Medical Physiology A Cellular and Molecular Approach, Updated 2nd Ed.

ORGANIZATION OF THE RESPIRATORY SYSTEM

Walter F. Boron

COMPARATIVE PHYSIOLOGY OF RESPIRATION

External respiration is the exchange of O2 and CO2 between the atmosphere and the mitochondria

For millennia, people have regarded breathing as being synonymous with life. Life begins and ends with breathing. The Bible states that God “breathed into [Adam’s] nostrils the breath of life” and then later used part of Adam’s ventilatory apparatus—a rib—to give life to Eve.

In the fourth and fifth centuries bc, writings attributed to Hippocrates suggested that the primary purpose of breathing is to cool the heart. It was not until the 18th century that the true role of breathing began to emerge as several investigators studied the chemistry of gases. Chemists had recognized similarities between combustion and breathing but thought that both involved the release of a “fire-essence” called phlogiston. According to their theory, neither combustion nor life could be supported once air became saturated with phlogiston. (See Note: Joseph Black (1728-1799))

In the 1750s, Joseph Black found that heating calcium carbonate produces a gas he called fixed air, now known to be carbon dioxide (CO2). This work revolutionized chemistry by showing that other gases exist besides ordinary “air” and that a chemical reaction can involve a gas. Shortly thereafter, Henry Cavendish found that fermentation and putrefaction also produce “fixed air.” Joseph Priestley discovered several new gases between the late 1760s and mid-1770s, including “dephlogistonated air,” co-discovered by Carl Scheele. Priestley found that combustion, putrefaction, and breathing all consume dephlogistonated air and all reduce the volume of room air by ~20%. Conversely, he found that green plants produce dephlogistonated air, which he quantitated by reacting it with nitric oxide (a colorless gas) to produce nitrogen dioxide (a red gas). (See Note: Henry Cavendish (1731-1810)Joseph Priestley (1733-1804)Carl Scheele (1742-1786))

In the mid-1770s, Priestley presented his findings to Antoine Lavoisier—often regarded as the father of modern chemistry. Lavoisier quickly put Priestley’s empirical observations into a theoretical framework that he used to demolish the phlogiston theory, which Priestley held to his death. Lavoisier recognized that dephlogistonated air, which he named oxygen (O2), represents the ~20% of room air consumed by combustion in Priestley’s experiments, leaving behind “nonvital” air, or nitrogen. Furthermore, he proposed that O2 is consumed because it reacts with one substance to produce another. The mathematician Joseph-Louis Lagrange suggested that O2 consumption and CO2production occur not in the lungs but in isolated tissues, as Lazzaro Spallanzani later rigorously demonstrated in the late 18th century. (See Note: Antoine Lavoisier (1743-1794))

Thus, by the end of the 18th century, chemists and physiologists appreciated that combustion, putrefaction, and respiration all involve chemical reactions that consume O2 and produce CO2. Subsequent advances in the chemistry of gases by Boyle, Henry, Avogadro, and others laid the theoretical foundation for the physiology of O2 and CO2. Thus, respiration was a unifying theme in the early histories of physiology, chemistry, and biochemistry.

Later work showed that mitochondrial respiration (i.e., the oxidation of carbon-containing compounds to form CO2) is responsible for the O2 consumption and CO2 production observed by Spallanzani. This aspect of respiration is often called internal respiration or oxidative phosphorylation (see Chapter 58). (See Note: Lazzaro Spallanzani (1729-1799))

In the chapters on respiratory physiology, we focus on external respiration, the dual processes of (1) transporting O2 from the atmosphere to the mitochondria and (2) transporting CO2 from the mitochondria to the atmosphere. We will also see that CO2 transport is intimately related to acid-base homeostasis.

Diffusion is the major mechanism of external respiration for small aquatic organisms

The most fundamental mechanism of O2 and CO2 transport is diffusion (see Chapter 5). Random movements of molecules such as O2 and CO2, whether in a gaseous phase or dissolved in water, result in a net movement of the substance from regions of high concentration to regions of low concentration (Fig. 26-1A, inset). No expenditure of energy is involved. The driving force for diffusion is the concentration gradient.

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Figure 26-1 Diffusion of O2 and CO2 for a single-celled organism. In A to D, the y-axis of grids shows the dissolved concentration (or partial pressure) of O2 and CO2. The x-axis represents distance (not to scale). In D, the broken red and blue lines and the enclosed violet trianglesrepresent the magnitude of the gradients driving O2 and CO2 diffusion. The red (O2) and blue (CO2) pathways represent the circuit of blood from the pulmonary capillaries to the systemic capillaries and back again.

Imagine a unicellular organism suspended in a beaker of pond water at 37°C. The water is in equilibrium with an atmosphere that has the usual composition of O2 and CO2 (Table 26-1). The partial pressures of O2 (PO2) and of CO2(PCO2) in the dry air are slightly higher than their corresponding values in the wet air immediately above the surface of the water (see the box on wet gases). It is these partial pressures in wet air that determine the concentrations of dissolved O2 ([O2]Dis) and dissolved CO2 ([CO2]Dis) in the water (see the box on partial pressures and Henry’s law). Thus, the PO2 in the wet air—as well as the water beneath it—will be ~149 mm Hg (or torr), and the PCO2 will be an almost negligible 0.2 mm Hg. These numbers describe the composition of the bulk phase of the pond water (Fig. 26-1A, left side), at some distance from the organism. However, because the mitochondria within the organism continuously consume O2 and produce CO2, the PO2 at the surface of the mitochondria will be lower than the bulk-phase PO2, whereas the PCO2 at the mitochondrial surface will be higher than the bulk-phase PCO2 (Fig. 26-1A, right side). These differences in partial pressure cause O2 to diffuse from the bulk pond water toward the mitochondria and the CO2 to diffuse in the opposite direction.

Table 26-1 Composition of Air

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Wet Gases: Partial Pressures of O2 and CO2 in Solutions That Are Equilibrated with Wet Air (See Note: Gas Laws)

Imagine that a beaker of water is equilibrated with a normal atmosphere and that both water and atmosphere have a temperature of 37°C. For dry air (i.e., air containing no water vapor), O2 makes up ~21% of the total gas by volume (Table 26-1). Thus, if the ambient pressure—or barometric pressure (PB)—is 760 mm Hg, the partial pressure of O2 (PO2) is 21% of 760 mm Hg, or 159 mm Hg (Fig. 26-2). However, if the air-water interface is reasonably stationary, water vapor will saturate the air immediately adjacent to the liquid. What is the PO2 in this wet air? At 37°C, the partial pressure of water (PH2O) is 47 mm Hg. Of the total pressure of the wet air, PH2O makes up 47 mm Hg, and the components of the dry air make up the remaining 760 − 47, or 713 mm Hg. Thus, the partial pressure of O2 in this wet air is

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Figure 26-2 Wet versus dry gases.

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The CO2 composition of dry air is ~0.03% (Table 26-1). Thus, the partial pressure of CO2 in wet air is

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These examples are realistic for respiratory physiology. As we inhale relatively cool and dry air, the nose and other upper respiratory passages rapidly warm and moisturize the passing air so that it assumes the composition of wet air given in Table 26-1.

