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40156 Boron BATCH SAUNM RIGHT top of RH base of RH CHAPTER 25 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 life as being synonymous with breathing. 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 distinguished investigators studied the chemistry of gases. At the time, chemists recognized similarities between combustion and breathing, but thought that both involved the production of a “fire-essence” principle called “phlogiston.” According to their theory, neither combustion nor life could be supported once air became saturated with phlogiston. In the 1750s, the Scottish scientist 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. It showed that a chemical reaction can involve a gas, and it further demonstrated that other gases exist besides ordinary “air.” Shortly thereafter, Cavendish, working in England, showed that fermentation and putrefaction produce “fixed air.” His countryman Priestley discovered several new gases between the late 1760s and mid-1770s, including “dephlogistonated air,” co-discovered by the Swedish chemist Scheele. Priestley found that combustion, putrefaction, and breathing all consume “dephlogistonated air,” and all reduce the volume of room air by approximately 20%. Conversely, he found that green plants produce “dephlogistonated air,” which he could quantitate by reacting it with nitric oxide (a colorless gas) to produce nitrogen dioxide (a red gas). In the mid-1770s, Priestley toured the Continent and presented his findings to the Frenchman Lavoisier, who is 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 “non-vital” air, or nitrogen. Furthermore, he proposed that O2 is consumed 3 short standard long 40156 4 Boron SAUNM BATCH 25 / Organization of the Respiratory System because it reacts with one substance to produce another substance. Spallanzani, working in Italy during the late 1790s, confirmed Lavoisier’s prediction that O2 consumption and CO2 production occur not in the lungs, but in isolated tissues. Therefore, by the end of the 18th century, chemists/ 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 dealing with the physiology of O2 and CO2. Thus, respiration was a unifying theme in the early histories of physiology, chemistry, and biochemistry. It is recognized 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, which is summarized in Chapter 57. 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) A LEFT UNICELLULAR ORGANISM, NO CONVECTION Net movement in direction from high concentration to low concentration. Net flow transporting CO2 from the mitochondria to the atmosphere. CO2 transport as it is intimately related to acidbase homeostasis is discussed. top of RH base of RH top of text base of text DIFFUSION IS THE MAJOR MECHANISM OF EXTERNAL RESPIRATION FOR SMALL AQUATIC ORGANISMS The most important and the most fundamental mechanism of O2 and CO2 transport is diffusion (see Chapter 3). The 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. 25 – 1A, inset). No expenditure of energy is involved. The driving force for diffusion is the concentration gradient. Imagine a unicellular organism, suspended in a beaker of water at 37oC. We will equilibrate the water with an atmosphere that has the usual composition of O2 and CO2 (Table 25 – 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 C MULTICELLULAR ORGANISM, WITH CONVECTION INSIDE O2 Gas-exchange barrier Extracellular fluid O2 …and larger O2 O2 CO2 Flow across barrier is proportional to ∆P. CO2 CO2 D CO2 Bulk fluid B Extracellular unstirred layer Intracellular unstirred layer UNICELLULAR ORGANISM, WITH CONVECTION OUTSIDE MULTICELLULAR ORGANISM WITH 4-CHAMBERED HEART Air pump delivers inspired air by convection. Circulatory system moves gases by convection. O2 Arterial O2 Mixed-venous As ∆P increases, the flow of gas becomes larger… O2 and CO2 cross alveolar wall by diffusion. O2 Mixed-venous Arterial CO2 CO2 O2 and CO2 cross ECF and cytoplasm by diffusion. CO2 Inspired air (“outside” organism) Alveoli Pulmonary Arteries capillary and veins Alveolar wall Interstitial space Systemic capillary FIGURE 25– 1. Diffusion of O2 and CO2 for a single-celled organism. In A through 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 lines in the pulmonary capillary and systemic interstitial space represent 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. short standard long 40156 Boron BATCH SAUNM RIGHT Organization of the Respiratory System / 25 5 TABLE 25– 1 top of RH base of RH top of text base of text COMPOSITION OF AIR WET AIR Trachea DRY AIR Atmosphere Fraction In Air (%) Gas Partial Pressure At Sea Level (mm Hg) Fraction In Air (%) Partial Pressure At Sea Level (mm Hg) Nitrogen 78.09 593.48 73.26 556.78 Oxygen 20.95 159.22 19.65 149.37 Carbon dioxide 0.03 