytes.

The alveoli contain phagocytic cells called alveolar macrophages. Alveolar macrophages keep the alveoli free of dust and debris because the alveoli have no cilia to perform this function. Macrophages fill with debris and migrate to the bronchioles, where the beating cilia carry debris to the upper airways and the pharynx, where it can be swallowed or expectorated.

Anatomic dead space

The anatomic dead space is the volume of the conducting airways including the nose (and/or mouth), trachea, bronchi, and bronchioles. It does not include the respiratory bronchioles and alveoli. The volume of the conducting airways is approximately 150 mL. Thus for example, when a tidal volume of 500 mL is inspired, the entire volume does not reach the alveoli for gas exchange; 150 mL fills the conducting airways (the anatomic dead space, where no gas exchange occurs), and 350 mL fills the alveoli. Figure 5.3 shows that at the end of expiration the conducting airways are filled with alveolar air; that is, they are filled with air that has already been in the alveoli and exchanged gases with pulmonary capillary blood. With the inspiration of the next tidal volume, this alveolar air is first to enter the alveoli, although it will not undergo further gas exchange (“already been there, done that”). The next air to enter the alveoli is fresh air from the inspired tidal volume (350 mL), which will undergo gas exchange. The rest of the tidal volume (150 mL) does not make it to the alveoli but remains in the conducting airways; this air will not participate in gas exchange and will be the first air expired. (A related point arises from this discussion: The first air expired is dead space air that has not undergone gas exchange. To sample alveolar air, one must sample end -expiratory air.)

Physiologic dead space

The concept of physiologic dead space is more abstract than the concept of anatomic dead space. By definition, the physiologic dead space is the total volume of the lungs that does not participate in gas exchange. Physiologic dead space includes the anatomic dead space of the conducting airways plus a functional dead space in the alveoli.

The functional dead space can be thought of as ventilated alveoli that do not participate in gas exchange. The most important reason that alveoli do not participate in gas exchange is a mismatch of ventilation and perfusion, or so-called ventilation/perfusion defect, in which ventilated alveoli are not perfused by pulmonary capillary blood.

In normal persons, the physiologic dead space is nearly equal to the anatomic dead space. In other words, alveolar ventilation and perfusion (blood flow) are normally well matched and functional dead space is small. In certain pathologic situations, however, the physiologic dead space can become larger than the anatomic dead space, suggesting a ventilation/perfusion defect. The ratio of physiologic dead space to tidal volume provides an estimate of how much ventilation is “wasted” (either in the conducting airways or in nonperfused alveoli).

The volume of the physiologic dead space is estimated with the following method, which is based on the measurement of the partial pressure of CO ₂ (P co ₂ ) of mixed expired air (P e _CO2 ) and the following three assumptions: (1) All of the CO ₂ in expired air comes from exchange of CO ₂ in functioning (ventilated and perfused) alveoli; (2) there is essentially no CO ₂ in inspired air; and (3) the physiologic dead space (nonfunctioning alveoli and airways) neither exchanges nor contributes any CO ₂ . If physiologic dead space is zero, then P e _CO2 will be equal to alveolar P co ₂ (P a _CO2 ). However, if a physiologic dead space is present, then P e _CO2 will be “diluted” by dead space air and P e _CO2 will be less than P a _CO2 by a dilution factor. Therefore, by comparing P e _CO2 with P a _CO2 , the dilution factor (i.e., volume of the physiologic dead space) can be measured. A potential problem in measuring physiologic dead space is that alveolar air cannot be sampled directly. This problem can be overcome, however, because alveolar air normally equilibrates with pulmonary capillary blood (which becomes systemic arterial blood). Thus the P co ₂ of systemic arterial blood (Pa _CO2 ) is equal to the P co ₂ of alveolar air (P a _CO2 ). Using this assumption, the volume of physiologic dead space is calculated by the following equation:

where

In words, the equation states that the volume of the physiologic dead space is the tidal volume (volume inspired with a single breath) multiplied by a fraction. The fraction represents the dilution of alveolar P co ₂ by dead space air (which contributes no CO ₂ ).

