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18 Gas Exchange and Transport Gas Exchange in the Lungs and Tissues Lower Alveolar PO2 Decreases Oxygen Uptake Diffusion Problems Cause Hypoxia Gas Solubility Affects Diffusion Gas Transport in the Blood Hemoglobin Binds to Oxygen Oxygen Binding Obeys the Law of Mass Action Hemoglobin Transports Most Oxygen to the Tissues PO2 Determines Oxygen-Hb Binding Oxygen Binding Is Expressed As a Percentage Several Factors Affect Oxygen-Hb Binding Carbon Dioxide Is Transported in Three Ways Regulation of Ventilation Neurons in the Medulla Control Breathing Carbon Dioxide, Oxygen, and pH Influence Ventilation Protective Reflexes Guard the Lungs Higher Brain Centers Affect Patterns of Ventilation The successful ascent of Everest without supplementary oxygen is one of the great sagas of the 20th century. —John B. West, Climbing with O’s, NOVA Online (www.pbs.org) Background Basics Exchange epithelia pH and buffers Law of mass action Cerebrospinal fluid Simple diffusion Autonomic and somatic motor neurons Structure of the brain stem Red blood cells and hemoglobin Blood-brain barrier Giant liposomes of pulmonary surfactant (40X) From Chapter 18 of Human Physiology: An Integrated Approach, Sixth Edition. Dee Unglaub Silverthorn. Copyright © 2013 by Pearson Education, Inc. All rights reserved. 633 Gas Exchange and Transport T he book Into Thin Air by Jon Krakauer chronicles an illfated trek to the top of Mt. Everest. To reach the summit of Mt. Everest, climbers must pass through the “death zone” located at about 8000 meters (over 26,000 ft). Of the thousands of people who have attempted the summit, only about 2000 have been successful, and more than 185 have died. What are the physiological challenges of climbing Mt. Everest (8850 m or 29,035 ft), and why did it take so many years before humans successfully reached the top? The lack of oxygen at high altitude is part of the answer. The mechanics of breathing includes the events that create bulk flow of air into and out of the lungs. In this chapter we focus on the two gases most significant to human physiology, oxygen and carbon dioxide, and look at how they move between alveolar air spaces and the cells of the body. The process can be divided into two components: the exchange of gases between compartments, which requires diffusion across cell membranes, and the transport of gases in the blood. Figure 18.1 presents an overview of the topics that we cover in this chapter. If the diffusion of gases between alveoli and blood is significantly impaired, or if oxygen transport in the blood is inadequate, hypoxia (a state of too little oxygen) results. Hypoxia frequently (but not always!) goes hand in hand with hypercapnia, RUNNING PROBLEM High Altitude In 1981 a group of 20 physiologists, physicians, and climbers, supported by 42 Sherpa assistants, formed the American Medical Research Expedition to Mt. Everest. The purpose of the expedition was to study human physiology at extreme altitudes, starting with the base camp at 5400 m (18,000 ft) and continuing on to the summit at 8850 m (over 29,000 ft). From the work of these scientists and others, we now have a good picture of the physiology of high-altitude acclimatization. elevated concentrations of carbon dioxide. These two conditions are clinical signs, not diseases, and clinicians must gather additional information to pinpoint their cause. Table 18.1 lists several types of hypoxia and some typical causes. To avoid hypoxia and hypercapnia, the body uses sensors that monitor arterial blood composition. These sensors respond to three regulated variables: 1 PULMONARY GAS EXCHANGE AND TRANSPORT CO2 2 O2 Airways Alveoli of lungs 3 CO2 O2 6 CO2 enters alveoli at alveolar-capillary interface. 1 Oxygen enters the blood at alveolarcapillary interface. O2 CO2 Pulmonary circulation 5 CO2 is transported dissolved, bound to hemoglobin, or as HCO3–. Systemic circulation CO2 2 Oxygen is transported in blood dissolved in plasma or bound to hemoglobin inside RBCs. 3 Oxygen diffuses into cells. Cells ATP Fig. 18.1 634 CO2 Cellular respiration determines metabolic CO2 production. The normal values for these three parameters are given in Table 18.2. In this chapter we will consider the mechanisms by which oxygen and CO2 move from the lungs to the cells and back again. Gas Exchange in the Lungs and Tissues O2 4 CO2 diffuses out of cells. Oxygen. Arterial oxygen delivery to the cells must be adequate to support aerobic respiration and ATP production. Carbon dioxide (CO2) is produced as a waste product during the citric acid cycle. Excretion of CO2 by the lungs is important for two reasons: high levels of CO2 are a central nervous system depressant, and elevated CO2 causes a state of acidosis (low pH) through the following reaction: CO2 + H2O Δ H2CO3 Δ H+ + HCO3-. pH. Maintaining pH homeostasis is critical to prevent denaturation of proteins. The respiratory system monitors plasma pH and uses changes in ventilation to alter pH. This process is discussed later along with renal contributions to pH homeostasis. O2 Nutrients Breathing is the bulk flow of air into and out of the lungs. Once air reaches the alveoli, individual gases such as oxygen and CO2 diffuse from the alveolar air space into the blood. Recall that diffusion is movement of a molecule from a region of higher concentration to one of lower concentration. Gas Exchange and Transport Table 18.1 Classification of Hypoxias Type Definition Typical Causes Hypoxic hypoxia Low arterial PO2 High altitude; alveolar hypoventilation; decreased lung diffusion capacity; abnormal ventilation-perfusion ratio Anemic hypoxia Decreased total amount of O2 bound to hemoglobin Blood loss; anemia (low [Hb] or altered HbO2 binding); carbon monoxide poisoning Ischemic hypoxia Reduced blood flow Heart failure (whole-body hypoxia); shock (peripheral hypoxia); thrombosis (hypoxia in a single organ) Histotoxic hypoxia Failure of cells to use O2 because cells have been poisoned Cyanide and other metabolic poisons Normal Blood Values in Pulmonary Medicine Table 18.2 Arterial Venous P O2 95 mm Hg (85–100) 40 mm Hg PCO2 40 mm Hg (35–45) 46 mm Hg pH 7.4 (7.38–7.42) 7.37 When we think of concentrations of solutions, units such as moles/liter and milliosmoles/liter come to mind. However, respiratory physiologists commonly express plasma gas concentrations in partial pressures to establish whether there is a concentration gradient between the alveoli and the blood. Gases move from regions of higher partial pressure to regions of lower partial pressure. Figure 18.2 shows the partial pressures of oxygen and CO2 in air, the alveoli, and inside the body. Normal alveolar PO2 at sea level is about 100 mm Hg. The PO2 of “deoxygenated” venous blood arriving at the lungs is 40 mm Hg. Oxygen therefore diffuses down its partial pressure (concentration) gradient from the alveoli into the capillaries. Diffusion goes to equilibrium, and the PO2 of arterial blood leaving the lungs is the same as in the alveoli: 100 mm Hg. When arterial blood reaches tissue capillaries, the gradient is reversed. Cells are continuously using oxygen for oxidative phosphorylation. In the cells of a person at rest, intracellular PO2 averages 40 mm Hg. Arterial blood arriving at the cells has a PO2 of 100 mm Hg. Because PO2 is lower in the cells, oxygen diffuses down its partial pressure gradient from plasma into cells. Once again, diffusion goes to equilibrium. As a result, venous blood has the same PO2 as the cells it just passed. Conversely, PCO2 is higher in tissues than in systemic capillary blood because of CO2 production during metabolism (Fig. 18.2). Cellular PCO2 in a person at rest is about 46 mm Hg, compared to an arterial plasma PCO2 of 40 mm Hg. The gradient causes CO2 to diffuse out of cells into the capillaries. Diffusion goes to equilibrium, and systemic venous blood averages a PCO2 of 46 mm Hg. At the pulmonary capillaries, the process reverses. Venous blood bringing waste CO2 from the cells has a PCO2 of 46 mm Hg. Alveolar PCO2 is 40 mm Hg. Because PCO2 is higher in the plasma, CO2 moves from the capillaries into the alveoli. By the time blood leaves the alveoli, it has a PCO2 of 40 mm Hg, identical to the PCO2 of the alveoli. In the sections that follow we will consider some of the other factors that affect the transfer of gases between the alveoli and the body’s cells. Concept Check 18 Answers: End of Chapter 1. Cellular metabolism review: which of the following three metabolic pathways—glycolysis, the citric acid cycle, and the electron transport system—is directly associated with (a) O2 consumption and with (b) CO2 production? 2. Why doesn’t the movement of oxygen from the alveoli to the plasma decrease the PO2 of the alveoli? 3. If nitrogen is 78% of atmospheric air, what is the partial pressure of this gas when the dry atmospheric pressure is 720 mm Hg? 635 Gas Exchange and Transport GASES DIFFUSE DOWN CONCENTRATION GRADIENTS Hypoxia is the primary problem that people experience when ascending to high altitude. High altitude is considered anything above 1500 m (5000 ft), but most pathological responses to altitude occur above 2500 m (about 8000 ft). By one estimate, 25% of people arriving at 2590 m will experience some form of altitude sickness. Dry air = 760 mm Hg PO = 160 mm Hg 2 PCO = 0.25 mm Hg 2 Alveoli Q1: If water vapor contributes 47 mm Hg to the pressure of fully humidified air, what is the PO2 of inspired air reaching the alveoli at 2500 m, where dry atmospheric pressure is 542 mm Hg? How does this value for PO2 compare with that of fully humidified air at sea level? PO = 100 mm Hg 2 PCO2 = 40 mm Hg O2 CO2 Pulmonary circulation Venous blood Arterial blood PO2 ≤ 40 mm Hg PCO2 ≥ 46 mm Hg PO2 = 100 mm Hg PCO2 = 40 mm Hg Systemic circulation O2 CO2 Cells PO ≤ 40 mm Hg 2 PCO2 ≥ 46 mm Hg Aerobic metabolism consumes O2 and produces CO2. Fig. 18.2 Lower Alveolar PO2 Decreases Oxygen Uptake Many variables influence the efficiency of alveolar gas exchange and determine whether arterial blood gases are normal ( Fig. 18.3a). First, adequate oxygen must reach the alveoli. A decrease in alveolar PO2 means that less oxygen is available to enter the blood. There can also be problems with the transfer of gases between the alveoli and pulmonary capillaries. Finally, blood flow, or perfusion, of the alveoli must be adequate. If something impairs blood flow to the lung, then the body is unable to acquire the oxygen it needs. Let’s look in more detail at these factors. There are two possible causes of low alveolar PO2: either (1) the inspired air has low oxygen content or (2) alveolar ventilation, is inadequate. 