The diffusion of O2 follows a gradient of decreasing PO2 (Fig. 26-1A). The region over which PO2 falls gradually from the bulk pond water toward the outer surface of the plasma membrane is the extracellular unstirred layer, so named because no convective mixing occurs in this zone. A similar gradual decline in PO2 drives O2 diffusion through the intracellular unstirred layer, from the inner surface of the plasma membrane to the mitochondria. The abrupt fall in PO2 across the plasma membrane reflects some resistance to gas flow. The profile for PCO2 is similar, although with the opposite orientation.

The rate at which O2 or CO2 moves across the surface of the organism is the flow (units: moles/s). According to a simplified version of Fick’s law (see Chapter 5), flow is proportional to the concentration difference across this barrier. Because we know from Henry’s law that the concentration of a dissolved gas is proportional to its partial pressure in the gas phase, flow is also proportional to the partial pressure difference (ΔP):

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Simple diffusion is the mechanism by which O2 and CO2 move short distances in the respiratory system: between the air and blood in the alveoli, and between the mitochondria and blood of the peripheral circulation.

Partial Pressures and Henry’s Law

Respiratory physiologists generally express the concentration of a gas, whether it is mixed with another gas (e.g., O2 mixed with N2, as is the case for air) or dissolved in an aqueous solution (e.g., O2 dissolved in water), in terms of partial pressure. Dalton’s law states that the total pressure (Ptotal) of a mixture of gases is the sum of their individual partial pressures. Imagine that we are dealing with an ideal gas (Z) mixed with other gases. Because the ratio of the partial pressure of Z (PZ) to the total pressure (Ptotal) is its mole fraction (XZ),

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Thus, if PZ in one sample of gas were twice as high as in another, XZ (i.e., concentration of Z) would also be twice as high.

It may not be immediately obvious why—when Z is dissolved in aqueous solutions—it is still reasonable to express the concentration of Z in terms of PZ. According to Henry’s law, the concentration of O2 dissolved in water ([O2]Dis) is proportional to PO2 in the gas phase:

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The proportionality constant s is the solubility; for O2s is ~0.0013 mM/mm Hg at 37°C for a solution mimicking blood plasma. The solubility of CO2 is ~23-fold higher. Consider a beaker of water at 37°C equilibrated with an atmosphere having a PO2 of 100 mm Hg, the partial pressure in mammalian arterial blood plasma (Fig. 26-3A, solution 1):

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Figure 26-3 Henry’s law and the diffusion of dissolved gases.

Now consider a second beaker equilibrated with an atmosphere having a PO2 of 40 mm Hg, the partial pressure of O2 in mixed-venous blood (Fig. 26-3A, solution 2):

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If we now place samples of these two solutions on opposite sides of a semipermeable barrier in a closed container (Fig. 26-3B), the O2 gradient across this barrier expressed in terms of concentrations (Δ[O2]) is 0.13 − 0.05 or 0.08 mM. Expressed in terms of partial pressures (ΔPO2), this same gradient is 100 − 40 = 60 mm Hg.

Imagine now that we take a 5-mL sample of each of the solutions in the beakers in Figure 26-3A, drawing the fluid up into syringes, sealing the syringes, putting them on ice, and sending them to a clinical laboratory for analysis—as is routinely done with samples of arterial blood. Even though there is no gas phase in equilibrium with either of the solutions in the syringes, the laboratory will report the O2 levels in millimeters of mercury (mm Hg). These are the partial pressures of O2 with which the solutions were or would have to be equilibrated to achieve the [O2]Dis in the liquid samples.

Convection enhances diffusion by producing steeper gradients across the diffusion barrier

A purely diffusive system can establish only a relatively small ΔP across the gas-exchange barrier of the organism (Fig. 26-1A). Yet, for small organisms, even this relatively small ΔP is adequate to meet the demands for O2 uptake and CO2 removal. However, when the organism’s diameter exceeds ~1 mm, simple diffusion becomes inadequate for gas exchange. One way of ameliorating this problem is to introduce a mechanism for convection on the outside surface of the organism. For a paramecium, the beating cilia bring bulk-phase water—having a PO2 of ~154 mm Hg at 25°C and a PCO2 of ~0.2 mm Hg—very near to the cell’s surface. This mixing reduces the size of the extracellular unstirred layer, thereby increasing the PO2 and decreasing the PCO2 on the outer surface of the organism. The net effect is that the partial pressure gradients for both O2 and CO2 increase across the gas exchange barrier (Fig. 26-1B), leading to a proportionate increase in the flow of both substances.

A filter feeder, such as an oyster or a clam, pumps bulk-phase water past its organ of gas exchange. Because of the relatively low solubility of O2 in water, such an organism may need to pump 16,000 mL of water to extract a mere 1 mL of O2 gas. In fish, which are far more efficient, the ratio may be considerably lower, ~400 : 1.

In mammals, the bulk phase is the atmosphere and the external convective system is an air pump that includes the chest wall, the respiratory muscles, and the passages through which the air flows (i.e., from the nose up to the alveoli). Ventilation is the process of moving air into and out of the lungs. Amphibians move air into their lungs by swallowing it. Reptiles, birds, and mammals expand their lungs by developing a negative pressure inside the thorax. Because of the much higher O2 content of air (about 210 mL O2/L of air at standard temperature and pressure/dry or STPD; see the box on page 617) as opposed to water (~35 mL O2/L of water), humans need to move far less air than oysters need to move water. For example, a human may ventilate the alveoli with 4000 mL of fresh air every minute and extract from this air 250 mL of O2 gas, a ratio of 16 : 1.

Although we are 1000-fold more efficient than oysters, the principle of external convective systems is the same: ensure that the external surface of the gas exchange barrier is in close contact with a fluid whose composition matches—as closely as is practical—that of the bulk phase. How “closely” is “practical”? The composition of alveolar air approaches that of wet inspired air as alveolar ventilation approaches infinity (see Chapter 31). Because high ventilatory rates have a significant metabolic cost, the body must trade off optimizing alveolar PO2 and PCO2 on the one hand against minimizing the work of ventilation on the other. In the average adult human, the compromise that has evolved is an alveolar ventilation of ~4000 mL/min, an alveolar PO2 of ~100 mm Hg (versus 149 mm Hg in a wet atmosphere at 37°C), and an alveolar PCO2 of ~40 mm Hg (versus 0.2 mm Hg).

Conventions for Measurement of Volumes of Gases

BTPS

Gases within the lung are saturated with water vapor at 37°C (310 K). At this temperature, PH2O is 47 mm Hg (see the box on wet gases). If the glottis is open and no air is flowing, then the total pressure of the air in the lungs is PB, which we will assume to be 760 mm Hg. In this case, the partial pressure of dry gases in the lungs is (760 − 47) = 713 mm Hg. The convention is to report the volume of gases in the lungs—and changes in the volume of these gases—at body temperature and pressure, saturated with water or BTPS. Such volumes include both wet and dry gases.