0.23 0.03 0.21 Argon 0.93 7.07 0.87 6.63 Water 0 0 6.18 47 760 100.00 760 Total 100.00 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 Henry’s Law). Thus, the Po2 in the wet air — as well as the water beneath it — will be approximately 149 mm Hg (or torr), and the Pco2 will be an almost negligible 0.2 mm Hg. These numbers describe the composition of the water in the bulk phase, 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. These differences in partial pressure cause O2 to diffuse from the bulk fluid toward the mitochondria, and the CO2 to diffuse in the opposite direction. The diffusion of O2 follows a gradient of decreasing Po2 (see Fig. 25 – 1A). The region over which Po2 falls gradually from the bulk fluid toward the organism’s outer surface 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 “WET GASES”: PARTIAL PRESSURES OF O2 AND CO2 IN SOLUTIONS THAT ARE EQUILIBRATED WITH WET AIR Imagine that a beaker of water is equilibrated with a normal atmosphere, both at a temperature of 37oC. For dry air (i.e., air containing no water vapor), O2 makes up ⬃21% of the total gas by volume (see Table 25–1). Thus, if the barometric pressure (PB) is 760 mm Hg, the partial pressure of O2 (PO2) is 21% of 760 mm Hg, or 159 mm Hg (Fig. 25– 2A). However, if the air-water interface is reasonably stationary, then water vapor will saturate the air immediately adjacent to the liquid. What is the PO2 in this wet air? At 37oC, the partial pressure of water (PH2O) is 47 mm Hg. Thus, 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. The partial pressure of O2 in this wet air is therefore: The CO2 composition of dry air is ⬃0.03% (see Table 25–1). Thus, the partial pressure of CO2 in wet air is: PCO2 ⫽ FCO2 ⫻ (PB ⫺ PH2O) ⫽ (0.03%) ⫻ (760 mm Hg ⫺ 47 mm Hg) ⫽ 0.21 mm Hg Box Equation 25–2 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 25–1. Fraction of dry air that is O2 p PO2 ⫽ FO2 ⫻ (PB ⫺ PH2O) ⫽ (21%) ⫻ (760 mm Hg ⫺ 47 mm Hg) ⫽ 149 mm Hg Box Equation 25–1 short standard long 40156 6 A Boron SAUNM BATCH LEFT top of RH base of RH top of text base of text 25 / Organization of the Respiratory System B PARTIAL PRESSURE OF O2 IN WET AIR HENRY'S LAW Atmospheric pressure 760 mm Hg PO 2 100 mm Hg P O2 159 mm Hg (21% of 760 mm Hg) Dry air (bulk phase) PO 2 149 mm Hg P H2 O (21% of 47 mm Hg 713 mm Hg) Wet air (unstirred layer above water) [O2]Dis 0.13 mMol [O2]Dis 0.05 mMol Solution #1 Solution #2 37° C PO 2 40 mm Hg 37° DIFFUSION OF DISSOLVED GAS 37° 37° [O2]Dis 0.13 mMol [O2]Dis 0.05 mMol Solution #1 Solution #2 Semipermeable membrane FIGURE 25– 2. Partial pressures. intracellular unstirred layer, from the organism’s inner surface to the mitochondria. The final remarkable feature of the Po2 profile is the abrupt fall in Po2 at the organism’s surface. The profile for Pco2 is similar, but has 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 3), the 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, the flow is also proportional to the partial-pressure difference (⌬P): Flow ⬀ ⌬P Equation 25 – 1 Simple diffusion (see Chapter 26) is the mechanism by which O2 and CO2 move short distances in the respiratory system: between the air and the blood in the alveoli, and between the mitochondria and the blood of the peripheral circulation. CONVECTION ENHANCES DIFFUSION BY PRODUCING STEEPER GRADIENTS ACROSS THE DIFFUSION BARRIER A purely diffusive system can establish only a relatively small ⌬P across the gas exchange barrier of the organism (see Fig. 25 – 1A). Yet, for small organisms, even this relatively small ⌬P is adequate to meet the demands for O2 uptake and CO2 removal. However, when the organism’s diameter exceeds approximately 1 mm, simple diffusion becomes inadequate for gas exchange. One way of ameliorating this problem is to introduce a mechanism for local convection on the outside surface of the organism. For a paramecium, the beating cilia bring bulk-phase water — having a Po2 of approximately 154 mm Hg at 25⬚C and a Pco2 of approximately 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 (see Fig. 25 – 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 is considerably lower, approximately 400:1. In mammals, the bulk phase is the atmosphere and the external convective system is an air pump consisting of the lungs, the airways, and the respiratory muscles. Ventilation is the process of moving air into and out of the short standard long 40156 Boron BATCH SAUNM RIGHT Organization of the Respiratory System / 25 7 top of RH base of RH top of text base of text PARTIAL PRESSURES AND HENRY’S LAW Respiratory physiologists generally express the concentration of a gas, whether mixed with another gas (e.g., O2 and 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. The ratio of the partial pressure of Z (PZ) to the total pressure (PTotal) is