To better appreciate the equation and its application, consider two extreme examples. In the first example, assume that physiologic dead space is zero; in the second example, assume that physiologic dead space is equal to the entire tidal volume. In the first example, in which dead space is zero, the P co ₂ of expired air (P e _CO2 ) will be the same as the P co ₂ of alveolar gas (P a _CO2 ) and arterial blood (Pa _CO2 ) because there is no “wasted” ventilation: The fraction in the equation is equal to zero, and thus the calculated value of V d is zero. In the second example, in which dead space is equal to the entire tidal volume, there is no gas exchange: Therefore P e _CO2 will be zero, the fraction will be 1.0, and V d will be equal to V t .

Muscles of inspiration

The diaphragm is the most important muscle for inspiration. When the diaphragm contracts, the abdominal contents are pushed downward and the ribs are lifted upward and outward. These changes produce an increase in intrathoracic volume, which lowers intrathoracic pressure and initiates the flow of air into the lungs. During exercise, when breathing frequency and tidal volume increase, the external intercostal muscles and accessory muscles may also be used for more vigorous inspiration.

Muscles of expiration

Expiration normally is a passive process. Air is driven out of the lungs by the reverse pressure gradient between the lungs and the atmosphere until the system reaches its equilibrium point again. During exercise or in diseases in which airway resistance is increased (e.g., asthma ), the expiratory muscles may aid the expiratory process. The muscles of expiration include the abdominal muscles, which compress the abdominal cavity and push the diaphragm up, and the internal intercostal muscles, which pull the ribs downward and inward.

Compliance of the lungs

The pressure-volume relationship in an isolated lung is illustrated in Figure 5.7 . For this demonstration, a lung is excised and placed in a jar. The space outside the lung is analogous to intrapleural pressure. The pressure outside the lung is varied with a vacuum pump to simulate changes in intrapleural pressures. As pressure outside the lung is varied, the volume of the lung is measured with a spirometer. The lung is inflated with negative outside pressure and then deflated by reducing the negative outside pressure. The sequence of inflation followed by deflation produces a pressure-volume loop. The slope of each limb of the pressure-volume loop is the compliance of the isolated lung.

In the experiment on the air-filled lung, the airways and the alveoli are open to the atmosphere and alveolar pressure equals atmospheric pressure. As the pressure outside the lung is made more negative with the vacuum pump, the lung inflates and its volume increases. This negative outside pressure that expands the lungs is therefore an expanding pressure. The lungs fill with air along the inspiration limb of the pressure-volume loop. At the highest expanding pressures, when the alveoli are filled to the limit, they become stiffer and less compliant and the curve flattens. Once the lungs are expanded maximally, the pressure outside the lungs is made gradually less negative, causing lung volume to decrease along the expiration limb of the pressure-volume loop.

An unusual feature of the pressure-volume loop for the air-filled lung is that the slopes of the relationships for inspiration and expiration are different, a phenomenon called hysteresis. Because the slope of the pressure-volume relationship is compliance, it follows that lung compliance also must differ for inspiration and for expiration. For a given outside pressure, the volume of the lung is greater during expiration than during inspiration (i.e., the compliance is higher during expiration than during inspiration). Usually, compliance is measured on the expiration limb of the pressure-volume loop because the inspiration limb is complicated by the decrease in compliance at maximal expanding pressures.

Why are the inspiration and expiration limbs of the lung compliance curve different? As compliance is an intrinsic property of the lung that depends on the amount of elastic tissue, one would think that the two curves would be the same. The explanation for the different curves (i.e., hysteresis) lies in surface tension at the liquid-air interface of the air-filled lung: The intermolecular attractive forces between liquid molecules lining the lung are much stronger than the forces between liquid and air molecules. Different curves are produced for inspiration and expiration in the air-filled lung as follows:

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  On the inspiration limb, one begins at low lung volume where the liquid molecules are closest together and intermolecular forces are highest; to inflate the lung, one must first break up these intermolecular forces. Surfactant, which is discussed in a later section, plays a role in hysteresis. Briefly, surfactant is a phospholipid that is produced by type II alveolar cells and functions as a detergent to reduce surface tension and increase lung compliance. During inflation of the lung (inspiration limb), surfactant, which is newly produced by type II alveolar cells, enters the liquid layer lining the alveoli and breaks up these intermolecular forces to reduce surface tension. In the initial part of the inspiration curve, at lowest lung volumes, the lung surface area is increasing faster than surfactant can be added to the liquid layer; thus surfactant density is low, surface tension is high, compliance is low, and the curve is flat. As inflation proceeds, the surfactant density increases, which decreases surface tension, increases compliance, and increases the slope of the curve.

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  On the expiration limb , one begins at high lung volume, where intermolecular forces between liquid molecules are low; one does not need to break up intermolecular forces to deflate the lung. During deflation of the lung (expiration limb), lung surface area decreases faster than surfactant can be removed from the liquid lining and the density of surfactant molecules rapidly increases, which decreases surface tension and increases compliance; thus the initial portion of the expiration limb is flat. As expiration proceeds, surfactant is removed from the liquid lining and the density of surfactant remains relatively constant, as does the compliance of the lung.

In summary, for the air-filled lung, the observed compliance curves are determined in part by the intrinsic compliance of the lung and in part by surface tension at the liquid-air interface. The role of surface tension is demonstrated by repeating the experiment in a saline-filled lung. The inspiration and expiration limbs are the same when the liquid-air interface, and thus surface tension, is eliminated.

Compliance of the chest wall

Figure 5.8 shows the relationship between the lungs and chest wall. The conducting airways are represented by a single tube, and the gas exchange region is represented by a single alveolus. The intrapleural space, between the lungs and chest wall, is shown much larger than its actual size. Like the lungs, the chest wall is compliant. Its compliance can be demonstrated by introducing air into the intrapleural space, which creates a pneumothorax.

To understand the consequences of a pneumothorax, it must first be recognized that, normally, the intrapleural space has a negative (less than atmospheric) pressure. This negative intrapleural pressure is created by two opposing elastic forces pulling on the intrapleural space: The lungs, with their elastic properties, tend to collapse, and the chest wall, with its elastic properties, tends to spring out ( Fig. 5.9 ). When these two opposing forces pull on the intrapleural space, a negative pressure, or vacuum, is created. In turn, this negative intrapleural pressure opposes the natural tendency of the lungs to collapse and the chest wall to spring out (i.e., it prevents the lungs from collapsing and the chest wall from springing out).

When a sharp object punctures the intrapleural space, air is introduced into the space (pneumothorax), and intrapleural pressure suddenly becomes equal to atmospheric pressure; thus instead of its normal negative value, intrapleural pressure becomes zero. There are two important consequences of a pneumothorax (see Fig. 5.9 ). First, without the negative intrapleural pressure to hold the lungs open, the lungs collapse. Second, without the negative intrapleural pressure to keep the chest wall from expanding, the chest wall springs out. (If you have trouble picturing why the chest wall would want to spring out, think of the chest wall as a spring that you normally contain by compressing it between your fingers. Of course, the real chest wall is “contained” by the negative intrapleural pressure, rather than the force of your fingers. If you release your fingers, or eliminate the negative intrapleural pressure, the spring or the chest wall springs out.)

Pressure-volume curves for the lungs, chest wall, and combined lung and chest wall

Pressure-volume curves can be obtained for the lungs alone (i.e., the isolated lung in a jar), for the chest wall alone, and for the combined lung and chest-wall system, as shown in Figure 5.10 . The curve for the chest wall alone is obtained by subtraction of the lung curve from the curve for the combined lung and chest wall, described subsequently. The curve for the lung alone is similar to that shown in Figure 5.7 , with the hysteresis eliminated for the sake of simplicity. The curve for the combined lung and chest-wall system is obtained by having a trained subject breathe in and out of a spirometer as follows: The subject inspires or expires to a given volume. The spirometer valve is closed, and as the subject relaxes his or her respiratory muscles, the subject’s airway pressure is measured (called relaxation pressure). In this way, values for airway pressure are obtained at a series of static volumes of the combined lung and chest-wall system. When the volume is FRC, airway pressure is zero and equal to atmospheric pressure. At volumes lower than FRC, airway pressures are negative (less volume, less pressure). At volumes higher than FRC, airway pressures are positive (more volume, more pressure).