636 RUNNING PROBLEM Composition of the Inspired Air The first requirement for adequate oxygen delivery to the tissues is adequate oxygen intake from the atmosphere. The main factor that affects atmospheric oxygen content is altitude. The partial pressure of oxygen in air decreases along with total atmospheric pressure as you move from sea level (where normal atmospheric pressure is 760 mm Hg) to higher altitudes. For example, Denver, 1609 m above sea level, has an atmospheric pressure of about 628 mm Hg. The PO2 of dry air in Denver is 132 mm Hg, down from 160 mm Hg at sea level. For fully humidified atmospheric air reaching the alveoli, the PO2 is even lower: Patm 628 mm Hg - PH2O 47 mm Hg) = 581 mm Hg * 21% = PO2 of 122 mm Hg, down from 150 mm Hg at sea level. Notice that water vapor pressure is the same no matter what the altitude, making its contribution to total pressure in the lungs more important as you go higher. Alveolar Ventilation Unless a person is traveling, altitude remains constant. If the composition of inspired air is normal but alveolar PO2 is low, then the problem must lie with alveolar ventilation. Low alveolar ventilation is also known as hypoventilation and is characterized by lower-than-normal volumes of fresh air entering the alveoli. Pathological changes that can result in alveolar hypoventilation (Fig. 18.3c) include decreased lung compliance, increased airway resistance, or CNS depression that slows ventilation rate and decreases depth. Common causes of CNS depression in young people include alcohol poisoning and drug overdoses. Concept Check Answers: End of Chapter 4. At the summit of Mt. Everest, an altitude of 8850 m, atmospheric pressure is only 250 mm Hg. What is the PO2 of dry atmospheric air atop Everest? If water vapor added to inhaled air at the summit has a partial pressure of 47 mm Hg, what is the PO2 of the inhaled air when it reaches the alveoli? Gas Exchange and Transport GAS EXCHANGE IN THE ALVEOLI (a) Alveolar gas exchange Alveolar Gas Exchange is influenced by O2 reaching the aveoli Alveolar ventilation Composition of inspired air Rate and depth of breathing Airway resistance Lung compliance Gas diffusion between alveoli and blood Surface area Adequate perfusion of alveoli Diffusion distance Barrier thickness Amount of fluid (b) Cells form a diffusion barrier between lung and blood. 18 Surfactant Alveoli Alveolar air space CO2 O2 Alveolar epithelium Fused basement membranes Capillary 0.1–1.5 μm Nucleus of endothelial cell O2 CO2 Capillary lumen Plasma RBC (c) Pathologies that cause hypoxia Diffusion ∝ surface area × barrier permeability/distance2 Normal lung Emphysema Fibrotic lung disease Pulmonary edema Asthma Destruction of alveoli means less surface area for gas exchange. Thickened alveolar membrane slows gas exchange. Loss of lung compliance may decrease alveolar ventilation. Fluid in interstitial space increases diffusion distance. Arterial PCO2 may be normal due to higher CO2 solubility in water. Increased airway resistance decreases alveolar ventilation. Bronchioles constricted PO2 normal PO normal 2 PO 2 normal or low PO2 low PO2 normal or low PO2 normal Exchange surface normal Increased diffusion distance PO2 low PO2 low PO2 low PO2 low Fig. 18.3 637 Gas Exchange and Transport Diffusion Problems Cause Hypoxia If hypoxia is not caused by hypoventilation, then the problem usually lies with some aspect of gas exchange between alveoli and blood. In these situations, alveolar PO2 may be normal, but the PO2 of arterial blood leaving the lungs is low. The transfer of oxygen from alveoli to blood requires diffusion across the barrier created by type I alveolar cells and the capillary endothelium (Fig. 18.3b). The exchange of oxygen and carbon dioxide across this diffusion barrier obeys the same rules as simple diffusion across a membrane. The diffusion rate is directly proportional to the available surface area, the concentration gradient of the gas, and the permeability of the barrier: Diffusion rate r surface area : concentration gradient : barrier permeability From the general rules for diffusion, we can add a fourth factor: diffusion distance. Diffusion is inversely proportional to the square of the distance or, in simpler terms—diffusion is most rapid over short distances B I O T E C H N O LO G Y The Pulse Oximeter One important clinical indicator of the effectiveness of gas exchange in the lungs is the concentration of oxygen in arterial blood. Obtaining an arterial blood sample is difficult for the clinician and painful for the patient because it means finding an accessible artery. (Most blood is drawn from superficial veins rather than from arteries, which lie deeper within the body). Over the years, however, scientists have developed instruments that quickly and painlessly measure blood oxygen levels through the surface of the skin on a finger or earlobe. One such instrument, the pulse oximeter, clips onto the skin and in seconds gives a digital reading of arterial hemoglobin saturation. The oximeter works by measuring light absorbance of the tissue at two wavelengths. Another instrument, the transcutaneous oxygen sensor, measures dissolved oxygen using a variant of traditional gasmeasuring electrodes. Both methods have limitations but are popular because they provide a rapid, noninvasive means of estimating arterial oxygen content. Diffusion rate r 1>distance2 Under most circumstances, diffusion distance, surface area, and barrier permeability in the body are constants and are maximized to facilitate diffusion. Gas exchange in the lungs is rapid, blood flow through pulmonary capillaries is slow, and diffusion reaches equilibrium in less than 1 second. This leaves the concentration gradient between alveoli and blood as the primary factor affecting gas exchange in healthy people. The factors of surface area, diffusion distance, and membrane permeability do come into play with various diseases. Pathological changes that adversely affect gas exchange include (1) a decrease in the amount of alveolar surface area available for gas exchange, (2) an increase in the thickness of the alveolarcapillary exchange barrier, and (3) an increase in the diffusion distance between the alveolar air space and the blood. Surface Area Physical loss of alveolar surface area can have devastating effects in emphysema, a degenerative lung disease most often caused by cigarette smoking (Fig. 18.3c). The irritating effect of smoke chemicals and tar in the alveoli activates alveolar macrophages that release elastase and other proteolytic enzymes. These enzymes destroy the elastic fibers of the lung and induce apoptosis of cells, breaking down the walls of the alveoli. The result is a high-compliance/low-elastic recoil lung with fewer and larger alveoli and less surface area for gas exchange. Diffusion Barrier Permeability Pathological changes in the alveolar-capillary diffusion barrier may alter its properties and slow gas exchange. For example, in fibrotic lung diseases, scar 638 tissue thickens the alveolar wall (Fig. 18.3c). Diffusion of gases through this scar tissue is much slower than normal. However, because the lungs have a built-in reserve capacity, one-third of the exchange epithelium must be incapacitated before arterial PO2 falls significantly. Diffusion Distance Normally the pulmonary diffusion distance is small because the alveolar and endothelial cells are thin and there is little or no interstitial fluid between the two cell layers (Fig. 18.3b). However, in certain pathological states, excess fluid increases the diffusion distance between the alveolar air space and the blood. Fluid accumulation may occur inside the alveoli or in the interstitial compartment between the alveolar epithelium and the capillary. In pulmonary edema, accumulation of interstitial fluid increases the diffusion distance and slows gas exchange (Fig. 18.3c). Gas Exchange and Transport Normally, only small amounts of interstitial fluid are present in the lungs, the result of low pulmonary blood pressure and effective lymph drainage. However, if pulmonary blood pressure rises for some reason, such as left ventricular failure or mitral valve dysfunction, the normal filtration/reabsorption balance at the capillary is disrupted. When capillary hydrostatic pressure increases, more fluid filters out of the capillary. If filtration increases too much, the lymphatics are unable to remove all the fluid, and excess accumulates in the pulmonary interstitial space, creating pulmonary edema. In severe cases, if edema exceeds the tissue’s ability to retain it, fluid leaks from the interstitial space into the alveolar air space, flooding the alveoli. Normally the inside of the alveoli is a moist surface lined by a very thin (about 2–5 mm) layer of fluid with surfactant (see Fig. 18.3b). With alveolar flooding, this fluid layer can become much thicker and seriously impair gas exchange. Alveolar flooding can also occur with leakage when alveolar epithelium is damaged, such as from inflammation or inhaling toxic gases. If hypoxia due to alveolar fluid accumulation is severe and cannot be corrected by oxygen therapy, the condition may be called adult respiratory distress syndrome or ARDS. Concept Check Answers: End of Chapter 5. Why would left ventricular failure or mitral valve dysfunction cause elevated pulmonary blood pressure? 