its mole fraction (XZ): PZ ⫽ XZ · PTotal ⫽ 0.13 mMol Box Equation 25–5 Now imagine that we have a second beaker equilibrated with an atmosphere having a PO2 of 40 mm Hg, the partial pressure of O2 in mixed-venous blood (see Fig. 25–3B, solution #2). For this solution, [O2]Dis ⫽ 0.0013 mMol/mm Hg ⫻ 40 mm Hg ⫽ 0.05 mMol ⫽ 0.05 mM Box Equation 25–3 Thus, if PZ were twice as high in one sample of gas than in another, XZ (i.e., concentration of Z) would also be twice as high. It may not be immediately obvious why partial pressures are also useful for expressing concentrations when dealing with situations in which Z is dissolved in aqueous solutions. According to Henry’s Law, the concentration of O2 dissolved in water ([O2]Dis) is proportional to the PO2 in the gas phase: [O2]Dis ⫽ s ⫻ PO2 [O2]Dis ⫽ 0.0013 mMol/mm Hg ⫻ 100 mm Hg Box Equation 25–4 The proportionality constant s is known as the solubility; for O2, this value is ⬃0.0013 mMol/mm Hg at 37ⴗC for a solution mimicking arterial blood plasma. The solubility of CO2 is ???-fold higher. Consider a beaker of water at 37oC equilibrated with an atmosphere having a PO2 of 100 mm Hg, the partial pressure in mammalian arterial blood plasma (see Fig. 25– 3B, solution #1). Thus, Box Equation 25–6 If we were to place samples of each of these two solutions on opposite sides of a semipermeable barrier in a closed container (see Fig. 25–3C), the O2 gradient across this barrier expressed in terms of concentrations (⌬[O2]) would be 0.13 ⫺ 0.05 or 0.08 mMol. Expressed in terms of partial pressures (⌬PO2), this same gradient would be 100 ⫺ 40 ⫽ 60 mm Hg. Imagine now that we take a 5-ml sample of each of the solutions in the beakers in Figure 25–3B, 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 “mm Hg.” These are the partial pressures of inspired O2 with which the solutions were or would have to be equilibrated to achieve the [O2]Dis in the samples. CONVENTIONS FOR MEASURING VOLUMES OF GASES Gases within the lung are saturated with water vapor at 37ⴗC (310 ⴗK). At this temperature, the partial pressure of water is 47 mm Hg. The total pressure of the air in the lungs is equal to barometric pressure, which we will assume to be 760 mm Hg. We can be certain that alveolar pressure equals barometric pressure if the glottis is open and no air is flowing. Thus, the partial pressure of the dry gases in the lungs is (760 ⫺ 47) ⫽ 713 mm Hg. Whereas the air in the lungs is at “Body Temperature and Pressure, Saturated with Water” (BTPS), this same air, when expelled from the lungs into the spirometer, is at “Ambient Temperature and Pressure, Saturated” (ATPS). Thus, we must correct the volume change (⌬VATPS) registered by the spirometer (at ATPS) to have an accurate measure of the volume (⌬VBTPS) that this same gas had previously occupied in the lungs (at BTPS). According to the ideal gas law: PBTPS · ⌬VBTPS PATPS · ⌬VATPS ⫽ TBTPS TATPS Box Equation 25–7 or ⌬VBTPS ⫽ PATPS TBTPS · · ⌬VATPS PBTPS TATPS Box Equation 25–8 We will assume that the ambient temperature is 25ⴗC (or 298ⴗK). The partial pressure of the dry gases at 25ⴗC is simply the total barometric pressure minus the vapor pressure of water at 25ⴗC, 24 mm Hg. Thus, substituting real numbers into Box Equation 25–8: ⌬VBTPS ⫽ (760 ⫺ 24) 310ⴗK · · ⌬VATPS ⫽ 1.074 · ⌬VATPS (760 ⫺ 47) 298ⴗK Box Equation 25–9 Thus, the same gas that occupies 1000 ml in the spirometer at ATPS, occupies 1074 ml in the body at BTPS. short standard long 40156 8 Boron SAUNM BATCH LEFT 25 / Organization of the Respiratory System 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 content of O2 of air (⬃210 ml O2/L of air at standard temperature and pressure/dry or STPD), 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 his/her 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 30). 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 approximately 4000 ml/min, an alveolar Po2 of approximately 100 mm Hg (versus 149 mm Hg in a wet atmosphere at 37⬚C) and an alveolar Pco2 of approximately 40 mm Hg (versus 0.2 mm Hg). 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 31), so that ventilation slows or even stops. From a theoretical perspective, 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 ⌬Po2 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 and arterial [CO2] rises to lethal levels. 