The slope of each of the curves in Figure 5.10 is compliance. The compliance of the chest wall alone is approximately equal to the compliance of the lungs alone. (Note that on the graph, the slopes are similar.) However, the compliance of the combined lung and chest-wall system is less than that of either structure alone (i.e., the curve for the combined lung and chest wall is “flatter”). Visualize one balloon (the lungs) inside another balloon (the chest wall). Each balloon is compliant by itself, but the combined system (the balloon within the balloon) is less compliant and harder to expand.

The easiest way to interpret the curves in Figure 5.10 is to begin at the volume called FRC, which is the resting, or equilibrium, volume of the combined lung and chest-wall system. FRC is the volume present in the lungs after a person has expired a normal tidal breath. When you understand the graphs at FRC, then compare the graphs at volumes less than FRC and greater than FRC.

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  Volume is FRC. When the volume is FRC, the combined lung and chest-wall system is at equilibrium. Airway pressure is equal to atmospheric pressure, which is called zero. (Note that when the volume is FRC, the combined lung and chest-wall curve intersects the X-axis at an airway pressure of zero.) At FRC, because they are elastic structures, the lungs “want” to collapse and the chest wall “wants” to expand. If these elastic forces were unopposed, the structures would do exactly that! However, at FRC, the equilibrium position, the collapsing force on the lungs is exactly equal to the expanding force on the chest wall, as shown by the equidistant arrows; the combined lung and chest-wall system neither has a tendency to collapse nor to expand.

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  Volume is less than FRC. When the volume in the system is less than FRC (i.e., the subject makes a forced expiration into the spirometer), there is less volume in the lungs and the collapsing (elastic) force of the lungs is smaller. The expanding force on the chest wall is greater, however, and the combined lung and chest-wall system “wants” to expand. (Notice on the graph that at volumes less than FRC, the collapsing force on the lungs is smaller than the expanding force on the chest wall and that airway pressure for the combined system is negative; thus the combined system tends to expand, as air flows into the lungs down the pressure gradient.)

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  Volume is greater than FRC. When the volume in the system is greater than FRC (i.e., the subject inspires from the spirometer), there is more volume in the lungs and the collapsing (elastic) force of the lungs is greater. The expanding force on the chest wall is smaller, however, and the combined lung and chest-wall system “wants” to collapse. (Notice on the graph that at volumes greater than FRC, the collapsing force on the lungs is greater than the expanding force on the chest wall and that airway pressure for the combined system is positive; thus the overall system tends to collapse, as air flows out of the lungs down the pressure gradient.) At highest lung volumes, both the lungs and the chest wall “want” to collapse [notice that the chest wall curve has crossed the vertical axis at high volumes], and there is a large collapsing force on the combined system.)

Diseases of lung compliance

If the compliance of the lungs changes because of disease, the slopes of the relationships change, and, as a result, the volume of the combined lung and chest-wall system also changes, as illustrated in Figure 5.11 . As a reference, the normal relationships from Figure 5.10 are shown at the top of Figure 5.11 . For convenience, each component of the system is shown on a separate graph (i.e., chest wall alone, lung alone, and combined lung and chest wall). The chest wall alone is included only for completeness because its compliance is not altered by these diseases. The solid lines in each of the three graphs show the normal relationships from Figure 5.10 . The dashed lines show the effects of disease.