6. If alveolar ventilation increases, what happens to arterial PO2? To arterial PCO2? To venous PO2 and PCO2? Explain your answers. Gas Solubility Affects Diffusion A final factor that can affect gas exchange in the alveoli is the solubility of the gas. The movement of gas molecules from air into a liquid is directly proportional to three factors: (1) the pressure gradient of the gas, (2) the solubility of the gas in the liquid, and (3) temperature. Because temperature is relatively constant in mammals, we can ignore its contribution in this discussion. When a gas is placed in contact with water and there is a pressure gradient, gas molecules move from one phase to the other. If gas pressure is higher in the water than in the gaseous phase, then gas molecules leave the water. If gas pressure is higher in the gaseous phase than in water, then the gas dissolves into the water. For example, consider a container of water exposed to air with a PO2 of 100 mm Hg ( Fig. 18.4a). Initially, the water has no oxygen dissolved in it (water PO2 = 0 mm Hg). As the air stays in contact with the water, some of the moving oxygen molecules in the air diffuse into the water and dissolve (Fig. 18.4b). This process continues until equilibrium is reached. At equilibrium (Fig. 18.4c), the movement of oxygen from the air into the water RUNNING PROBLEM Acute mountain sickness is the mildest illness caused by altitude hypoxia. The primary symptom is a headache that may be accompanied by dizziness, nausea, fatigue, or confusion. More severe illnesses are high-altitude pulmonary edema (HAPE) and high-altitude cerebral edema. HAPE is the major cause of death from altitude sickness. It is characterized by high pulmonary arterial pressure, extreme shortness of breath, and sometimes a productive cough yielding a pink, frothy fluid. Treatment is immediate relocation to lower altitude and administration of oxygen. Q2: Why would someone with HAPE be short of breath? Q3: Based on what you learned about the mechanisms for matching ventilation and perfusion in the lung, can you explain why patients with HAPE have elevated pulmonary arterial blood pressure? is equal to the movement of oxygen from the water back into the air. We refer to the concentration of oxygen dissolved in the water at any given PO2 as the partial pressure of the gas in solution. In our example, therefore, if the air has a PO2 of 100 mm Hg, at equilibrium the water also has a PO2 of 100 mm Hg. Note that this does not mean that the concentration of oxygen is the same in the air and in the water! The concentration of dissolved oxygen also depends on the solubility of oxygen in water. The ease with which a gas dissolves in a liquid is the solubility of the gas in that liquid. If a gas is very soluble, large numbers of gas molecules go into solution at a low gas partial pressure. With less soluble gases, even a high partial pressure may cause only a few molecules of the gas to dissolve in the liquid. For example, when PO2 is 100 mm Hg in both the air and the water, air contains 5.2 mmol O2>L air, but water contains only 0.15 mmol O2>L water (Fig. 18.4c). As you can see, oxygen is not very soluble in water and, by extension, in any aqueous solution. Its low solubility was a driving force for the evolution of oxygencarrying molecules in the aqueous solution we call blood. Now compare oxygen solubility with CO2 solubility (Fig. 18.4d). Carbon dioxide is 20 times more soluble in water than oxygen is. At a PCO2 of 100 mm Hg, the CO2 concentration in air is 5.2 mmol CO2>L air, and its concentration in water is 3.0 mmol>L water. So although PO2 and PCO2 are both 100 mm Hg in the water, the amount of each gas that dissolves in the water is very different. Why is solubility important in physiology? The answer is that oxygen’s low solubility in aqueous solutions means that very little oxygen can be carried dissolved in plasma. Its low solubility 18 639 Gas Exchange and Transport GASES IN SOLUTION When temperature remains constant, the amount of a gas that dissolves in a liquid depends on both the solubility of the gas in the liquid and the partial pressure of the gas. Oxygen solubility (a) Initial state: no O2 in solution (b) Oxygen dissolves. (c) At equilibrium, PO2 in air and water are equal. Low O2 solubility means concentrations are not equal. PO2 = 100 mm Hg [O2] = 5.20 mmol/L PO2 = 100 mm Hg PO2 = 100 mm Hg [O2] = 0.15 mmol/L PO = 0 mm Hg 2 CO2 solubility (d) When CO2 is at equilibrium at the same partial pressure (100 mm Hg), more CO2 dissolves. PCO2 = 100 mm Hg [CO2] = 5.20 mmol/L PCO2 = 100 mm Hg [CO2] = 3.00 mmol/L FIGURE QUESTION Physiologists also express dissolved gases in blood using the following equation: [Gas]diss = α [Pgas] α for oxygen is (0.03 mL O2/L blood)/mm Hg PO2 α for CO2 is (0.7 mL CO2/L blood)/mm Hg PCO2 If arterial blood has a PO2 of 95 mm Hg and a PCO2 of 40 mm Hg, what are the oxygen and CO2 concentrations (in mL gas/L blood)? Fig. 18.4 also means oxygen is slower to cross the increased diffusion distance present in pulmonary edema. Diffusion of oxygen into alveolar capillaries does not have time to come to equilibrium before the blood has left the capillaries. The result is decreased arterial PO2 even though alveolar PO2 may be normal. Carbon dioxide, in contrast, is relatively soluble in body fluids, so increased diffusion distance may not significantly affect CO2 exchange. In some cases of pulmonary edema, arterial PO2 is low but arterial PCO2 is normal because of the different solubilities of the two gases. Concept Check Answers: End of Chapter 7. True or false? Plasma with a PO2 of 40 mm Hg and a PCO2 of 40 mm Hg has the same concentrations of oxygen and carbon dioxide. 8. A saline solution is exposed to a mixture of nitrogen gas and hydrogen gas in which PH2 = PN2. What information do you need to predict whether equal amounts of H2 and N2 dissolve in the solution? 640 Gas Transport in the Blood Now that we have described how gases enter and leave the capillaries, we turn our attention to oxygen and carbon dioxide transport in the blood. Gases that enter the capillaries first dissolve in the plasma. But dissolved gases play only a small part in providing the cells with oxygen. The red blood cells, or erythrocytes, have a critical role in ensuring that gas transport between lung and cells is adequate to meet cell needs. Without hemoglobin in the red blood cells, the blood would be unable to transport sufficient oxygen to sustain life ( Fig. 18.5). Oxygen transport in the circulation and oxygen consumption by tissues are excellent ways to illustrate the general principles of mass flow and mass balance. Mass flow is defined as amount of x moving per minute, where mass flow = concentration * volume flow. We can calculate the mass flow of oxygen traveling from lungs to the cells by using the oxygen content of the arterial blood * cardiac output. Gas Exchange and Transport OXYGEN TRANSPORT MASS BALANCE AND THE FICK EQUATION More than 98% of the oxygen in blood is bound to hemoglobin in red blood cells, and less than 2% is dissolved in plasma. Venous O2 transport (mL O2/min) ARTERIAL BLOOD O2 dissolved in plasma (~ PO2) < 2% Red blood cell O2 + Hb HbO2 > 98% O2 Arterial O2 transport (mL O2/min) Cellular oxygen consumption (QO2) (mL O2/min) Alveolus Alveolar membrane Capillary endothelium Transport to cells Mass Balance Cells Arterial O2 transport – QO2 = Venous O2 transport HbO2 Hb + O2 Rearranges to: O2 dissolved in plasma O2 18 Arterial O2 transport – Venous O2 transport = QO 2 Used in cellular respiration Mass Flow O2 transport = Cardiac output (CO) (L blood/min) × O2 concentration (mL O2/L blood) FIGURE QUESTION How many cell membranes will O2 cross in its passage between the airspace of the alveolus and binding to hemoglobin? Fig. 18.5 Fick Equation Substitute the mass flow equation for O2 transport in the mass balance equation: If arterial blood contains, on average, 200 mL O2 >L blood and the cardiac output is 5 L>min: mL O2 >min to cells = 200 mL O2 >L blood * 5 L blood>min = 1000 mL O2 >min delivered to tissues If we know the mass flow of oxygen in the venous blood leaving the cells, we can use the principle of mass balance to calculate the uptake and consumption of oxygen by the cells ( Fig. 18.6): Arterial O2 transport - cell use of O2 = venous O2 transport where oxygen transport is mass flow, mL O2 being transported per minute. This equation rearranges to: Arterial O2 transport - venous O2 transport = cell use of O2 (CO × Arterial [O2] ) – (CO × Venous [O2] ) = QO2 Using algebra (AB) – (AC) = A(B – C): CO × ( Arterial [O2] – Venous [O2] ) = QO2 Fig. 18.6 Adolph Fick, the nineteenth-century physiologist who derived Fick’s law of diffusion, combined the mass flow and mass balance equations above to relate oxygen consumption (QO2), cardiac output (CO), and blood oxygen content. The result is the Fick equation: QO2 = CO * (arterial oxygen content - venous oxygen content) The Fick equation can be used to estimate cardiac output or oxygen consumption, assuming that arterial and venous blood gases can be measured. 