ATPS

If we exhale a volume of air from the lungs (ΔVBTPS) into a spirometer, the “floor” of which is formed by water (Fig. 26-8), the exhaled air will now be at ambient temperature and pressure, saturated with water or ATPS. Thus, we must correct the volume change (ΔVATPS) registered by the spirometer (at ATPS) to know the volume that this same gas had occupied in the lungs (at BTPS). Two factors are at work as warm alveolar air moves into a cooler spirometer: (1) PH2O decreases and some gaseous H2O condenses into liquid H2O, according to the temperature dependence of PH2O; and (2) the pressure exerted by the dry gas molecules decreases, according to Charles’ law. Starting from the Boyle-Charles law: (See Note: Gas Laws)

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Figure 26-8 The workings of a simple spirometer.

it is possible to show that (See Note: Conversion from VBTPS to VATPS)

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Here, Tbody and Tambient are absolute temperatures.

If Tbody is 37°C (310 K), then the corresponding PH2O is 47 mm Hg. If Tambient is 25°C (or 298 K), then the corresponding PH2O is 24 mm Hg. For these conditions, the conversion from an ATPS volume to a BTPS volume becomes

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Thus, the same wet gas that occupies 1000 mL in the spirometer at ATPS occupies 1074 mL in the lungs at BTPS.

STPD

The convention is to report the volume of gases in the blood (e.g., dissolved CO2 or O2 bound to hemoglobin) in the same way that chemists would—at standard temperature and pressure/dry or STPD. The standard temperature is 0°C (273 K), and the standard pressure is 760 mm Hg. You may recall from introductory chemistry that a mole of an ideal gas occupies 22.4 L at STPD. If you wish to convert a ΔVSTPD to a ΔVBTPS, it is possible to show that (See Note: Conversion from VBTPS to VSTPD)

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For a body temperature of 37°C, the conversion from a BTPS volume to an STPD volume becomes

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Thus, the same dry gas that occupies 1000 mL under standard chemical conditions occupies 1210 mL in the body at BTPS.

A clinical example in which the external convective system fails is barbiturate poisoning. Here, drug intoxication inhibits the respiratory control centers in the medulla (see Chapter 32), so that ventilation slows or even stops. The consequence is that the unstirred layer between the bulk-phase atmosphere and the alveolar blood-gas barrier becomes extremely large (i.e., the distance between the nose and the alveoli). As a result, alveolar PO2 falls to such low levels that the ΔPO2 across the alveolar wall cannot support an O2 flow and an arterial [O2] that is compatible with life. Cessation of ventilation also causes the alveolar PCO2 to rise to such high levels that the CO2 flow from blood to alveolar air is unacceptably low.

An external convective system maximizes gas exchange by continuously supplying bulk-phase water or air to the external surface of the gas exchange barrier, thereby maintaining a high external PO2 and a low external PCO2. A circulatory system is an internal convective system that maximizes flow of O2 and CO2 across the gas exchange barrier by delivering, to the inner surface of this barrier, blood that has as low a PO2 and as high a PCO2 as is practical. Perfusion is the process of delivering blood to the lungs. Figure 26-1C shows a primitive—and hypothetical—internal convective system, one that essentially stirs the entire internal contents of the organism, so that the PO2 of the bulk internal fluids is uniform, right up to the surface of the mitochondria. The result is that the ΔPO2 across the gas exchange barrier is rather large, but the ΔPO2 between the bulk internal fluid and the mitochondria is rather small.

Figure 26-1D summarizes the PO2 and PCO2 profiles for a sophisticated circulatory system built around a four-chambered heart and separate pulmonary and systemic circulations. The circulatory system carries (by convection) low-PO2 blood from a systemic capillary near the mitochondria to the alveolar wall. At the beginning of a pulmonary capillary, a high alveolar-to-blood PO2 gradient ensures a high O2 inflow (by diffusion), and blood PO2 rises to match the alveolar (i.e., external) PO2 by the time the blood leaves the pulmonary capillary. Finally, the systemic arterial blood carries (by convection) this high-PO2 blood to the systemic capillaries, where a high blood-to-mitochondria PO2gradient maximizes the O2 flux into the mitochondria (by diffusion). The opposite happens with CO2. Thus, separate pulmonary and systemic circulations ensure maximal gradients for gas diffusion in both the pulmonary and systemic capillaries.

The scenario outlined in Figure 26-1D requires the four-chambered heart characteristic of mammals as well as of advanced reptiles and birds. The right ventricle pumps low-PO2/high-PCO2 blood received from the peripheral veins to the lungs, whereas the left ventricle pumps high-PO2/low-PCO2 blood received from pulmonary veins to the periphery (i.e., mitochondria). Maintenance of maximal gradients for O2 and CO2 diffusion in both the pulmonary and systemic capillaries at the mitochondria requires that right and left ventricular blood not mix. However, this sort of mixing is exactly what occurs in fish and amphibians, whose hearts have a common ventricle. In these animals, the aortic blood has PO2 and PCO2 values that are intermediate between the extreme values of venous blood returning from the systemic circulation and the blood returning from the gas-exchange barrier. The result is less than optimal PO2and PCO2 gradients at both the gas exchange barrier and the mitochondria.

In humans, the internal convective system may fail when diseased heart valves cause a decrease in cardiac output. Another example is the shunting of blood between the pulmonary and the systemic circulations, as may occur in newborns with congenital anomalies (e.g., atrial or ventricular septal defects). The result is the same sort of mixing of systemic venous and gas exchange barrier blood that occurs in amphibians and fish. Thus, patients with shunts cannot establish normal PO2 and PCO2 gradients in the pulmonary and peripheral capillaries and thus cannot generate normal flows of O2 and CO2.

Surface area amplification enhances diffusion

the passive flow of O2 or CO2 across a barrier is proportional not only to the concentration gradient but also to the area of the barrier: (See Note: Flow versus Flux)

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Indeed, higher animals have increased their ability to exchange O2 and CO2 with their environment by increasing the surface area across which gas exchange takes place. For example, mollusks (e.g., squid) and fish have gills, which they form by evaginating the gas exchange barrier, thus greatly amplifying its surface area. Higher land animals amplify their gas exchange barriers by invaginating them, forming lungs. In an amphibian such as the adult frog, the lungs are simple air sacs with a relatively small surface area. Not surprisingly, a large portion of their gas exchange must occur across the skin. The gas exchange barrier is considerably more sophisticated in reptiles, which line their lungs with alveoli or even subdivide them with alveoli-lined barriers. The net effect is to increase the surface-to-volume ratio of the lungs. Mammals increase the area available for diffusion even more, by developing highly complex lungs with bronchi and a large number of alveoli.