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  Emphysema (increased lung compliance). Emphysema, a component of COPD, is associated with loss of elastic fibers in the lungs. As a result, the compliance of the lungs increases. (Recall again the inverse relationship between elastance and compliance.) An increase in compliance is associated with an increased (steeper) slope of the volume-versus-pressure curve for the lung (see Fig. 5.11 B). As a result, at a given volume, the collapsing (elastic recoil) force on the lungs is decreased. At the original value for FRC, the tendency of the lungs to collapse is less than the tendency of the chest wall to expand, and these opposing forces will no longer be balanced. In order for the opposing forces to be balanced, volume must be added to the lungs to increase their collapsing force. Thus the combined lung and chest-wall system seeks a new higher FRC, where the two opposing forces can be balanced (see Fig. 5.11 C); the new intersection point, where airway pressure is zero, is increased. A patient with emphysema is said to breathe at higher lung volumes (in recognition of the higher FRC) and will have a barrel-shaped chest.

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  Fibrosis (decreased lung compliance). Fibrosis, a so-called restrictive disease, is associated with stiffening of lung tissues and decreased compliance. A decrease in lung compliance is associated with a decreased slope of the volume-versus-pressure curve for the lung (see Fig. 5.11 B). At the original FRC, the tendency of the lungs to collapse is greater than the tendency of the chest wall to expand and the opposing forces will no longer be balanced. To reestablish balance, the lung and chest-wall system will seek a new lower FRC (see Fig. 5.11 C); the new intersection point, where airway pressure is zero, is decreased.

Surface tension of alveoli

The small size of alveoli presents a special problem in keeping them open. This “problem” can be explained as follows: Alveoli are lined with a film of fluid. The attractive forces between adjacent molecules of the liquid are stronger than the attractive forces between molecules of liquid and molecules of gas in the alveoli, which creates a surface tension. As the molecules of liquid are drawn together by the attractive forces, the surface area becomes as small as possible, forming a sphere (like soap bubbles blown at the end of a tube). The surface tension generates a pressure that tends to collapse the sphere. The pressure generated by such a sphere is given by the law of Laplace:

where

or

The law of Laplace states that the pressure tending to collapse an alveolus is directly proportional to the surface tension generated by the molecules of liquid lining the alveolus and inversely proportional to alveolar radius ( Fig. 5.12 ). Because of the inverse relationship with radius, a large alveolus (one with a large radius) will have a low collapsing pressure and therefore will require only minimal pressure to keep it open. On the other hand, a small alveolus (one with a small radius) will have a high collapsing pressure and require more pressure to keep it open. Thus small alveoli are not ideal because of their tendency to collapse. Yet from the standpoint of gas exchange, alveoli need to be as small as possible to increase their total surface area relative to volume. This fundamental conflict is solved by surfactant.

Surfactant

From the discussion of the effect of the radius on collapsing pressure, the question that arises is How do small alveoli remain open under high collapsing pressures? The answer to this question is found in surfactant, a mixture of phospholipids that line the alveoli and reduce their surface tension. By reducing surface tension, surfactant reduces the collapsing pressure for a given radius.

Figure 5.12 shows two small alveoli, one with surfactant and one without. Without surfactant, the law of Laplace predicts that the small alveolus will collapse ( atelectasis ). With surfactant present, the same small alveolus will remain open (inflated with air) because the collapsing pressure has been reduced.

Surfactant is synthesized from fatty acids by type II alveolar cells. The exact composition of surfactant remains unknown, but the most important constituent is dipalmitoyl phosphatidylcholine (DPPC). The mechanism by which DPPC reduces surface tension is based on the amphipathic nature of the phospholipid molecules (i.e., hydrophobic on one end and hydrophilic on the other). The DPPC molecules align themselves on the alveolar surface, with their hydrophobic portions attracted to each other and their hydrophilic portions repelled. Intermolecular forces between the DPPC molecules break up the attracting forces between liquid molecules lining the alveoli (which had been responsible for the high surface tension). Thus when surfactant is present, surface tension and collapsing pressure are reduced and small alveoli are kept open.

Surfactant provides a second advantage for pulmonary function: It increases lung compliance, which reduces the work of expanding the lungs during inspiration. (Recall from Figure 5.11 that increasing the compliance of the lungs reduces the collapsing force at any given volume so that it is easier for the lungs to expand.)