641 Gas Exchange and Transport Hemoglobin Binds to Oxygen Oxygen transport in the blood has two components: the oxygen that is dissolved in the plasma (the PO2) and oxygen bound to hemoglobin (Hb). In other words: Total blood O2 content = dissolved O2 + O2 bound to Hb As you learned in the previous section, oxygen is only slightly soluble in aqueous solutions, and less than 2% of all oxygen in the blood is dissolved. That means hemoglobin transports more than 98% of our oxygen (Fig. 18.5). Hemoglobin, the oxygen-binding protein that gives red blood cells their color, binds reversibly to oxygen, as summarized in the equation Once arterial blood reaches the tissues, the exchange process that took place in the lungs reverses. Dissolved oxygen diffuses out of systemic capillaries into cells, and the resultant decrease in plasma PO2 disturbs the equilibrium of the oxygenhemoglobin binding reaction by removing oxygen from the left side of the equation. The equilibrium shifts to the left according to the law of mass action, and the hemoglobin molecules release their oxygen stores, as represented in the bottom half of Figure 18.5. Like oxygen loading at the lungs, this process of transferring oxygen to the body’s cells takes place very rapidly and goes to equilibrium. The PO2 of the cells determines how much oxygen is unloaded from hemoglobin. As cells increase their metabolic activity, their PO2 decreases, and hemoglobin releases more oxygen to them. Hb + O2 m HbO2 Why is hemoglobin an effective oxygen carrier? The answer lies in its molecular structure. Hemoglobin (Hb) is a tetramer with four globular protein chains (globins), each centered around an iron-containing heme group. The central iron atom of each heme group can bind reversibly with one oxygen molecule. With four heme groups per hemoglobin molecule, one hemoglobin molecule has the potential to bind four oxygen molecules. The iron-oxygen interaction is a weak bond that can be easily broken without altering either the hemoglobin or the oxygen. Hemoglobin bound to oxygen is known as oxyhemoglobin, abbreviated HbO2. It would be more accurate to show the number of oxygen molecules carried on each hemoglobin molecule—Hb(O2)1 - 4—but we use the simpler abbreviation because the number of bound oxygen molecules varies from one hemoglobin molecule to another. Oxygen Binding Obeys the Law of Mass Action The hemoglobin binding reaction Hb + O2 m HbO2 obeys the law of mass action. As the concentration of free O2 increases, more oxygen binds to hemoglobin and the equation shifts to the right, producing more HbO2. If the concentration of O2 decreases, the equation shifts to the left. Hemoglobin releases oxygen and the amount of oxyhemoglobin decreases. In the blood, the free oxygen available to bind to hemoglobin is dissolved oxygen, indicated by the PO2 of plasma (Fig. 18.5). In the pulmonary capillaries, oxygen from the alveoli dissolves in plasma. Dissolved O2 then diffuses into the red blood cells, where it can binds to hemoglobin. The hemoglobin acts like a sponge, soaking up oxygen from the plasma until the reaction Hb + O2 m HbO2 reaches equilibrium. The transfer of oxygen from alveolar air to plasma to red blood cells and onto hemoglobin occurs so rapidly that blood in the pulmonary capillaries normally picks up as much oxygen as the PO2 of the plasma and the number of red blood cells permit. 642 Hemoglobin Transports Most Oxygen to the Tissues To understand why we must have adequate amounts of hemoglobin in our blood to survive, consider the following example. Assume that a person’s oxygen consumption at rest is about 250 mL O2 >min and the cardiac output is 5 L blood >min. To meet the cells’ needs for oxygen, the 5 L of blood >min coming to the tissues would need to contain at least 250 mL O2, or 50 mL O2 >L blood. The low solubility of oxygen means that only 3 mL of O2 will dissolve in the plasma fraction of 1 liter of arterial blood ( Fig. 18.7a). The dissolved oxygen delivery to the cells is 3 mL O2 >L blood * 5 L blood>min = 15 mL O2 >min The cells use at least 50 mL O2 >min, so the small amount of oxygen that dissolves in plasma cannot meet the needs of the tissues at rest. Now let’s consider the difference in oxygen delivery if hemoglobin is available. At normal hemoglobin levels, red blood cells carry about 197 mL O2 >L blood (Fig. 18.7b). Total blood O2 content = dissolved O2 + O2 bound to Hb = 3 mL O2 >L blood + 197 mL HbO2 >L blood = 200 mL O2 >L blood If cardiac output remains 5 L>min, hemoglobin-assisted oxygen delivery to cells is 1000 mL>min: 200 mL O2 >L blood * 5 L blood>min = 1000 mL O2 >min This is four times the oxygen consumption needed by the tissues at rest. The extra serves as a reserve for times when oxygen demand increases, such as with exercise. Gas Exchange and Transport HEMOGLOBIN INCREASES OXYGEN TRANSPORT (a) Oxygen transport in blood without hemoglobin. Alveolar PO2 = arterial PO2 PO2 = 100 mm Hg (b) Oxygen transport at normal PO2 in blood with hemoglobin PO = 100 mm Hg 2 Alveoli O2 molecule Arterial plasma PO = 100 mm Hg 2 Oxygen dissolves in plasma. (c) Oxygen transport at reduced PO 2 in blood with hemoglobin PO = 28 mm Hg 2 PO2 = 100 mm Hg Red blood cells with hemoglobin are carrying 98% of their maximum load of oxygen. PO2 = 28 mmHg Red blood cells carrying 50% of their maximum load of oxygen. 18 O2 content of plasma = 3 mL O2/L blood O2 content of plasma = O2 content of red blood cells O2 content of red blood cells =0 Total O2 carrying capacity 3 mL O2/L blood Total O2 carrying capacity 3 mL O2/L blood = 197 mL O2/L blood 200 mL O2/L blood O2 content of plasma = O2 content of red blood cells Total O2 carrying capacity 0.8 mL O2/L blood = 99.5 mL O2/L blood 100.3 mL O2/L blood Fig. 18.7 EMERGING CONCEPTS Blood Substitutes Physiologists have been attempting to find a substitute for blood ever since 1878, when an intrepid physician named T. Gaillard Thomas transfused a patient with whole milk in place of blood. (It helped but the patient died anyway.) Although milk seems an unlikely replacement for blood, it has two important properties: proteins to provide colloid osmotic pressure and molecules (emulsified lipids) capable of binding to oxygen. In the development of hemoglobin substitutes, oxygen transport is the most difficult property to mimic. A hemoglobin solution would seem to be the obvious answer, but hemoglobin that is not compartmentalized in red blood cells behaves differently than hemoglobin that is compartmentalized. Investigators are making progress by polymerizing hemoglobin into larger, more stable molecules and loading these hemoglobin polymers into phospholipid liposomes. Perfluorocarbon emulsions are also being tested as oxygen carriers. To learn more about this research, read “Physiological properties of blood substitutes,” News Physiol Sci 16(1): 38–41, 2001 Feb (http://nips.physiology.org). PO2 Determines Oxygen-Hb Binding The amount of oxygen that binds to hemoglobin depends on two factors: (1) the PO2 in the plasma surrounding the red blood cells and (2) the number of potential Hb binding sites available in the red blood cells ( Fig. 18.8). Plasma PO2 is the primary factor determining what percentage of the available hemoglobin binding sites are occupied by oxygen, known as the percent saturation of hemoglobin. As you learned in previous sections, arterial PO2 is established by (1) the composition of inspired air, (2) the alveolar ventilation rate, and (3) the efficiency of gas exchange from alveoli to blood. Figure 18.7c shows what happens to O2 transport when PO2 decreases. The total number of oxygen-binding sites depends on the number of hemoglobin molecules in red blood cells. Clinically, this number can be estimated either by counting the red blood cells and quantifying the amount of hemoglobin per red blood cell (mean corpuscular hemoglobin) or by determining the blood hemoglobin content (g Hb>dL whole blood). Any pathological condition that decreases the amount of hemoglobin in the cells or the number of red blood cells adversely affects the blood’s oxygen-transporting capacity. People who have lost large amounts of blood need to replace hemoglobin for oxygen transport. A blood transfusion is 643 Gas Exchange and Transport The amount of oxygen bound to Hb depends on RUNNING PROBLEM Plasma O2 The amount of hemoglobin which determines which determines % Saturation of Hb × Total number of Hb binding sites calculated from Hb content per RBC × Number of RBCs In most people arriving at high altitude, normal physiological responses kick in to help acclimatize the body to the chronic hypoxia. Within two hours of arrival, hypoxia triggers the release of erythropoietin from the kidneys and liver. This hormone stimulates red blood cell production, and as a result, new erythrocytes appear in the blood within days. Q4: How does adding erythrocytes to the blood help a person acclimatize to high altitude? Q5: What does adding erythrocytes to the blood do to the viscosity of the blood? What effect will that change in viscosity have on blood flow? Fig. 18.8 the ideal replacement for blood loss, but in emergencies this is not always possible. Saline infusions can replace lost blood volume, but saline (like plasma) cannot transport sufficient quantities of oxygen to support cellular respiration. Faced with this problem, researchers are currently testing artificial oxygen carriers to replace hemoglobin. In times of large-scale disasters, these hemoglobin substitutes would eliminate the need to identify a patient’s blood type before giving transfusions. Oxygen Binding Is Expressed As a Percentage As you just learned, the amount of oxygen bound to hemoglobin at any given PO2 is expressed as the percent saturation of hemoglobin, where (Amount of O2 bound>maximum that could be bound) * 100 = percent saturation of hemoglobin If all binding sites on all hemoglobin molecules are occupied by oxygen molecules, the blood is 100% oxygenated, or saturated with oxygen. If half the available binding sites are carrying oxygen, the hemoglobin is 50% saturated, and so on. The relationship between plasma PO2 and percent saturation of hemoglobin can be explained with the following analogy. The hemoglobin molecules carrying oxygen are like students moving books from an old library to a new one. Each student (a hemoglobin molecule) can carry a maximum of four books (100% saturation). The librarian in charge controls how many books (O2 molecules) each student will carry, just as plasma PO2 determines the percent saturation of hemoglobin. The total number of books being carried depends on the number of available students, just as the amount of oxygen delivered to the tissues depends on the number of available hemoglobin molecules. For example, if there are 100 students, and the 644 librarian gives each of them four books (100% saturation), then 400 books are carried to the new library. If the librarian gives three books to each student (decreased plasma PO2), then only 300 books go to the new library, even though each student could carry four. (Students carrying only