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 the 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 practical. Perfusion is the process of delivering blood to the lungs. Figure 1C shows a very 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 ⌬Po2 across the gas-exchange barrier is rather large, but the ⌬Po2 between the bulk internal fluid and the mitochondria is rather small. Figure 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 insures 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-tomitochondria Po2 gradient 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 at the level of both the alveoli and the peripheral mitochondria. The scenario outlined in Figure 1D requires the fourchambered heart characteristic of mammals as well as 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 highPo2/low-Pco2 blood received from pulmonary veins to the periphery (i.e., mitochondria). Maintaining maximal gradients for O2 and CO2 diffusion at both the gas-exchange barrier and 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 circulation. The result is less-than-optimal Po2 and Pco2 gradients at both the gasexchange 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 maximal Po2 and Pco2 gradients in the pulmonary and peripheral capillaries, and thus cannot generate maximal fluxes of O2 and CO2. top of RH base of RH top of text base of text 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: Flow ⬀ ⌬P ⫻ Area Equation 25 – 2 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, molluscs (e.g., squid) and fish have gills, which they form by evaginating the gas-exchange barrier, and 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 short standard long 40156 Boron SAUNM BATCH RIGHT Organization of the Respiratory System / 25 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 that the surface-to-volume ratio of the lungs is greatly increased. 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 approximately three-fold faster than necessary when cardiac output is normal. Nevertheless, this redundancy is extremely important during exercise (when cardiac output can increase markedly), 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 looses a lung, the remaining surface area may not be large enough to sustain normal rates of gas exchange and normal blood levels of O2 and CO2. 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 O2 and 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” would be 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 approximately 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 approximately 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 greatly increase the carrying capacity of blood for O2 and CO2. In some arthropods and molluscs, the pigment is hemocyanin, a protein containing copper. Polychaete worms and brachiopods use hemerythrins. However, the most common respiratory pigments are the hemoglobins, which contain iron. All vertebrates as well as numerous unrelated groups of animals use hemoglobin (Hb), which is the chief component of red blood cells (erythrocytes). The presence of Hb markedly improves the dynamics of O2 uptake by blood passing through the lungs. The Hb 9 reversibly binds approximately 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 Hb content of blood is reduced, thus lowering the carrying capacity of blood for O2 and CO2. The most common cause of anemia in industrialized societies is a shortage in the diet of the iron necessary to synthesize Hb. An individual with anemia can compensate only if the systemic tissues extract more O2 from each liter of blood and/or if cardiac output increases. However, there are limits to the amount of O2 tissues can extract, or to the level to which the heart can increase its output. top of RH base of RH top of text base of text PATHOPHYSIOLOGY RECAPITULATES PHYLOGENY — IN REVERSE It should be clear from the pathophysiologic examples discussed that whenever one of the key components of the respiratory system fails in a higher organism, external respiration in that organism becomes more like that of an organism that is 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 that lacks a respiratory pigment in the extracellular fluid. ORGANIZATION OF THE RESPIRATORY SYSTEM IN HUMANS HUMANS OPTIMIZE EACH OF THE PROCESSES INVOLVED IN EXTERNAL RESPIRATIONVENTILATION, CIRCULATION, AREA AMPLIFICATION, GAS CARRIAGE, LOCAL CONTROL, AND CENTRAL CONTROL The human respiratory system (Fig. 25 – 3) 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: 1. An air pump: The external convective system in humans consists of the lungs and other airways, the thoracic cavity and its 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 the muscles of respiration increase the volume of the thoracic cavity, creating a partial vacuum in the alveolar air spaces, and causing the alveoli to expand passively. A quiet expiration occurs when these muscles relax, as discussed in Chapter 26 (“Mechanics of Respiration”). short standard long 40156 SAUNM BATCH LEFT 25 / Organization of the Respiratory System External convection 10 Boron 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. The anatomy of the alveoli is discussed later in this chapter, and pulmonary gas exchange is explored in Chapter 29 (“Gas Exchange in the Lungs”). A similar process of gas exchange occurs between the systemic capillaries and (p. [⬃/???]). Control centers in medulla Motor output to respiratory muscles O2 sensor CO2 Pulmonary diffusion Chest wall CO2 pH O2 Lung Hb • O2 Right heart Left heart H+ Internal convection Hb HC – 3 O Hb • CO Tissue diffusion 2 CO2 Hb • Hb O2 Cell CO2 O2 FIGURE 25– 3. The respiratory apparatus in humans. 