Finally, a third advantage of surfactant: It keeps alveolar size relatively uniform. During inspiration, some alveoli inflate more quickly than others. Such unevenness of ventilation would impair gas exchange (as explained in the discussion of V/Q defects). Surfactant, conveniently, helps alveoli adjust their inflation rates so that they are more uniform. For example, in a rapidly-inflating alveolus, alveolar size increases faster than surfactant can be drawn to the alveolar surface, causing an increase in surface tension that puts the brakes on further expansion. On the other hand, in a slowly-inflating alveolus, there is sufficient time for surfactant to be drawn to the alveolar surface and no brake is needed. As a result, the inflation rates of alveoli become more uniform, which is ideal for gas exchange.

In neonatal respiratory distress syndrome, surfactant is lacking. In the developing fetus, surfactant synthesis begins as early as gestational week 24 and it is almost always present by week 35. The more prematurely the infant is born, the less it is likely that surfactant will be present. Infants born before gestational week 24 will never have surfactant, and infants born between weeks 24 and 35 will have uncertain surfactant status. The consequences of the lack of surfactant in the newborn should now be clear: Without surfactant, small alveoli have increased surface tension and increased pressures and will collapse ( atelectasis ). Collapsed alveoli are not ventilated and therefore cannot participate in gas exchange (this is called a shunt, which is discussed later in the chapter); consequently, hypoxemia develops. Without surfactant, lung compliance will be decreased and the work of inflating the lungs during breathing will be increased.

Airway resistance

In the respiratory system, as in the cardiovascular system, flow is inversely proportional to resistance (Q = ΔP/R). Resistance is determined by Poiseuille law. Thus

where

Notice the powerful relationship that exists between resistance (R) and radius (r) of the airways because of the fourth-power dependence. For example, if the radius of an airway decreases by a factor of 2, resistance does not simply increase twofold, it increases by 2 ⁴ , or sixteen fold. When resistance increases by sixteen fold, air flow decreases by sixteen fold, a dramatic effect.

The medium-sized bronchi are the sites of highest airway resistance. It would seem that the smallest airways would provide the highest resistance to air flow, based on the inverse fourth-power relationship between resistance and radius. However, because of their parallel arrangement, the smallest airways do not have the highest collective resistance. Recall that when blood vessels are arranged in parallel, the total resistance is less than the individual resistances and that adding a blood vessel in parallel decreases total resistance (see Chapter 4 ). These same principles of parallel resistances apply to airways.

Changes in airway resistance

The relationship between airway resistance and airway diameter (radius) is a powerful one, based on the fourth-power relationship. It is logical, therefore, that changes in airway diameter provide the major mechanism for altering resistance and air flow. The smooth muscle in the walls of the conducting airways is innervated by autonomic nerve fibers; when activated, these fibers produce constriction or dilation of the airways. Changes in lung volume and in the viscosity of inspired air also may change resistance to air flow.

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  Autonomic nervous system. Bronchial smooth muscle is innervated by parasympathetic cholinergic nerve fibers and by sympathetic adrenergic nerve fibers. Activation of these fibers produces constriction or dilation of bronchial smooth muscle, which decreases or increases the diameter of the airway as follows: (1) Parasympathetic stimulation produces constriction of bronchial smooth muscle, decreasing airway diameter and increasing resistance to air flow. These effects can be simulated by muscarinic agonists (e.g., muscarine and carbachol) and can be blocked by muscarinic antagonists (e.g., atropine). Constriction of bronchial smooth muscle also occurs in asthma and in response to irritants. (2) Sympathetic stimulation produces relaxation of bronchial smooth muscle via stimulation of β ₂ receptors. Relaxation of bronchial smooth muscle results in increases in airway diameter and decreases in resistance to air flow. Therefore β ₂ agonists such as epinephrine (released from the adrenal medulla), isoproterenol, and albuterol produce relaxation of bronchial smooth muscle, which underlies their usefulness in the treatment of asthma.