three of a possible four books correspond to 75% saturation of hemoglobin.) If the librarian is handing out four books per student but only 50 students show up (fewer hemoglobin molecules), then only 200 books get to the new library, even though the students are taking the maximum number of books they can carry. The physical relationship between PO2 and how much oxygen binds to hemoglobin can be studied in vitro. Researchers expose samples of hemoglobin to various PO2 levels and quantitatively determine the amount of oxygen that binds. Oxyhemoglobin saturation curves , such as the ones shown in Figure 18.9, are the result of these in vitro binding studies. (These curves are also called dissociation curves.) The shape of the Hb # O2 saturation curve reflects the properties of the hemoglobin molecule and its affinity for oxygen. If you look at the curve, you find that at normal alveolar and arterial PO2 (100 mm Hg), 98% of the hemoglobin is bound to oxygen (Fig. 18.9a). In other words, as blood passes through the lungs under normal conditions, hemoglobin picks up nearly the maximum amount of oxygen that it can carry. Notice that the curve is nearly flat at PO2 levels higher than 100 mm Hg (that is, the slope approaches zero). At PO2 above 100 mm Hg, even large changes in PO2 cause only minor changes in percent saturation. In fact, hemoglobin is not 100% saturated until the PO2 reaches nearly 650 mm Hg, a partial pressure far higher than anything we encounter in everyday life. The flattening of the saturation curve at higher PO2 also means that alveolar PO2 can fall a good bit below 100 mm Hg Fig. 18.9 E S S E N T I A L S Oxygen-hemoglobin Binding Curves Binding properties of adult and fetal hemoglobin (b) Maternal and fetal hemoglobin have different oxygenbinding properties. 100 100 90 90 Hemoglobin saturation, % Hemoglobin saturation, % (a) The oxyhemoglobin saturation curve is determined in vitro in the laboratory. 80 70 60 50 40 30 20 Fetal hemoglobin 80 70 60 Maternal hemoglobin 50 40 30 20 10 10 0 20 40 60 80 Resting cell PO (mm Hg) 2 0 100 Alveoli 20 40 60 80 PO (mm Hg) 2 100 120 Physical factors alter hemoglobin’s affinity for oxygen (d) Effect of temperature (e) Effect of PCO 100 100 100 80 7.6 7.4 60 7.2 40 20 0 20 40 60 PO2 (mm Hg) 80 100 2 37° C 43° C 80 60 40 20 0 20 40 60 PO2 (mm Hg) 80 100 Hemoglobin saturation, % 20° C Hemoglobin saturation, % Hemoglobin saturation, % (c) Effect of pH 80 PCO2 = 20 mm Hg 60 PCO2 = 40 mm Hg PCO2 = 80 mm Hg 40 20 0 20 40 60 PO2 (mm Hg) 80 100 (f) Effect of the metabolic compound 2,3-DPG GRAPH QUESTIONS Hemoglobin saturation, % 100 1. For the graph in (a): (a) When the PO2 is 20 mm Hg, what is the percent O2 saturation of hemoglobin? (b) At what PO2 is hemoglobin 50% saturated with O2? 80 2. At a PO2 of 20 mm Hg, how much more oxygen is released at an exercising muscle cell whose pH is 7.2 than at a cell with a pH of 7.4? No 2,3-DPG 60 Normal 2,3-DPG Added 2,3-DPG 40 3. What happens to oxygen release when the exercising muscle cell warms up? 4. Blood stored in blood banks loses its normal content of 2,3-DPG. Is this good or bad? Explain. 20 5. Because of incomplete gas exchange across the thick membranes of the placenta, hemoglobin in fetal blood leaving the placenta is 80% saturated with oxygen. What is the PO2 of that placental blood? 0 20 40 60 PO2 (mm Hg) 80 100 6. Blood in the vena cava of the fetus has a PO2 around 10 mm Hg. What is the percent O2 saturation of maternal hemoglobin at the same PO2? 645 Gas Exchange and Transport without significantly lowering hemoglobin saturation. As long as PO2 in the alveoli (and thus in the pulmonary capillaries) stays above 60 mm Hg, hemoglobin is more than 90% saturated and maintains near-normal levels of oxygen transport. However, once PO2 falls below 60 mm Hg, the curve becomes steeper. The steep slope means that a small decrease in PO2 causes a relatively large release of oxygen. For example, if PO2 falls from 100 mm Hg to 60 mm Hg, the percent saturation of hemoglobin goes from 98% to about 90%, a decrease of 8%. This is equivalent to a saturation change of 2% for each 10 mm Hg change. If PO2 falls further, from 60 to 40 mm Hg, the percent saturation goes from 90% to 75%, a decrease of 7.5% for each 10 mm Hg. In the 40–20 mm Hg range, the curve is even steeper. Hemoglobin saturation declines from 75% to 35%, a change of 20% for each 10 mm Hg change. What is the physiological significance of the shape of the saturation curve? In blood leaving systemic capillaries with a PO2 of 40 mm Hg (an average value for venous blood in a person at rest), hemoglobin is still 75% saturated, which means that at the cells it released only one-fourth of the oxygen it is capable of carrying. The oxygen that remains bound serves as a reservoir that cells can draw on if metabolism increases. When metabolically active tissues use additional oxygen, their cellular PO2 decreases, and hemoglobin releases additional oxygen at the cells. At a PO2 of 20 mm Hg (an average value for exercising muscle), hemoglobin saturation falls to about 35%. With this 20 mm Hg decrease in PO2 (40 mm Hg to 20 mm Hg), hemoglobin releases an additional 40% of the oxygen it is capable of carrying. This is another example of the built-in reserve capacity of the body. Several Factors Affect Oxygen-Hb Binding Any factor that changes the conformation of the hemoglobin protein may affect its ability to bind oxygen. In humans, physiological changes in plasma pH, PCO2, and temperature all alter the oxygen-binding affinity of hemoglobin. Changes in binding affinity are reflected by changes in the shape of the HbO2 saturation curve. Increased temperature, increased PCO2, or decreased pH decrease the affinity of hemoglobin for oxygen and shift the oxygen-hemoglobin saturation curve to the right (Fig. 18.9c–e). When these factors change in the opposite direction, binding affinity increases, and the curve shifts to the left. Notice that when the curve shifts in either direction, the changes are much more pronounced in the steep part of the curve. Physiologically, this means that oxygen binding at the lungs (in the 90–100 mm Hg PO2 range) is not greatly affected, but oxygen delivery at the tissues (in the 20–40 mm Hg range) is significantly altered. Let’s examine one situation, the affinity shift that takes place when pH decreases from 7.4 (normal) to 7.2 (more acidic). (The normal range for blood pH is 7.38–7.42, but a pH of 7.2 is 646 compatible with life). Look at the graph in Figure 18.c. At a PO2 of 40 mm Hg (equivalent to a resting cell) and pH of 7.4, hemoglobin is about 75% saturated. At the same PO2, if the pH falls to 7.2, the percent saturation decreases to about 62%. This means that hemoglobin molecules release 13% more oxygen at pH 7.2 than they do at pH 7.4. When does the body undergo shifts in blood pH? One situation is with maximal exertion that pushes cells into anaerobic metabolism. Anaerobic metabolism in exercising muscle fibers releases H + into the cytoplasm and extracellular fluid. As H + concentrations increase, pH falls, the affinity of hemoglobin for oxygen decreases, and the HbO2 saturation curve shifts to the right. More oxygen is released at the tissues as the blood becomes more acidic (pH decreases). A shift in the hemoglobin saturation curve that results from a change in pH is called the Bohr effect. An additional factor that affects oxygen-hemoglobin binding is 2,3-diphosphoglycerate (2,3-DPG; also called 2,3-bisphosphoglycerate or 2,3-BPG), a compound made from an intermediate of the glycolysis pathway. Chronic hypoxia (extended periods of low oxygen) triggers an increase in 2,3-DPG production in red blood cells. Increased levels of 2,3-DPG lower the binding affinity of hemoglobin and shift the HbO2 saturation curve to the right (Fig. 18.9f). Ascent to high altitude and anemia are two situations that increase 2,3-DPG production. Changes in hemoglobin’s structure also change its oxygenbinding affinity. For example, fetal hemoglobin (HbF) has two gamma protein chains in place of the two beta chains found in adult hemoglobin. The presence of gamma chains enhances the ability of fetal hemoglobin to bind oxygen in the low-oxygen environment of the placenta. The altered binding affinity is reflected by the different shape of the fetal HbO2 saturation curve (Fig. 18.9b). At any given placental PO2 , oxygen released by maternal hemoglobin is picked up by the higher-affinity fetal hemoglobin for delivery to the developing fetus. Shortly after birth, fetal hemoglobin is replaced with the adult form as new red blood cells are made. Figure 18.10 summarizes all the factors that influence the total oxygen content of arterial blood. Concept Check Answers: End of Chapter 9. Can a person breathing 100% oxygen at sea level achieve 100% saturation of her hemoglobin? 10. What effect does hyperventilation have on the percent saturation of arterial hemoglobin? 