In humans, the lung surface is so large and so thin that O2 and CO2 transport across the alveolar wall is ~3-fold faster than necessary—at least when the person is resting at sea level. Nevertheless, this redundancy is extremely important during exercise (when cardiac output can increase markedly), for life at high altitude (where the PO2 is low), and in old age (when lung function diminishes). A substantial decrease in surface area, or thickening of the barrier, can be deleterious. Examples are the surgical removal of a lung (which reduces the total surface for gas exchange by about half) and pulmonary edema (which increases the effective thickness of the barrier). Thus, if an individual with a thickened barrier loses a lung, the remaining surface area may not be large enough to sustain adequate rates of gas exchange.

Respiratory pigments such as hemoglobin increase the carrying capacity of the blood for both O2 and CO2

In mammals, the external convective system (i.e., ventilatory apparatus), the internal convective system (i.e., circulatory system), and the barrier itself (i.e., alveolar wall) are so efficient that the diffusion of O2and CO2 is not what limits the exchange of gases, at least not in healthy subjects at sea level.

Imagine what would happen if the mixed-venous blood flowing down a pulmonary capillary contained only water and salts. The diffusion of O2 from the alveolar air space into the “blood” is so fast—and the solubility of O2 in saline is so low (see the box on Henry’s law)—that before the blood could move ~1% of the way down the capillary, the PO2 of the blood would match the PO2 of the alveolar air (i.e., all of the O2 that could move would have moved). For the remaining ~99% of the capillary, the PO2 gradient across the barrier would be nil, and no more O2 would flow into the blood. As a result, at a normal cardiac output, the “blood” could never carry away enough O2 from the lungs to the tissues to sustain life. The same is true in reverse for the elimination of CO2.

Animals solve this problem with respiratory pigments, specialized metalloproteins that—via the metal—reversibly bind O2, greatly increasing the carrying capacity of blood for O2. In some arthropods and mollusks, the pigment is hemocyanin, which coordinates two copper atoms. Polychaete worms and brachiopods use hemerythrins, which coordinate two iron atoms. However, the most common—and most efficient—respiratory pigments are the hemoglobins, which coordinate a porphyrin ring that contains iron. All vertebrates as well as numerous unrelated groups of animals use hemoglobin, which is the chief component of erythrocytes or red blood cells. (See Note: HemocyaninHemerythrins)

The presence of hemoglobin markedly improves the dynamics of O2 uptake by blood passing through the lungs. Under normal conditions, hemoglobin reversibly binds ~96% of the O2 that diffuses from the alveolar air spaces to the pulmonary capillary blood, greatly increasing the carrying capacity of blood for O2. Hemoglobin also plays a key role in the transport or carriage of CO2 by reversibly binding CO2 and by acting as a powerful pH buffer. In anemia, the hemoglobin content of blood is reduced, thus lowering the carrying capacity of blood for O2 and CO2. An individual with anemia can compensate only if the systemic tissues extract more O2 from each liter of blood or if cardiac output increases. However, there are limits to the amount of O2 that tissues can extract or to the level to which the heart can increase its output.

Pathophysiology recapitulates phylogeny—in reverse

It should be clear from the pathophysiological examples discussed that when a key component of the respiratory system fails in a higher organism, external respiration becomes more like that of an organism lower on the evolutionary ladder. For example, a failure of a mammal’s air pump makes this individual behave more like a unicellular aquatic organism without cilia. A reduction in the surface area of the alveoli in a mammal creates the same problems faced by an amphibian with simple sack-like lungs. A major shunt in the circulatory system makes a mammal behave more like a fish. In severe anemia, a mammal faces the same problems as a lower life form with a less efficient respiratory pigment.

ORGANIZATION OF THE RESPIRATORY SYSTEM IN HUMANS

Humans optimize each aspect of external respiration—ventilation, circulation, area amplification, gas carriage, local control, and central control

The human respiratory system (Fig. 26-4) has two important characteristics. First, it uses highly efficient convective systems (i.e., ventilatory and circulatory systems) for long-distance transport of O2 and CO2. Second, it reserves diffusion exclusively for short-distance movements of O2 and CO2. The key components of this respiratory system are the following:

1. An air pump. The external convective system consists of the upper respiratory tract and large pulmonary airways, the thoracic cavity and associated skeletal elements, and the muscles of respiration. These components deliver air to and remove air from the alveolar air spaces—alveolar ventilation. Inspiration occurs when muscle contractions increase the volume of the thoracic cavity, thereby lowering intrathoracic pressure, which causes the alveoli to expand passively, which in turn lowers alveolar pressure. Air then flows from the environment to the alveoli, down a pressure gradient. A quiet expiration occurs when the muscles relax. We discuss the mechanics of ventilation in Chapter 27.

2. Mechanisms for carrying O2 and CO2 in the blood. Red blood cells are highly specialized for transporting O2 from the lungs to the peripheral tissues and for transporting CO2 in the opposite direction. They have extremely high levels of hemoglobin and other components that help to rapidly load and unload huge amounts of O2 and CO2. In the pulmonary capillaries, hemoglobin binds O2, thereby enabling the blood to carry ~65-fold more O2 than saline. In the systemic capillaries, hemoglobin plays a key role in the carriage of CO2—produced by the mitochondria—to the lungs. Hemoglobin accomplishes this task by chemically reacting with some of the CO2 and by buffering the H+ formed as carbonic anhydrase converts CO2 to HCO3 and H+. Thus, hemoglobin plays a central role in acid-base chemistry, as discussed in Chapter 28, as well as for the carriage of O2 and CO2, treated in Chapter 29.

3. A surface for gas exchange. The gas exchange barrier in humans consists of the alveoli, which provide a huge but extremely thin surface area for passive diffusion of gases between the alveolar air spaces and the pulmonary capillaries. We discuss the anatomy of the alveoli later in this chapter and explore pulmonary gas exchange in Chapter 30. A similar process of gas exchange occurs between the systemic capillaries and mitochondria.

4. A circulatory system. The internal convective system in humans consists of a four-chambered heart and separate systemic and pulmonary circulations. We discuss the flow of blood to the lungs—perfusion—in Chapter 31.

5. A mechanism for locally regulating the distribution of ventilation and perfusion. Efficient gas exchange requires that the ratio of ventilation to perfusion be uniform for all alveoli to the extent possible. However, neither the delivery of fresh air to the entire population of alveoli nor the delivery of mixed-venous blood to the entire population of pulmonary capillaries is uniform throughout the lungs. The lungs attempt to maximize the uniformity of ventilation-perfusion ratios by using sophisticated feedback control mechanisms to regulate local air flow and blood flow, as discussed in Chapter 31.

6. A mechanism for centrally regulating ventilation. Unlike the rhythmicity of the heart, that of the respiratory system is not intrinsic to the lungs or the chest wall. Instead, respiratory control centers in the central nervous systemrhythmically stimulate the muscles of inspiration. Moreover, these respiratory centers appropriately modify the pattern of ventilation during exercise or other changes in physical or mental activity. Sensors for arterial PO2, PCO2, and pH are part of feedback loops that stabilize these three “blood gas” parameters. We discuss these subjects in Chapter 32.

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Figure 26-4 The respiratory apparatus in humans.

Respiratory physiologists have agreed on a set of symbols to describe parameters that are important for pulmonary physiology and pulmonary function tests (Table 26-2).