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  Histamine and several leukotrienes are potent bronchoconstrictors that increase airway resistance.

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  Lung volume. Changes in lung volume alter airway resistance, whereby decreased lung volume causes increased airway resistance (even to the point of airway collapse) and increased lung volume causes decreased airway resistance. One mechanism for the effects of lung volume involves the principle of interdependence of alveoli —that is, alveoli tend to hold their neighbors open by radial traction or mechanical tethering. When alveoli are more inflated (higher lung volume), they pull on both adjacent alveoli and nearby bronchioles, pulling the bronchioles open and decreasing their resistance. Persons with asthma breathe at higher lung volumes and partially offset the high airway resistance of their disease (i.e., the volume mechanism helps to reduce airway resistance as a compensatory mechanism).

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  Viscosity of inspired air (η). The effect of the viscosity of inspired air on resistance is clear from the Poiseuille relationship. Although not common, increases in gas viscosity (e.g., as occur during deep sea diving) produce increases in resistance, and decreases in viscosity (e.g., breathing a low-density gas such as helium) produce decreases in resistance.

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  Compensatory bronchoconstriction. An adaptive mechanism involving airway resistance is utilized when ventilated alveoli are not perfused with pulmonary capillary blood. Recall that such alveoli comprise dead space —without pulmonary blood flow, the ventilation is “wasted” and gas exchange cannot occur. As a result, the PA _O2 and PA _CO2 of those alveoli approach their values in inspired air (i.e., PA _O2 increases and PA _CO2 decreases). The local decrease in Pco ₂ (and accompanying increase in pH) causes bronchoconstriction of nearby airways, which redirects airflow away from regions of dead space (where gas exchange cannot occur) and toward regions that are well-perfused and where gas exchange can occur.

Rest

Rest is the period between breathing cycles when the diaphragm is at its equilibrium position (see Figs. 5.13 and 5.14 A). At rest, no air is moving into or out of the lungs. Alveolar pressure equals atmospheric pressure, and because lung pressures are always referred to atmospheric pressure, alveolar pressure is said to be zero. There is no air flow at rest because there is no pressure difference between the atmosphere (the mouth or nose) and the alveoli.

At rest, intrapleural pressure is negative, or approximately −5 cm H ₂ O. The reason that intrapleural pressure is negative has been explained previously: The opposing forces of the lungs trying to collapse and the chest wall trying to expand create a negative pressure in the intrapleural space between them. Recall from the experiment on the isolated lung in a jar that an outside negative pressure (i.e., negative intrapleural pressure) keeps the lungs inflated or expanded. The transmural pressure across the lungs at rest is +5 cm H ₂ O (alveolar pressure minus intrapleural pressure), which means that these structures will be open.

The volume present in the lungs at rest is the equilibrium volume or FRC, which, by definition, is the volume remaining in the lungs after a normal expiration.

Inspiration

During inspiration, the diaphragm contracts, causing the volume of the thorax to increase. As lung volume increases, the pressure in the lungs must decrease. (Boyle’s law states that P × V is constant at a given temperature.) Halfway through inspiration (see Figs. 5.13 and 5.14 B), alveolar pressure falls below atmospheric pressure (−1 cm H ₂ O). The pressure gradient between the atmosphere and the alveoli drives air flow into the lung. Air flows into the lungs until, at the end of inspiration (see Fig. 5.14 C), alveolar pressure is once again equal to atmospheric pressure; the pressure gradient between the atmosphere and the alveoli has dissipated, and air flow into the lungs ceases. The volume of air inspired in one breath is the tidal volume (V t ), which is approximately 0.5 L. Thus the volume present in the lungs at the end of normal inspiration is the FRC plus one tidal volume (FRC + V t ).

During inspiration, intrapleural pressure becomes even more negative than at rest. There are two explanations for this effect: (1) As lung volume increases, the elastic recoil of the lungs also increases and pulls more forcefully against the intrapleural space, and (2) airway and alveolar pressures become negative.