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 (2,3-diphosphoglycerate, carbonic anhydrase; and Cl-HCO3 exchangers) that help to rapidly load and unload huge amounts of O2 and CO2. In the pulmonary capillaries, Hb binds O2, thereby enabling the blood to carry approximately 65-fold more O2 than ordinary saline. At the same time, Hb chemically reacts with approximately 20% of the CO2 produced by the mitochondria and carries this CO2 back to the lungs. Hemoglobin also plays a key role as it buffers 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 27 (“Acid-Base Physiology”) as well as for the carriage of O2 and CO2, treated in Chapter 28 (“The Transport of Oxygen and Carbon Dioxide in the Blood”). top of RH base of RH top of text base of text 4. A circulatory system: The internal convective system in humans consists of a four-chambered heart, and separate systemic and pulmonary circulations. The flow of blood to the lungs — perfusion — is discussed in Chapter 30 (“Ventilation, Perfusion and VentilationPerfusion Ratio”). 5. A mechanism for locally regulating the distribution of ventilation and perfusion: 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. Nevertheless, efficient gas exchange requires that, to the extent possible, the ratio of ventilation to perfusion be uniform for all alveoli. The lungs attempt to achieve a uniform distribution of ventilation/perfusion ratios by using sophisticated feedback-control mechanisms to regulate local air flow and blood flow, as discussed in Chapter 30. 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 system (CNS) rhythmically stimulate the muscles of inspiration. Moreover, these respiratory centers must 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. These subjects are the topic of Chapter 31 (“Control of Ventilation”). Respiratory physiologists have agreed on a set of symbols for describing parameters that are important for pulmonary physiology and pulmonary-function tests (Table 25 – 2). CONDUCTING AIRWAYS DELIVER FRESH AIR TO THE ALVEOLAR SPACES Lung development is discussed in Chapter 56. 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 latter 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 short standard long 40156 Boron BATCH SAUNM RIGHT Organization of the Respiratory System / 25 11 TABLE 25– 2 top of RH base of RH top of text base of text SYMBOL CONVENTIONS IN RESPIRATORY PHYSIOLOGY RESPIRATORY MECHANICS GAS EXCHANGE Main Symbols Main Symbols C Compliance C Concentration (or content) in a liquid f Respiratory frequency D Diffusion capacity P Pressure f Respiratory frequency R Resistance F Fraction V ⴢ V Volume of gas P ⴢ Q Pressure R Gas-exchange ratio S Saturation of hemoglobin V ⴢ V Volume of gas Flow Flow of blood (perfusion) Ventilation A Modifiers Alveolar a Modifiers Systemic arterial aw Airway A Alveolar B Barometric B Barometric c Pulmonary capillary E Expired I Inspired v Systemic venous (in any vascular bed) v Mixed systemic venous Macklem PT: Symbols and abbreviations. In The American Physiological Society Staff: Handbook of Physiology. Section 3: The Respiratory System. Vol 1. Bethesda, MD, American Physiological Society, 1985. fluid probably lubricates the pleural space, facilitating physiologic changes in the size and shape of the lung. 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 approximately 55% of total lung mass and function. We refer to the progressively bifurcating pulmonary airways by their generation number (Fig. 25 – 4): 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 does the left, and is more nearly parallel with the trachea, inhaled foreign bodies more commonly lodge in the right lung than in the left. There is a total of approximately 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 problematic during expiration (see Chapter 29). Airways maintain some cartilage to about the 10th generation, up to which point they are referred to as bronchi. At about the 11th and succeeding generations, the now cartilage-free airways are called bronchioles. Because these bronchioles lack cartilage, they 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 approximately 16, no alveoli are present, and the air cannot exchange with the pulmonary-capillary blood. These alveoli-free airways 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 total aggregate volume of conducting airways, from the lips/nose to the generation-16 