11. A muscle that is actively contracting may have a cellular PO2 of 25 mm Hg. What happens to oxygen binding to hemoglobin at this low PO2? What is the PO2 of the venous blood leaving the active muscle? Gas Exchange and Transport ARTERIAL OXYGEN The total oxygen content of arterial blood depends on the amount of oxygen dissolved in plasma and bound to hemoglobin. TOTAL ARTERIAL O2 CONTENT Oxygen dissolved in plasma (PO2 of plasma) Oxygen bound to Hb helps determine is influenced by Composition of inspired air Rate and depth of breathing Alveolar ventilation Airway resistance Oxygen diffusion between alveoli and blood Lung compliance Surface area Membrane thickness Adequate perfusion of alveoli % Saturation of Hb x Total number of binding sites affected by Diffusion distance PCO 2 pH Temperature 2,3-DPG Hb content per RBC Number x of RBCs Amount of interstitial fluid 18 Fig. 18.10 Carbon Dioxide Is Transported in Three Ways Gas transport in the blood includes carbon dioxide removal from the cells as well as oxygen delivery to cells, and hemoglobin also plays an important role in CO2 transport. Carbon dioxide is a by-product of cellular respiration. It is more soluble in body fluids than oxygen is, but the cells produce far more CO2 than can dissolve in the plasma. Only about 7% of the CO2 carried by venous blood is dissolved in the blood. The remaining 93% diffuses into red blood cells, where 70% is converted to bicarbonate ion, as explained below, and 23% binds to hemoglobin (HbCO2). Figure 18.11 summarizes these three mechanisms of carbon dioxide transport in the blood. Why is removing CO2 from the body so important? First, elevated PCO2 (hypercapnia) causes the pH disturbance known as acidosis . Extremes of pH interfere with hydrogen bonding of molecules and can denature proteins. Abnormally high PCO2 levels also depress central nervous system function, causing confusion, coma, or even death. For these reasons, CO2 is a potentially toxic waste product that must be removed by the lungs. CO2 and Bicarbonate Ions As we just noted, about 70% of the CO2 that enters the blood is transported to the lungs as bicarbonate ions (HCO3- ) dissolved in the plasma. The conversion of CO2 to HCO3- serves two purposes: (1) it provides an additional means of CO2 transport from cells to lungs, and (2) HCO3- is available to act as a buffer for metabolic acids, thereby helping stabilize the body’s pH. How does CO2 turn into HCO3- ? The rapid conversion depends on the presence of carbonic anhydrase (CA), an enzyme found concentrated in red blood cells. Let’s see how this happens. Dissolved CO2 in the plasma diffuses into red blood cells, where it may react with water in the presence of carbonic anhydrase to form carbonic acid (H2CO3, top portion of Fig. 18.11). Carbonic acid then dissociates into a hydrogen ion and a bicarbonate ion: Carbonic anhydrase CO2 + H2O m H2CO3 m H + + HCO3Carbonic acid Because carbonic acid dissociates readily, we sometimes ignore the intermediate step and summarize the reaction as: CO2 + H2O m H + + HCO3This reaction is reversible. The rate in either direction depends on the relative concentrations of the substrates and obeys the law of mass action. The conversion of carbon dioxide to H + and HCO3- continues until equilibrium is reached. (Water is always in excess in the body, so water concentration plays no role in the dynamic equilibrium of this reaction.) To keep the reaction going, the products (H + and HCO3- ) must be removed from the cytoplasm of the red blood cell. If the product concentrations are kept low, the reaction cannot reach equilibrium. Carbon dioxide continues to move out of plasma into the red blood cells, which in turn allows more CO2 to diffuse out of tissues into the blood. 647 Gas Exchange and Transport CARBON DIOXIDE TRANSPORT Most CO2 in the blood has been converted to bicarbonate ion, HCO3–. 1 CO2 diffuses out of cells into systemic capillaries. 2 Only 7% of the CO2 remains dissolved in plasma. 3 Nearly a fourth of the CO2 binds to hemoglobin, forming carbaminohemoglobin. VENOUS BLOOD 1 2 CO2 Cellular respiration in peripheral tissues Dissolved CO2 (7%) Red blood cell 3 CO2 + Hb 4 CO2 + H2O CA Cell membrane 5 HCO3 enters the plasma in exchange for Cl– (the chloride shift). 8 The carbonic acid reaction reverses, pulling HCO3– back into the RBC and converting it back to CO2. H+ + Hb HbH HCO3– in plasma (70%) Transport to lungs – 7 By the law of mass action, CO2 unbinds from hemoglobin and diffuses out of the RBC. HCO3– H2CO3 5 Capillary endothelium 4 70% of the CO2 load is converted to bicarbonate and H+. Hemoglobin buffers H+. 6 At the lungs, dissolved CO2 diffuses out of the plasma. Cl– HbCO2 (23%) 6 Dissolved CO2 Dissolved CO2 – 8 HCO3 in plasma Hb + CO2 HbCO2 Cl– HCO3– HbH H2CO3 CA 7 CO2 Alveoli H2O + CO2 H+ + Hb KEY CA = carbonic anhydrase Fig. 18.11 Two separate mechanisms remove free H + and HCO3- . In the first, bicarbonate leaves the red blood cell on an antiport protein. This transport process, known as the chloride shift, exchanges HCO3- for Cl - . The anion exchange maintains the cell’s electrical neutrality. The transfer of HCO3- into the plasma makes this buffer available to moderate pH changes caused by the production of metabolic acids. Bicarbonate is the most important extracellular buffer in the body. produced from the reaction of CO2 and water. In those cases, excess H + accumulates in the plasma, causing the condition known as respiratory acidosis. You will learn more about the role of the respiratory system in maintaining pH homeostasis when you study acid-base balance. Hemoglobin and H+ The second mechanism removes free H + from the red blood cell cytoplasm. Hemoglobin within the red blood cell acts as a buffer and binds hydrogen ions in the reaction Hemoglobin and CO2 Although most carbon dioxide that enters red blood cells is converted to bicarbonate ions, about 23% of the CO2 in venous blood binds directly to hemoglobin. At the cells, when oxygen leaves its binding sites on the hemoglobin molecule, CO2 binds with free hemoglobin at exposed amino groups (-NH2), forming carbaminohemoglobin: H+ + Hb m HbH CO2 + Hb m HbCO2 (carbaminohemoglobin) Hemoglobin’s buffering of H + is an important step that prevents large changes in the body’s pH. If blood PCO2 is elevated much above normal, the hemoglobin buffer cannot soak up all the H + The presence of CO2 and H + facilitates formation of carbaminohemoglobin because both these factors decrease hemoglobin’s binding affinity for oxygen (see Fig. 18.9). 648 Gas Exchange and Transport RUNNING PROBLEM SUMMARY OF O2 AND CO2 EXCHANGE AND TRANSPORT The usual homeostatic response to high-altitude hypoxia is hyperventilation, which begins on arrival. Hyperventilation enhances alveolar ventilation, but this may not help elevate arterial PO2 levels significantly when atmospheric PO2 is low. However, hyperventilation does lower plasma PCO2. Dry air = 760 mm Hg PO = 160 mm Hg 2 PCO2 = 0.25 mm Hg Q6: What happens to plasma pH during hyperventilation? (Hint: Apply the law of mass action to figure out what happens to the balance between CO2 and H+ + HCO3-). Alveoli PO2 = 100 mm Hg PCO2 = 40 mm Hg Q7: How does this change in pH affect oxygen binding at the lungs when PO2 is decreased? How does it affect unloading of oxygen at the cells? CO2 O2 O2 transport CO2 transport HCO3– = 70% HbCO2 = 23% Dissolved CO2 = 7% CO2 Removal at the Lungs When venous blood reaches the lungs, the processes that took place in the systemic capillaries reverse (bottom portion of Fig. 18.11). The PCO2 of the alveoli is lower than that of venous blood in the pulmonary capillaries. Therefore, CO2 diffuses down its pressure gradient—in other words, out of plasma into the alveoli—and the plasma PCO2 begins to fall. The decrease in plasma PCO2 allows dissolved CO2 to diffuse out of the red blood cells. As CO2 levels in the red blood cells decrease, the equilibrium of the CO2 -HCO3- reaction is disturbed, shifting toward production of more CO2. Removal of CO2 causes H + to leave the hemoglobin molecules, and the chloride shift reverses: Cl - returns to the plasma in exchange for HCO3- moving back into the red blood cells. The HCO3and newly released H + re-form into carbonic acid, which is then converted into water and CO2. This CO2 is then free to diffuse out of the red blood cell and into the alveoli. Figure 18.12 shows the combined transport of CO2 and O2 in the blood. At the alveoli, O2 diffuses down its pressure gradient, moving from the alveoli into the plasma and then from the plasma into the red blood cells. Hemoglobin binds to O2, increasing the amount of oxygen that can be transported to the cells. At the cells, the process reverses. Because PO2 is lower in cells than in the arterial blood, O2 diffuses from the plasma into the cells. The decrease in plasma PO2 causes hemoglobin to release O2, making additional oxygen available to enter cells. Carbon dioxide from aerobic metabolism simultaneously leaves cells and enters the blood, dissolving in the plasma. From there, CO2 enters red blood cells, where most is converted to HCO3- and H + . The HCO3- is returned to the plasma in exchange for a Cl - while the H + binds to hemoglobin. A fraction of the CO2 that enters red blood cells also binds directly to Pulmonary circulation HbO2 > 98% Dissolved O2 < 2% (~PO2) 18 Venous blood Arterial blood PO2 ≤ 40 mm Hg PCO2 ≥ 46 mm Hg PO2 = 100 mm Hg PCO2 = 40 mm Hg Systemic circulation O2 CO2 Cells PO2 ≤ 40 mm Hg PCO2 ≥ 46 mm Hg Fig. 18.12 hemoglobin. At the lungs, the process reverses as CO2 diffuses out of the pulmonary capillaries and into the alveoli. To understand fully how the respiratory system coordinates delivery of oxygen to the lungs with transport of oxygen in the circulation, we now consider the central nervous system control of ventilation. Concept Check Answers: End of Chapter 12. How would an obstruction of the airways affect alveolar ventilation, arterial PCO2, and the body’s pH? Regulation of Ventilation Breathing is a rhythmic process that usually occurs without conscious thought or awareness. In that respect, it resembles the rhythmic beating of the heart. However, skeletal muscles, unlike 649 Gas Exchange and Transport autorhythmic cardiac muscles, are not able to contract spontaneously. Instead, skeletal muscle contraction must be initiated by somatic motor neurons, which in turn are controlled by the central nervous system. In the respiratory system, contraction of the diaphragm and other muscles is initiated by a spontaneously firing network of neurons in the brain stem ( Fig. 18.13). Breathing occurs automatically throughout a person’s life but can also be controlled voluntarily, up to a point. Complicated synaptic interactions between neurons in the network create the rhythmic cycles of inspiration and expiration, influenced continuously by sensory input, especially that from chemoreceptors for CO2, O2, and H + . Ventilation pattern depends in large part on the levels of those three substances in the arterial blood and extracellular fluid. The neural control of breathing is one of the few “black boxes” left in systems-level physiology. Although we know the