Table 26-2 Symbol Conventions in Respiratory Physiology

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Conducting airways deliver fresh air to the alveolar spaces

We will discuss lung development in Chapter 57. In the embryo, each lung invaginates into a separate pleural sac, which reflects over the surface of the lung.

The parietal pleura, the wall of the sac that is farthest from the lung, contains blood vessels that are believed to produce an ultrafiltrate of the plasma called pleural fluid. About 10 mL of this fluid normally occupies the virtual space between the parietal and the visceral pleura. The visceral pleura lies directly on the lung and contains lymphatics that drain the fluid from the pleural space. When the production of pleural fluid exceeds its removal, the volume of pleural fluid increases (pleural effusion), limiting the expansion of the lung. Under normal circumstances, the pleural fluid probably lubricates the pleural space, facilitating physiological changes in lung size and shape.

The lungs themselves are divided into lobes, three in the right lung (i.e., upper, middle, and lower lobes) and two in the left (i.e., upper and lower lobes). The right lung, which is less encumbered than the left by the presence of the heart, makes up ~55% of total lung mass and function.

We refer to the progressively bifurcating pulmonary airways by their generation number (Fig. 26-5). The zeroth generation is the trachea, the first-generation airways are the right and left mainstem bronchi, and so on. Inasmuch as the right mainstem bronchus has a greater diameter than the left and is more nearly parallel with the trachea, inhaled foreign bodies more commonly lodge in the right lung than in the left. Humans have ~23 generations of airways. As generation number increases (i.e., as airways become smaller), the amount of cilia, the number of mucus-secreting cells, the presence of submucosal glands, and the amount of cartilage in the airway walls all gradually decrease. The mucus is important for trapping small foreign particles. The cilia sweep the carpet of mucus—kept moist by secretions from the submucosal glands—up toward the pharynx, where swallowing eventually disposes of the mucus. The cartilage is important for preventing airway collapse, which is especially a problem during expiration (see Chapter 27). Airways maintain some cartilage to about the 10th generation, up to which point they are referred to as bronchi.

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Figure 26-5 Generations of airways.

Beginning at about the 11th generation, the now cartilage-free airways are called bronchioles. Because they lack cartilage, bronchioles can maintain a patent lumen only because the pressure surrounding them may be more negative than the pressure inside and because of the outward pull (radial traction or tethering) of surrounding tissues. Thus, bronchioles are especially susceptible to collapse during expiration. Up until generation ~16, no alveoli are present, and the air cannot exchange with the pulmonary capillary blood. The airways from the nose and lips down to the alveoli-free bronchioles are the conducting airways, which serve only to move air by convection (i.e., like water moving through a pipe) to those regions of the lung that participate in gas exchange. The most distal conducting airways are the terminal bronchioles(generation ~16). The aggregate volume of conducting airways, the anatomical dead space, amounts to ~150 mL in healthy young males and somewhat more than 100 mL in females. The anatomical dead space is only a small fraction of the total lung capacity, which averages 5 to 6 L in adults, depending on the size and health of the individual.

Alveolar air spaces are the site of gas exchange

Alveoli first appear budding off bronchioles at generation ~17. These respiratory bronchioles participate in gas exchange over at least part of their surface. Respiratory bronchioles extend from generation ~17 to generation ~19, the density of alveoli gradually increasing with generation number (Fig. 26-5). Eventually, alveoli completely line the airways. These alveolar ducts (generations 20 to 22) finally terminate blindly as alveolar sacs (generation 23). The aggregation of all airways arising from a single terminal bronchiole (i.e., the respiratory bronchioles, alveolar ducts, and alveolar sacs), along with their associated blood and lymphatic vessels, is a terminal respiratory unit or primary lobule.

The cross-sectional area of the trachea is ~2.5 cm2. Unlike the situation in systemic arteries (see Chapter 19), wherein the aggregate cross-sectional area of the branches always exceeds the cross-sectional area of the parent vessel, the aggregate cross-sectional area falls from the trachea through the first four generations of airways (Fig. 26-6). Because all of the air that passes through the trachea also passes through the two mainstem bronchi and so on, the product of aggregate cross-sectional area and linear velocity is the same for each generation of conducting airways. Thus, the linear velocity of air in the first four generations is higher than that in the trachea, which may be important during coughing (see Chapter 32). In succeeding generations, the aggregate cross-sectional area rises, at first slowly and then very steeply. As a result, the linear velocity falls to very low values. For example, the terminal bronchioles (generation 16) have an aggregate cross-sectional area of ~180 cm2, so that the average linear velocity of the air is only (2.5 cm2)/(180 cm2) = 1.4% of the value in the trachea.

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Figure 26-6 Dependence of aggregate cross-sectional area and of linear velocity on generation number. At generation 3, the aggregate cross-sectional area has a minimum (not visible) where velocity has its maximum. (Data from Bouhuys A, The Physiology of Breathing. New York: Grune & Stratton, 1977.)

As air moves into the respiratory bronchioles and further into the terminal respiratory unit, where linear velocity is minuscule, convection becomes less and less important for the movement of gas molecules, and diffusion dominates. Notice that the long-distance movement of gases from the nose and lips to the end of the generation-16 airways occurs by convection. However, the short-distance movement of gases from generation-17 airways to the farthest reaches of the alveolar ducts occurs by diffusion, as does the movement of gases across the gas-exchange barrier (~0.6 μm).

The alveolus is the fundamental unit of gas exchange. Alveoli are hemispheric structures with diameters that range from 75 to 300 μm. The ~300 million alveoli have a combined surface area of 50 to 100 m2and an aggregate maximal volume of 5 to 6 L in the two lungs. Both the diameter and the surface area depend on the degree of lung inflation. The lungs have a relatively modest total volume (i.e., ~5.5 L), very little of which is invested in conducting airways (i.e., ~0.15 L). However, the alveolar area is tremendously amplified. For example, a sphere with a volume of 5.5 L would have a surface area of only 0.16 m2, which is far less than 1% of the alveolar surface area.

The alveolar lining consists of two types of epithelial cells, type I and type II alveolar pneumocytes. The cuboidal type II cells exist in clusters and are responsible for elaborating pulmonary surfactant, which substantially eases the expansion of the lungs (see Chapter 27). The type I cells are much thinner than the type II cells. Thus, even though the two cell types are present in about equal numbers, the type I cells cover 90% to 95% of the alveolar surface and represent the shortest route for gas diffusion. After an injury, type I cells slough and degenerate, whereas type II cells proliferate and line the alveolar space, re-establishing a continuous epithelial layer. Thus, the type II cells appear to serve as repair cells.