airways, the anatomic dead space, amounts to approximately 150 ml in healthy young males and somewhat over 100 ml in females. The anatomic 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. short standard long 40156 SAUNM BATCH LEFT 25 / Organization of the Respiratory System Generation # Trachea Cartilage 0 Mainstem bronchi top of RH base of RH top of text base of text 1 2 Bronchi (cartilage) 10 Conducting airways (anatomic dead space) 11 12 13 14 Terminal bronchiole Bronchioles (no cartilage) 15 Terminal bronchiole 16 Respiratory bronchioles 12 Boron Alveolar air spaces Alveolus 17 Smooth muscle fibers 18 Pulmonary venule 19 20 Alveolar ducts 21 22 Alveolar sacs Alveolus Terminal respiratory unit Alveolar capillaries Pores of Kohn 23 Type-I pneumocyte Pulmonary arteriole Air in alveolus Alveolar acinus Air in alveolus Interstitial space Endothelial cell Red blood cells FIGURE 25– 4. Generations of airways. 600 200% Conducting airways Alveolar airways 400 Velocity Relative air 100% velocity (—) Crosssectional area 200 0% 0 2 4 6 8 10 12 14 Airway generation number 16 18 20 Aggregate cross-sectional area (cm2) (—) 0 FIGURE 25– 5. Dependence of aggregate cross-sectional area and of linear velocity on generation number. short standard long 40156 Boron SAUNM BATCH RIGHT Organization of the Respiratory System / 25 ALVEOLAR AIR SPACES ARE THE SITE OF GAS EXCHANGE Alveoli first appear budding off bronchioles at approximately generation 17. These respiratory bronchioles participate in gas exchange over at least part of their surface. Respiratory bronchioles extend from approximately generation 17 to generation 19, the density of alveoli gradually increasing with generation number (see Fig. 25 – 4). Eventually, alveoli completely line the airways. These alveolar ducts (generations 20 – 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 approximately 2.5 cm2. Unlike the situation in systemic arteries (see Chapter 18), wherein the aggregate cross-sectional area of the branches always exceeds the cross-sectional area of the parent vessel, an aggregate cross-sectional area falls from the trachea through the first four generations of airways (Fig. 25 – 5). Because all of the air that passes through the trachea also passes through each generation of conducting airways, the product of aggregate crosssectional area and linear velocity is a constant. 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 later). In succeeding generations, however, 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, at the level of the terminal bronchioles (generation 16), the aggregate cross-sectional area is approximately 180 cm2. Thus, the average linear velocity of the air at generation 16 is only (2.5 cm2)/ (180 cm2) ⫽ 1.4% of the value in the trachea. As air moves into the respiratory bronchioles and further into the terminal respiratory unit, where the linear velocity is minuscule, convection gradually becomes even less and less important for the movement of gas molecules, and diffusion dominates. Notice that the long-distance movement of gases from lips/nose to the end of the generation16 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. The movement of gases across the gas-exchange barrier (⬍0.5 m) also occurs by diffusion. Thus, the distances over which convection occurs are long, whereas the distances over which diffusion takes place are short. The alveolus is the fundamental unit of gas exchange. Alveoli are hemispheric structures with diameters that range from 75 to 300 m. The approximately 300 million alveoli have a combined surface area of 50 to 100 m2 and 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. 13 The alveolar lining consists of two distinct types of epithelial cells, called 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 29). The type-I cells are much thinner than the type-II cells. Thus, even though the two cell types are present in approximately 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 flowing blood almost forms an 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 – 0.30 m 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. The lung receives two blood supplies: (1) the pulmonary arteries and (2) the bronchial arteries (Fig. 25 – 6). 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 approximately 8 m, and each segment of the capillary network is approximately 10 m in length. The average erythrocyte spends approximately 0.75 sec 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. 