major regions of the brain stem that are involved, the details remain elusive and controversial. The brain stem network that controls breathing behaves like a central pattern generator, with intrinsic rhythmic activity that probably arises from pacemaker neurons with unstable membrane potentials. Some of our understanding of how ventilation is controlled has come from observing patients with brain damage. Other information has come from animal experiments in which neural connections between major parts of the brain stem are severed, or sections of brain are studied in isolation. Research on CNS respiratory control is difficult because of the complexity of the neural network and its anatomical location, THE REFLEX CONTROL OF VENTILATION Central and peripheral chemoreceptors monitor blood gases and pH. Control networks in the brain stem regulate activity in somatic motor neurons leading to respiratory muscles. Emotions and voluntary control CO2 O2 and pH Higher brain centers Medullary chemoreceptors Carotid and aortic chemoreceptors 16 15 1 2 14 13 3 4 Limbic system Afferent sensory neurons 12 5 6 Medulla oblongata and pons 7 8 11 Somatic motor neurons (inspiration) 10 Somatic motor neurons (expiration) 9 Inspiration FIGURE QUESTION 650 Expiration Scalene and sternocleidomastoid muscles External intercostals Diaphragm Internal intercostals Abdominal muscles KEY Match the numbers on the figure to the boxes of the map. Stimuli Integrating centers Sensors Efferent neurons Fig. 18.13 Afferent neurons Targets Gas Exchange and Transport but in recent years scientists have developed better techniques for studying the system. The details that follow represent a contemporary model for the control of ventilation. Although some parts of the model are well supported with experimental evidence, other aspects are still under investigation. This model states that: 1 2 3 4 Neural networks in the brain stem control ventilation. Respiratory neurons in the medulla control inspiratory and expiratory muscles. Neurons in the pons integrate sensory information and interact with medullary neurons to influence ventilation. The rhythmic pattern of breathing arises from a neural network with spontaneously discharging neurons. Ventilation is subject to continuous modulation by various chemoreceptor- and mechanoreceptor-linked reflexes and by higher brain centers. Higher brain centers Pons PRG NTS Neurons in the Medulla Control Breathing Classic descriptions of how the brain controls ventilation divided the brain stem into various control centers. More recent descriptions, however, are less specific about assigning function to particular “centers” and instead look at complex interactions between neurons in a network. We know that respiratory neurons are concentrated bilaterally in two areas of the medulla oblongata. Figure 18.14 shows these areas on the left side of the brain stem. One area called the nucleus tractus solitarius (NTS) contains the dorsal respiratory group (DRG) of neurons that control mostly muscles of inspiration. Output from the DRG goes via the phrenic nerves to the diaphragm and via the intercostal nerves to the intercostal muscles. In addition, the NTS receives sensory information from peripheral chemoand mechanoreceptors through the vagus and glossopharyngeal nerves (cranial nerves X and IX). Respiratory neurons in the pons receive sensory information from the DRG and in turn influence the initiation and termination of inspiration. The pontine respiratory groups (previously called the pneumotaxic center) and other pontine neurons provide tonic input to the medullary networks to help coordinate a smooth respiratory rhythm. The ventral respiratory group (VRG) of the medulla has multiple regions with different functions. One area known as the pre-Bötzinger complex contains spontaneously firing neurons that may act as the basic pacemaker for the respiratory rhythm. Other areas control muscles used for active expiration or for greater-than-normal inspiration, such as occurs during vigorous exercise. In addition, nerve fibers from the VRG innervate muscles of the larynx, pharynx, and tongue to keep the upper airways open during breathing. Inappropriate relaxation of these muscles during sleep contributes to obstructive sleep apnea, a sleeping disorder associated with snoring and excessive daytime sleepiness. The integrated action of the respiratory control networks can be seen by monitoring electrical activity in the phrenic Medullary chemoreceptors monitor CO2. Sensory input from CN IX, X (mechanical and chemosensory) 18 DRG Medulla pre-Bötzinger complex VRG Output to expiratory, some inspiratory, pharynx, larynx, and tongue muscles Output primarily to inspiratory muscles KEY PRG = Pontine respiratory group DRG = Dorsal respiratory group VRG = Ventral respiratory group NTS = Nucleus tractus solitarius Fig. 18.14 nerve and other motor nerves ( Fig. 18.15 ). During quiet breathing, a pacemaker initiates each cycle, and inspiratory neurons gradually increase stimulation of the inspiratory muscles. This increase is sometimes called ramping because of the shape of the graph of inspiratory neuron activity. A few inspiratory neurons fire to begin the ramp. The firing of these neurons recruits other inspiratory neurons to fire in an apparent positive feedback loop. As more neurons fire, more skeletal muscle fibers are recruited. The rib cage expands smoothly as the diaphragm contracts. At the end of inspiration, the inspiratory neurons abruptly stop firing, and the respiratory muscles relax. Over the next few seconds, passive expiration occurs because of elastic recoil of the inspiratory muscles and elastic lung tissue. However, some 651 Gas Exchange and Transport NEURAL ACTIVITY DURING QUIET BREATHING Tidal volume (liters) Number of active inspiratory neurons During inspiration, the activity of inspiratory neurons increases steadily, apparently through a positive feedback mechanism. At the end of inspiration, the activity shuts off abruptly and expiration takes place through recoil of elastic lung tissue. ive sit op po k lo d pi bac Ra ed fe Inspiration shuts off 0.5 0 Inspiration 2 sec Passive expiration 3 sec Inspiration 2 sec Time GRAPH QUESTION What is the ventilation rate of the person in this example? Fig. 18.15 motor neuron activity can be observed during passive expiration, suggesting that perhaps muscles in the upper airways contract to slow the flow of air out of the respiratory system. Many neurons of the VRG remain inactive during quiet respiration. They function primarily during forced breathing, when inspiratory movements are exaggerated, and during active expiration. In forced breathing, increased activity of inspiratory neurons stimulates accessory muscles, such as the sternocleidomastoids. Contraction of these accessory muscles enhances expansion of the thorax by raising the sternum and upper ribs. With active expiration, expiratory neurons from the VRG activate the internal intercostal and abdominal muscles. There seems to be some communication between inspiratory and expiratory neurons, as inspiratory neurons are inhibited during active expiration. Carbon Dioxide, Oxygen, and pH Influence Ventilation Sensory input from central and peripheral chemoreceptors modifies the rhythmicity of the control network to help maintain blood gas homeostasis. Carbon dioxide is the primary 652 stimulus for changes in ventilation. Oxygen and plasma pH play lesser roles. The chemoreceptors for oxygen and carbon dioxide are strategically associated with the arterial circulation. If too little oxygen is present in arterial blood destined for the brain and other tissues, the rate and depth of breathing increase. If the rate of CO2 production by the cells exceeds the rate of CO2 removal by the lungs, arterial PCO2 increases, and ventilation is intensified to match CO2 removal to production. These homeostatic reflexes operate constantly, keeping arterial PO2 and PCO2 within a narrow range. Peripheral chemoreceptors located in the carotid and aortic arteries sense changes in the PO2 , pH, and PCO2 of the plasma (Fig. 18.13). These carotid and aortic bodies are close to the locations of the baroreceptors involved in reflex control of blood pressure. Central chemoreceptors in the brain respond to changes in the concentration of CO2 in the cerebrospinal fluid. These central receptors lie on the ventral surface of the medulla, close to neurons involved in respiratory control. Peripheral Chemoreceptors When specialized glomus cells {glomus, a ball-shaped mass} in the carotid and aortic bodies are activated by a decrease in PO2 or pH or by an increase in PCO2, Gas Exchange and Transport they trigger a reflex increase in ventilation. Under most normal circumstances, oxygen is not an important factor in modulating ventilation because arterial PO2 must fall to less than 60 mm Hg before ventilation is stimulated. This large decrease in PO2 is equivalent to ascending to an altitude of 3000 m. (For reference, Denver is located at an altitude of 1609 m). However, any condition that reduces plasma pH or increases PCO2 will activate the carotid and aortic glomus cells and increase ventilation. The details of glomus cell function remain to be worked out, but the basic mechanism by which these chemoreceptors respond to low oxygen is similar to the mechanism you learned for insulin release by pancreatic beta cells or taste transduction in taste buds. In all three examples, a stimulus inactivates K + channels, causing the receptor cell to depolarize ( Fig. 18.16). Depolarization opens voltage-gated Ca2 + channels, and Ca2 + entry GLOMUS CELLS The carotid body oxygen sensor releases neurotransmitter when PO decreases. 