The pulmonary capillaries are usually sandwiched between two alveolar air spaces. In fact, the blood forms an almost uninterrupted sheet that flows like a twisted ribbon between abutting alveoli. At the type I cells, the alveolar wall (i.e., pneumocyte plus endothelial cell) is typically 0.15 to 0.30 μm thick. Small holes (pores of Kohn) perforate the septum separating two abutting alveoli. The function of these pores, which are surrounded by capillaries, is unknown. (See Note: Pores of Kohn)

The lung receives two blood supplies: the pulmonary arteries and the bronchial arteries (Fig. 26-7). The pulmonary arteries, by far the major blood supply to the lung, carry the relatively deoxygenated mixed-venous blood. After arising from the right ventricle, they bifurcate as they follow the bronchial tree, and their divisions ultimately form a dense, richly anastomosing, hexagonal array of capillary segments that supply the alveoli of the terminal respiratory unit. The pulmonary capillaries have an average internal diameter of ~8 μm, and each segment of the capillary network is ~10 μm in length. The average erythrocyte spends ~0.75 second in the pulmonary capillaries as it traverses up to three alveoli. After gas exchange in the alveoli, the blood eventually collects in the pulmonary veins.

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Figure 26-7 The blood supply to the airways.

The bronchial arteries are branches of the aorta and thus carry freshly oxygenated blood. They supply the conducting airways. At the level of the respiratory bronchioles, capillaries derived from bronchial arteries anastomose with those derived from pulmonary arteries. Because capillaries of the bronchial circulation drain partially into pulmonary veins, there is some venous admixture of the partially deoxygenated blood from the bronchial circulation and the newly oxygenated blood (see Chapter 31). This mixing represents part of a small physiological shunt. A small amount of the bronchial blood drains into the azygos and accessory hemiazygos veins.

The lungs play important nonrespiratory roles, including filtering the blood, serving as a reservoir for the left ventricle, and performing several biochemical conversions

Although their main function is to exchange O2 and CO2 between the atmosphere and the blood, the lungs also play important roles that are not directly related to external respiration.

Olfaction Ventilation is essential for delivery of odorants to the olfactory epithelium (see Chapter 15). Sniffing behavior, especially important for some animals, allows one to sample the chemicals in the air without the risk of bringing potentially noxious agents deep into the lungs.

Processing of Inhaled Air Before It Reaches the Alveoli Strictly speaking, the warming, moisturizing, and filtering of inhaled air in the conducting airways is a respiratory function. It is part of the cost of doing the business of ventilation. Warming of cool, inhaled air is important so that gas exchange in the alveoli takes place at body temperature. If the alveoli and the associated blood were substantially cooler than body temperature, the solubility of these alveolar gases in the cool pulmonary capillary blood would be relatively high. As the blood later warmed, the solubility of these gases would decrease, resulting in air bubbles (i.e., emboli) that could lodge in small systemic vessels and cause infarction. Moisturizing is important to prevent the alveoli from becoming desiccated. Finally, filtering of large particles is important to prevent small airways from being clogged with debris that may also be toxic.

Warming, moisturizing, and filtering are all more efficient with nose breathing rather than with mouth breathing. The nose, including the nasal turbinates, has a huge surface area and a rich blood supply. Nasal hairs tend to filter out large particles (greater than ~15 μm in diameter). The turbulence set up by these hairs—as well as the highly irregular surface topography of the nasal passages—increases the likelihood that particles larger than ~10 μm in diameter will impact and embed themselves in the mucus that coats the nasal mucosa. Moreover, air inspired through the nose makes a right-angle turn as it heads toward the trachea. The inertia of larger particles causes them to strike the posterior wall of the nasopharynx, which coincidentally is endowed with large amounts of lymphatic tissue that can mount an immunological attack on inspired microbes. Of the larger particles that manage to escape filtration in the upper airways, almost all will impact on the mucus of the trachea and the bronchi.

Smaller particles (2 to 10 μm in diameter) also may impact a mucus layer. In addition, gravity may cause them to sediment from the slowly moving air in small airways and to become embedded in mucus. Particles with diameters below ~0.5 μm tend to reach the alveoli suspended in the air as aerosols. The airways do not trap most (~80%) of these aerosols but expel them in the exhaled air.

The lung has a variety of strategies for dealing with particles that remain on the surface of the alveoli or penetrate into the interstitial space. Alveolar macrophages (on the surface) or interstitial macrophages may phagocytose these particles, enzymes may degrade them, or lymphatics may carry them away. In addition, particles suspended in the fluid covering the alveolar surface may flow with this fluid up to terminal bronchioles, where they meet a layer of mucus that the cilia propel up to progressively larger airways. There, they join larger particles—which entered the mucus by impaction or sedimentation—on their journey to the oropharynx. Coughing and sneezing (see Chapter 32for the box on sighs, yawns, coughs, and sneezes), reflexes triggered by airway irritation, accelerate the movement of particulates up the conducting airways.

Left Ventricular Reservoir The highly compliant pulmonary vessels of the prototypic 70-kg human contain ~500 mL of blood (see Table 19-2), which is an important buffer for filling of the left ventricle. For example, if one clamps the pulmonary artery of an experimental animal so that no blood may enter the lungs, the left side of the heart can suck enough blood from the pulmonary circulation to sustain cardiac output for about two beats.

Filtering Small Emboli from the Blood The mixed-venous blood contains microscopic emboli, small particles (e.g., blood clots, fat, air bubbles) capable of occluding blood vessels. If these emboli were to reach the systemic circulation and lodge in small vessels that feed tissues with no collateral circulation, the consequences—over time—could be catastrophic. Fortunately, the pulmonary vasculature can trap these emboli before they have a chance to reach the left side of the heart. If the emboli are sufficiently few and small, the affected alveoli can recover their function. Keep in mind that alveolar cells do not need the circulation to provide them with O2 or to remove their CO2. In addition, after a small pulmonary embolism, alveolar cells may obtain nutrients from anastomoses with the bronchial circulation. However, if pulmonary emboli are sufficiently large or frequent, they can cause serious symptoms or even death. A liability of the blood filtration function is that emboli made up of cancer cells may find the perfect breeding ground for support of metastatic disease.

Biochemical Reactions The entire cardiac output passes through the lungs, exposing the blood to the tremendous surface area of the pulmonary capillary endothelium. It is apparently these cells that are responsible for executing biochemical reactions that selectively remove many agents from the circulation while leaving others unaffected (Table 26-3). Thus, the lung can be instrumental in determining which signaling molecules in the mixed-venous blood reach the systemic arterial blood. The pulmonary endothelium also plays an important role in converting angiotensin I (a decapeptide) to angiotensin II (an octapeptide), a reaction that is catalyzed by angiotensin-converting enzyme (see Chapter 40).

Table 26-3 Handling of Agents by the Pulmonary Circulation

Unaffected

Largely Removed

PGA1, PGA2, PGI2

PGE1, PGE2, PGF, leukotrienes

Histamine, epinephrine, dopamine

Serotonin, bradykinin

Angiotensin II, arginine vasopressin, gastrin, oxytocin

Angiotensin I (converted to angiotensin II)

Data from Levitzky MG: Pulmonary Physiology, 4th ed. New York: McGraw-Hill, 1999.