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 primarily into pulmonary veins, there is some venous admixture of the partially deoxygenated blood from the bronchial circulation and the newly oxygenated blood. This mixing represents part of a small physiologic shunt. A small amount of the bronchial blood drains into the azygos and accessory hemiazygos veins. top of RH base of RH top of text base of text THE LUNGS PLAY IMPORTANT NONRESPIRATORY ROLES, INCLUDING FILTERING THE BLOOD, SERVING AS A RESERVOIR FOR THE LEFT VENTRICLE, AND PERFORMING SEVERAL BIOCHEMICAL CONVERSIONS Although the main function of the lungs 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. short standard long 40156 14 Boron SAUNM BATCH LEFT 25 / Organization of the Respiratory System Deoxygenated blood from right heart goes to alveoli… Pulmonary artery …whereas oxygenated blood from left heart goes to conducting airways. Bronchial artery Bronchiole All blood returns to left heart via pulmonary veins. Pulmonary vein Shunt FIGURE 25– 6. The blood supply to the airways. OLFACTION. Ventilation is essential for delivering odorants to the olfactory epithelium (see Chapter 13). Sniffing behavior, especially important for some animals, allows one to sample the chemicals in the air without the risk of bringing potential noxious agents deep into the lungs. PROCESSING OF INHALED AIR BEFORE IT REACHES THE ALVEOLI. Strictly speaking, warming, moisturizing, and filtering the inhaled air in the conducting airways is a respiratory function. It is part of the cost of doing the business of ventilation. Warming 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, then 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 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 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 m 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 approximately 10 m in diameter will impact and embed themselves in the mucus that coats the nasal mucosa. Moreover, air inspired through the nose must make 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 immunologic 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 – 10 m 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 embed themselves in mucus. Particles with diameters below approximately 0.5 m 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 phagocytize 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 impacting or sedimenting — on their journey to the oropharynx. Coughing and sneezing (see Chapter 31), reflexes triggered by airway irritation, accelerate the movement of particulates up the conducting airways and out of the body. top of RH base of RH top of text base of text LEFT-VENTRICULAR RESERVOIR. The highly compliant pulmonary vessels of the typical 70-kg human contain approximately 500 ml of blood (see Chapter 18), which is an important buffer for filling the left ventricle. For example, even if — under experimental conditions — one clamps the pulmonary artery, so that no blood may enter the lungs, the left 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 a blood vessel. 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, short standard long 40156 Boron BATCH SAUNM RIGHT Organization of the Respiratory System / 25 TABLE 25– 3 HANDLING OF AGENTS BY THE PULMONARY CIRCULATION UNAFFECTED LARGELY REMOVED PGA1 , PGA2 , PGI2 PGE1 , PGE2 , PGF2␣ , leukotrienes Histamine, epinephrine, dopamine Serotonin Bradykinin Angiotensin II, arginine vasopressin, gastrin, oxytocin Angiotensin I (converted to angiotensin II) From Levitzky MG: Pulmonary Physiology, 4th ed. New York, McGraw-Hill, 1999. the pulmonary vasculature can trap these emboli before they have a chance to reach the left 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 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 supporting metastatic disease. 15 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 25 – 3). Thus, the lung can be instrumental in determining which signalling 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 (ACE) (see Chapter ??). top of RH base of RH top of text base of text BIBLIOGRAPHY Bouhuys A: The Physiology of Breathing. New York, Grune & Stratton, 1977. Kellog RH: Laws of physics pertaining to gas exchange. In The American Physiological Society Staff: Handbook of Physiology, Section 3: The Respiratory System, Vol IV. Bethesda, MD, American Physiological Society, 1985. Macklem PT: Symbols and abbreviations. In The American Physiological Society Staff: Handbook of Physiology, Section 3: The Respiratory System, Vol I. Bethesda, MD, American Physiological Society, 1985. Mason RJ, Williams MC: Alveolar type II cells. In Crystal RG, West JB: The Lung. New York, Raven, 1991. Satir P, Sleigh MA: The physiology of cilia and mucociliary interactions. Annu Rev Physiol 52:137, 1990. Schneeberger EE: Alveolar type I cells. In Crystal RG, West JB: The Lung. New York, Raven, 1991. Weibel ER: Lung cell biology. In The American Physiological Society Staff: Handbook of Physiology, Section 3: The Respiratory System, Vol I. Bethesda, MD, American Physiological Society, 1985. short standard long