Together, these two effects cause the intrapleural pressure to become more negative, or approximately −8 cm H ₂ O at the end of inspiration. The extent to which intrapleural pressure changes during inspiration can be used to estimate the dynamic compliance of the lungs.

Expiration

Normally, expiration is a passive process. Alveolar pressure becomes positive (higher than atmospheric pressure) because the elastic forces of the lungs compress the greater volume of air in the alveoli. When alveolar pressure increases above atmospheric pressure (see Figs. 5.13 and 5.14 D), air flows out of the lungs and the volume in the lungs returns to FRC. The volume expired is the tidal volume. At the end of expiration (see Figs. 5.13 and 5.14 A), all volumes and pressures return to their values at rest and the system is ready to begin the next breathing cycle.

Forced expiration

In a forced expiration, a person deliberately and forcibly breathes out. The expiratory muscles are used to make lung and airway pressures even more positive than those seen in a normal, passive expiration. Figure 5.15 shows an example of the pressures generated during a forced expiration; a person with normal lungs is compared with a person with COPD.

In a person with normal lungs, the forced expiration makes the pressures in the lungs and airways very positive. Both airway and alveolar pressures are raised to much higher values than those occurring during passive expiration. Thus during a normal passive expiration, alveolar pressure is +1 cm H ₂ O (see Fig. 5.14 D); in this example of forced expiration, airway pressure is +25 cm H ₂ O and alveolar pressure is +35 cm H ₂ O (see Fig. 5.15 ).

During forced expiration, contraction of the expiratory muscles also raises intrapleural pressure, now to a positive value of, for example, +20 cm H ₂ O. An important question is Will the lungs and airways collapse under these conditions of positive intrapleural pressure? No, as long as the transmural pressure is positive, the airways and lungs will remain open. During a normal forced expiration, transmural pressure across the airways is airway pressure minus intrapleural pressure, or +5 cm H ₂ O (+25 − [+20] = +5 cm H ₂ O); transmural pressure across the lungs is alveolar pressure minus intrapleural pressure, or +15 cm H ₂ O (+35 − [+20] = +15 cm H ₂ O). Therefore both the airways and the alveoli will remain open because transmural pressures are positive. Expiration will be rapid and forceful because the pressure gradient between the alveoli (+35 cm H ₂ O) and the atmosphere (0) is much greater than normal.

In a person with emphysema, however, forced expiration may cause the airways to collapse. In emphysema, lung compliance increases because of loss of elastic fibers. During forced expiration, intrapleural pressure is raised to the same value as in the normal person, +20 cm H ₂ O. However, because the structures have diminished elastic recoil, alveolar pressure and airway pressure are lower than in a normal person. The transmural pressure gradient across the lungs remains a positive expanding pressure, +5 cm H ₂ O, and the alveoli remain open. However, the large airways collapse because the transmural pressure gradient across them reverses, becoming a negative (collapsing) transmural pressure of −5 cm H ₂ O. Obviously, if the large airways collapse, resistance to air flow increases and expiration is more difficult. Persons with emphysema learn to expire slowly with pursed lips, which creates a high resistance at the mouth and raises airway pressure, thus preventing the reversal of the transmural pressure gradient across the large airways and preventing their collapse.

General gas law

The general gas law (familiar from chemistry courses) states that the product of pressure times volume of a gas is equal to the number of moles of the gas multiplied by the gas constant multiplied by the temperature. Thus

where

The only “trick” in applying the general gas law to respiratory physiology is to know that in the gas phase BTPS is used, but in the liquid phase, STPD is used. BTPS means body temperature (37° C, or 310 K), ambient pressure, and gas saturated with water vapor. For gases dissolved in blood, STPD is used, meaning standard temperature (0° C, or 273 K), standard pressure (760 mm Hg), and dry gas. Gas volume at BTPS can be converted to volume at STPD by multiplying the volume (at BTPS) by 273/310 × P b − 47/760 (where P b is barometric pressure and 47 mm Hg is water vapor pressure at 37° C).