LUNG VOLUMES AND CAPACITIES

The spirometer measures changes in lung volume

The maximal volume of all the airways in an adult—the nasopharynx, the trachea, and all airways down to the alveolar sacs—is typically 5 to 6 L. Respiratory physiologists have defined a series of lung “volumes” and “capacities” that, although not corresponding to a particular anatomical locus, are easy to measure with simple laboratory instruments and that convey useful information for clinical assessment.

spirometer measures the volume of air inspired and expired and therefore the change in lung volume. Spirometers today are complex computers, many so small that they can easily be held in the palm of one hand. The subject blows against a predetermined resistance, and the device performs all the calculations and interpretations. Nevertheless, the principles of spirometric analysis are very much the same as those for the “old-fashioned” spirometer shown in Figure 26-8A, which is far easier to conceptualize. This simple spirometer has a movable, inverted bell that is partially submerged in water. An air tube extends from the subject’s mouth, through the water, and emerges in the bell, just above water level. Thus, when the subject exhales, air enters the bell and lifts it. The change in bell elevation, which we can record on moving paper, is proportional to the volume of air that the subject exhales. Because air in the lungs is saturated with water vapor at 37°C (body temperature and pressure, saturated with water vapor or BTPS), and the air in the spirometer is ambient temperature and pressure, saturated with water vapor or ATPS, we must apply a temperature correction to the spirometer reading (see the box on page 617).

The amount of air entering and leaving the lungs with each breath is the tidal volume (VT). During quiet respirations, the VT is ~500 mL. The initial portion of the spirograph of Figure 26-8B illustrates changes in lung volume during quiet breathing. The product of tidal volume and the frequency of breaths is total ventilation, given in liters (BTPS) per minute.

Because, with a typical Western diet, metabolism consumes more O2 (~250 mL/min) than it produces CO2 (~200 mL/min; see Chapter 28), the volume of air entering the body with each breath is slightly greater (~1%) than the volume leaving. In reporting changes in lung volume, respiratory physiologists have chosen to measure the volume leaving—the expired lung volume (VE).

At the end of a quiet inspiration, the additional volume of air that the subject could inhale with a maximal effort is known as the inspiratory reserve volume (IRV). The magnitude of IRV depends on several factors, including the following:

1. Current lung volume. The greater the lung volume after inspiration, the smaller the IRV.

2. Lung compliance. A decrease in compliance, a measure of how easy it is to inflate the lungs, will cause IRV to fall as well.

3. Muscle strength. If the respiratory muscles are weak, or if their innervation is compromised, IRV will decrease.

4. Comfort. Pain associated with injury or disease limits the desire or ability to make a maximal inspiratory effort.

5. Flexibility of skeleton. Joint stiffness, caused by diseases such as arthritis and kyphoscoliosis (i.e., curvature of the spine), reduces the maximal volume to which one can inflate the lungs.

6. Posture. IRV falls when a subject is in a recumbent position because it is more difficult for the diaphragm to move the abdominal contents.

After a quiet expiration, the additional volume of air that one can expire with a maximal effort is the expiratory reserve volume (ERV). The magnitude of the ERV depends on the same factors listed before and on the strength of abdominal and other muscles needed to produce a maximal expiratory effort.

Even after a maximal expiratory effort, a considerable amount of air remains inside the lungs—the residual volume (RV). Because a spirometer can measure only the air entering or leaving the lungs, it obviously is of no use in ascertaining the RV. However, we will see that other methods are available to measure RV. Is it a design flaw for the lungs to contain air that they cannot exhale? Would it not be better for the lungs to exhale all their air and to collapse completely during a maximal expiration? Total collapse would be detrimental for at least two reasons. (1) After an airway collapses, an unusually high pressure is required to re-inflate it. By minimizing airway collapse, the presence of an RV optimizes energy expenditure. (2) Blood flow to the lungs and other parts of the body is continuous, even though ventilation is episodic. Thus, even after a maximal expiratory effort, the RV allows a continuous exchange of gases between mixed-venous blood and alveolar air. If the RV were extremely low, the composition of blood leaving the lungs would oscillate widely between a high PO2 at the peak of inspiration and a low PO2 at the nadir of expiration.

The four primary volumes that we have defined—VT, IRV, ERV, and RV—do not overlap (Fig. 26-8B). The lung capacities are various combinations of these four primary volumes:

Total lung capacity (TLC) is the sum of all four volumes.

Functional residual capacity (FRC) is the sum of ERV and RV and is the amount of air remaining inside the respiratory system after a quiet expiration. Because FRC includes RV, we cannot measure it using only a spirometer.

Inspiratory capacity (IC) is the sum of IRV and TV. After a quiet expiration, the IC is the maximal amount of air that one could still inspire.

Vital capacity (VC) is the sum of IRV, TV, and ERV. In other words, VC is the maximal achievable tidal volume and depends on the same factors discussed earlier for IRV and ERV. In patients with pulmonary disease, the physician may periodically monitor VC to follow the progress of the disease.

At the end of the spirographic record in Figure 26-8B, the subject made a maximal inspiratory effort and then exhaled as rapidly and completely as possible. The volume of air exhaled in 1 second under these conditions is the forced expiratory volume in 1 second (FEV1). In healthy young adults, FEV1 is ~80% of VC. FEV1 depends on all the factors that affect VC as well as on airway resistance. Thus, FEV1 is a valuable measurement for monitoring a variety of pulmonary disorders and the effectiveness of treatment.

The volume of distribution of helium or nitrogen in the lung is an estimate of the residual volume

Although we cannot use a spirometer to measure residual volume or any capacity containing RV (i.e., FRC or TLC), we can use two general approaches to measure RV, both based on the law of conservation of mass. In the first approach, we compute RV from the volume of distribution of either helium (He) or nitrogen (N2). However, any nontoxic gas would do, as long as it does not rapidly cross the blood-gas barrier. In the second approach, discussed in the next section, we compute RV by use of Boyle’s law.

The principle underlying the volume of distribution approach is that the concentration of a substance is the ratio of mass (moles) to volume (liters). If the mass is constant, and if we can measure the mass and concentration, then we can calculate the volume of the physiological compartment in which the mass is distributed. In our case, we ask the subject to breathe a gas that cannot escape from the airways. From the experimentally determined mass and concentration of that gas, we calculate lung volume.

Helium-Dilution Technique We begin with a spirometer containing air with 10% He—this is the initial helium concentration, [He]initial = 10% (Fig. 26-9A). We use He because it is poorly soluble in water and therefore diffuses slowly across the alveolar wall (see Chapter 30). In this example, the initial spirometer volume, VS(initial), including all air up to the valve at the subject’s mouth, is 2 L. The amount of He in the spirometer system at the outset of our experiment is thus [He]initial × VS(initial), or (10%) × (2 L) = 0.2 L.

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Figure 26-9 Volume of distribution and plethysmographic methods for measurement of lung volume. In C, the spirometer is usually replaced in modern plethysmographs by an electronic pressure gauge. In such instruments, the change in lung volume is computed from the change in pressure inside the plethysmograph (see Fig. 27-10).

We now open the valve at the mouth and allow the subject to breathe spirometer air until the He distributes evenly throughout the spirometer and airways. After equilibration, the final He concentration ([He]final) is the same in the airways as it is in the spirometer. The volume of the “system”—the spirometer volume (VS) plus lung volume (VL)—is fixed from the instant that we open the valve between the spirometer and the mouth. When the subject inhales, VL increases and VS decreases by equal amounts. When the subject exhales, VL decreases and VS increases, but (VL + VS) remains unchanged. Because the system does not lose He, the total He content after equilibration must be the same as it was at the outset. In our example, we assume that [He]final is 5%.

If the spirometer and lung volumes at the end of the experiment are the same as those at the beginning, (See Note: Helium Dilution Technique)

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Solving for lung volume,

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If we now insert the values from our experiment:

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VL corresponds to the lung volume at the instant we open the valve and allow He to begin equilibrating. If we wish to measure FRC, we open the valve just after the completion of a quiet expiration. If we open the valve after a maximal expiration, then the computed VL is RV. Because the subject rebreathes the air mixture in the spirometer until [He] stabilizes, the He-dilution approach is a closed-circuit method.

Nitrogen-Washout Method Imagine that you have a paper cup that contains a red soft drink. You plan to “empty” the cup but wish to know the “residual volume” of soft drink that will remain stuck to the inside of the cup (Vcup) after it is emptied. First, before emptying the cup, you determine the concentration of red dye in the soft drink; this is [red dye]cup. Now empty the cup. Although you do not yet know Vcup, the product [red dye]cup × Vcup is the mass of residual red dye that remains in the cup. Next, add hot water to the cup, swish it around inside the glass, and dump the now reddish water into a graduated cylinder. After repeating this exercise several times, you see that virtually all the red dye is now in the graduated cylinder. Finally, determine the volume of fluid in the cylinder (Vcylinder) and measure its red dye concentration. Because [red dye]cup × Vcup is the same as [red dye]cylinder × Vcylinder, you can easily calculate the residual volume of the soft drink that had been in the glass. This is the principle behind the nitrogen-washout method.

Assume that the initial lung volume is VL and that the initial concentration of nitrogen gas in the lungs is [N2]initial. Thus, the mass of N2 in the lungs at the outset is [N2]initial × VL. We now ask the subject to breathe through a mouthpiece equipped with a special valve (Fig. 26-9B). During inspiration, the air comes from a reservoir of 100% O2; the key point is that this inspired air contains no N2. During expiration, the exhaled air goes to a sack with an initial volume of zero. Each inspiration of 100% O2 dilutes the N2 in the lungs. Each expiration sends a fraction of the remaining N2 into the sack. Thus, the [N2] in the lungs falls stepwise with each breath until eventually the subject has washed out into the sack virtually all the N2 that had initially been in the lungs. Also entering the sack are some of the inspired O2 and all expired CO2. The standard period for washing out of the N2 with normal breathing is 7 minutes, after which the sack has a volume of Vsack and an N2 concentration of [N2]sack. Because the mass of N2 now in the sack is the same as that previously in the lungs:

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Thus, the lung volume is

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To illustrate, consider an instance in which [N2]initial is 75%. If the volume of gas washed into the sack is 40 L, roughly a total ventilation of 6 L/min for 7 minutes, and [N2]sack is 3.75%, then:

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What particular lung volume or capacity does VL represent? The computed VL is the lung volume at the instant the subject begins to inhale the 100% O2. Therefore, if the subject had just finished a quiet expiration before beginning to inhale the O2, VL would be FRC; if the subject had just finished a maximal expiratory effort, VL would represent RV.

The key element in the nitrogen-washout method is the requirement that during the period of O2 breathing, all N2 previously in the lungs—and no more—ends up in the sack. In other words, we assume that N2does not significantly diffuse between blood and alveolar air during our 7-minute experiment. Because N2 has a low water solubility, and therefore the amount dissolved in body fluids is very low at normal barometric pressure, the rate of N2diffusion across the alveolar wall is very low (see Chapter 30). Therefore, our assumption is very nearly correct. In principle, we could preload the lung with any nontoxic, water-insoluble gas (e.g., He) and then wash it out with any different gas (e.g., room air). Because the subject inhales from one reservoir and exhales into another in the nitrogen-washout method, it is an open-system technique.

The plethysmograph, together with Boyle’s law, is a tool for estimation of residual volume

We also can compute VL from small changes in lung pressure and volume that occur as a subject attempts to inspire through an obstructed airway. This approach is based on Boyle’s law, which states that if the temperature and number of gas molecules are constant, the product of pressure and volume is a constant:

image

To take advantage of this relationship, we have the subject step inside an airtight box called a plethysmograph (from the Greek plethein [to be full]), which is similar to a telephone booth. The subject breathes through a tube that is connected to the outside world (Fig. 26-9C). Attached to this tube is a gauge that registers pressure at the mouth and an electronically controlled shutter that can, on command, completely obstruct the tube. The Mead-type plethysmograph in Figure 26-9C has an attached spirometer. As the subject inhales, lung volume and the volume of the subject’s body increase by the same amount, displacing an equal volume of air from the plethysmograph into the spirometer, which registers the increase in lung volume (ΔVL).

As the experiment starts, the shutter is open, and the subject quietly exhales, so that VL is FRC. Because no air is flowing at the end of the expiration, the mouth and alveoli are both at barometric pressure, which is registered by the pressure gauge (P). We now close the shutter, and the subject makes a small inspiratory effort, typically only ~50 mL, against the closed inlet tube. The subject’s inspiratory effort will cause lung volume to increase to a new value, VL+ ΔVL (see graph in Fig. 26-9C). However, the number of gas molecules in the airways is unchanged, so this increase in volume must be accompanied by a decrease in airway pressure (ΔP) to a new value, P − ΔP. Because no air is flowing at the peak of this inspiratory effort, the pressure measured by the gauge at the mouth is once again the same as the alveolar pressure. According to Boyle’s law:

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Rearranging Equation 26-9 yields the initial lung volume:

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As an example, assume that ΔVL at the peak of the inspiratory effort is 50 mL and that the corresponding pressure decrease in the airways is 12 mm Hg. If the initial pressure (P) was 760 mm Hg,

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What lung volume or capacity does 3.1 L represent? Because, in our example, the inspiratory effort against the closed shutter began after a quiet expiratory effort, the computed VL is FRC. If it had begun after a maximal expiration, the measured VL would be RV.

REFERENCES

Books and Reviews

Macklem PT: Symbols and abbreviations. In Handbook of Physiology, Section 3: The Respiratory System, vol I. Bethesda, MD: American Physiological Society, 1985: ix.

Mortola JP, Frappell PB: On the barometric method for measurements of ventilation, and its use in small animals. Can J Physiol Pharmacol 1998; 76:937-944.

Satir P, Sleigh MA: The physiology of cilia and mucociliary interactions. Annu Rev Physiol 1990; 52:137-155.

Journal Articles

Fowler WS: Lung function studies. II. The respiratory dead space. Am J Physiol 1948; 154:405-416.