2 Blood vessel Low PO 2 1 Low PO 2 K+ channels close 2 3 Cell depolarizes Glomus cell in carotid body 5 Ca2+ enters 4 Voltage-gated Ca2+ channel opens 6 Exocytosis of neurotransmitters Receptor on sensory neuron Action potential 7 Signal to medullary centers to increase ventilation Fig. 18.16 causes exocytosis of neurotransmitter onto the sensory neuron. In the carotid and aortic bodies, neurotransmitters initiate action potentials in sensory neurons leading to the brain stem respiratory networks, signaling them to increase ventilation. Because the peripheral chemoreceptors respond only to dramatic changes in arterial PO2, arterial oxygen concentrations do not play a role in the everyday regulation of ventilation. However, unusual physiological conditions, such as ascending to high altitude, and pathological conditions, such as chronic obstructive pulmonary disease (COPD), can reduce arterial PO2 to levels that are low enough to activate the peripheral chemoreceptors. Central Chemoreceptors The most important chemical controller of ventilation is carbon dioxide, mediated both through the peripheral chemoreceptors just discussed and through central chemoreceptors located in the medulla ( Fig. 18.17). These receptors set the respiratory pace, providing continuous input into the control network. When arterial PCO2 increases, CO2 crosses the blood-brain barrier and activates the central chemoreceptors. These receptors signal the control network to increase the rate and depth of ventilation, thereby enhancing alveolar ventilation and removing CO2 from the blood. Although we say that the central chemoreceptors monitor CO2, they actually respond to pH changes in the cerebrospinal fluid (CSF). Carbon dioxide that diffuses across the blood-brain barrier into the CSF is converted to carbonic acid, which dissociates to bicarbonate and H + . Experiments indicate that the H + produced by this reaction is what initiates the chemoreceptor reflex, rather than the increased level of CO2. Note, however, that pH changes in the plasma do not usually influence the central chemoreceptors directly. Although plasma PCO2 enters the CSF readily, plasma H + crosses the blood-brain barrier very slowly and therefore has little direct effect on the central chemoreceptors. When plasma PCO2 increases, the chemoreceptors initially respond strongly by increasing ventilation. However, if PCO2 remains elevated for several days, ventilation falls back toward normal rates as the chemoreceptor response adapts by mechanisms that are not clear. Fortunately for people with chronic lung diseases, the response of peripheral chemoreceptor to low arterial PO2 remains intact over time, even though the central chemoreceptor response adapts to high PCO2. In some situations, low PO2 becomes the primary chemical stimulus for ventilation. For example, patients with severe chronic lung disease, such as COPD, have chronic hypercapnia and hypoxia. Their arterial PCO2 may rise to 50–55 mm Hg (normal is 35–45) while their PO2 falls to 45–50 mm Hg (normal 75–100). Because these levels are chronic, the chemoreceptor response adapts to the elevated PCO2. Most of the chemical stimulus for ventilation in this situation then comes from low PO2, sensed by the carotid and aortic chemoreceptors. If these patients are given too much oxygen, they may stop breathing because their chemical stimulus for ventilation is eliminated. 18 653 Gas Exchange and Transport CHEMORECEPTOR RESPONSE Carotid and aortic chemoreceptors monitor CO2, O2, and H+. Central chemoreceptors monitor CO2 in cerebrospinal fluid. Plasma PCO2 KEY CA = carbonic anhydrase – Cerebral capillary Blood-brain barrier 2 CO2 + H2O Cerebrospinal fluid CO2 H+ PCO CA H2CO3 H+ + (in plasma) HCO3– H+ + HCO3– Stimulates peripheral chemoreceptors in carotid and aortic bodies Plasma PO2 < 60 mm Hg Central chemoreceptor Medulla oblongata at brain Respiratory control centers – Sensory neurons Ventilation Plasma PO2 Plasma PCO Negative feedback 2 Fig. 18.17 The central chemoreceptors respond to decreases in arterial PCO2 as well as to increases. If alveolar PCO2 falls, as it might during hyperventilation, plasma PCO2 and cerebrospinal fluid PCO2 follow suit. As a result, central chemoreceptor activity declines, and the control network slows the ventilation rate. When ventilation decreases, carbon dioxide begins to accumulate in alveoli and the plasma. Eventually, the arterial PCO2 rises above the threshold level for the chemoreceptors. At that point, the receptors fire, and the control network again increases ventilation. Protective Reflexes Guard the Lungs In addition to the chemoreceptor reflexes that help regulate ventilation, the body has protective reflexes that respond to physical injury or irritation of the respiratory tract and to overinflation of the lungs. The major protective reflex is bronchoconstriction, mediated through parasympathetic neurons that innervate bronchiolar smooth muscle. Inhaled particles or noxious gases stimulate irritant receptors in the airway mucosa. 654 The irritant receptors send signals through sensory neurons to integrating centers in the CNS that trigger bronchoconstriction. Protective reflex responses also include coughing and sneezing. The Hering-Breuer inflation reflex was first described in the late 1800s in anesthetized dogs. In these animals, if tidal volume exceeded a certain volume, stretch receptors in the lung signaled the brain stem to terminate inspiration. However, this reflex is difficult to demonstrate in adult humans and does not operate during quiet breathing and mild exertion. Studies on human infants, however, suggest that the Hering-Breuer inflation reflex may play a role in limiting their ventilation volumes. Higher Brain Centers Affect Patterns of Ventilation Conscious and unconscious thought processes also affect respiratory activities. Higher centers in the hypothalamus and cerebrum can alter the activity of the brain stem control network Gas Exchange and Transport to change ventilation rate and depth. Voluntary control of ventilation falls into this category. Higher brain center control is not a requirement for ventilation, however. Even if the brain stem above the pons is severely damaged, essentially normal respiratory cycles continue. Respiration can also be affected by stimulation of portions of the limbic system. For this reason, emotional and autonomic activities such as fear and excitement may affect the pace and depth of respiration. In some of these situations, the neural pathway goes directly to the somatic motor neurons, bypassing the control network in the brain stem. Although we can temporarily alter our respiratory performance, we cannot override the chemoreceptor reflexes. Holding your breath is a good example. You can hold your breath voluntarily only until elevated PCO2 in the blood and cerebrospinal fluid activates the chemoreceptor reflex, forcing you to inhale. Small children having temper tantrums sometimes attempt to manipulate parents by threatening to hold their breath until they die. However, the chemoreceptor reflexes make it impossible for the children to carry out that threat. Extremely strongwilled children can continue holding their breath until they turn blue and pass out from hypoxia, but once they are unconscious, normal breathing automatically resumes. RUNNING PROBLEM The hyperventilation response to hypoxia creates a peculiar breathing pattern called periodic breathing, in which the person goes through a 10–15-second period of breathholding followed by a short period of hyperventilation. Periodic breathing occurs most often during sleep. Q8: Based on your understanding of how the body controls ventilation, why do you think periodic breathing occurs most often during sleep? Breathing is intimately linked to cardiovascular function. The integrating centers for both functions are located in the brain stem, and interneurons project between the two networks, allowing signaling back and forth. The cardiovascular, respiratory, and renal systems all work together to maintain fluid and acid-base homeostasis. 18 RUNNING PROBLEM CONCLUSION High Altitude On May 29, 1953, Edmund Hillary and Tenzing Norgay of the British Everest Expedition were the first humans to reach the summit of Mt. Everest. They carried supplemental oxygen with them, as it was believed that this feat was impossible without it. In 1978, however, Reinhold Messner and Peter Habeler achieved the “impossible.” On May 8, they struggled to the summit using sheer willpower and no extra oxygen. In Messner’s words, “I am nothing more than a single narrow gasping lung, floating over the mists and summits.” Learn more about these Everest expeditions by doing a Google search for Hillary Everest or Messner Everest. To learn more about different types of mountain sickness, see the International Society for Mountain Medicine (www.ismmed.org/np_altitude_tutorial.htm); “High altitude medicine,” Am Fam Physician 1998 Apr. 15 (www.aafp.org/ afp/980415ap/harris.html); and “High-altitude pulmonary edema” (www.emedicine.com/MED/topic1956.htm). In this running problem you learned about normal and abnormal responses to high altitude. Check your understanding of the physiology behind this respiratory challenge by comparing your answers with the information in the following table. Question Facts Integration and Analysis 1. What is the PO2 of inspired air reaching the alveoli when dry atmospheric pressure is 542 mm Hg? How does this value for PO2 compare with the PO2 value for fully humidified air at sea level? Water vapor contributes a partial pressure of 47 mm Hg to fully humidified air. Oxygen is 21% of dry air. Normal atmospheric pressure at sea level is 760 mm Hg. Correction for water vapor: 542 - 47 = 495 mm Hg * 21% PO2 = 104 mm Hg PO2. In humidified air at sea level, PO2 = 150 mm Hg. 2. Why would someone with HAPE be short of breath? Pulmonary edema increases the diffusion distance for oxygen. Slower oxygen diffusion means less oxygen reaching the blood, which worsens the normal hypoxia of altitude. 655 Gas Exchange and Transport R U N N I N G P R O B L E M CO N C LU S I O N (continued) Question Facts Integration and Analysis 3. Based on mechanisms for matching ventilation and perfusion in the lung, why do patients with HAPE have elevated pulmonary arterial blood pressure? Low oxygen levels constrict pulmonary arterioles. Constriction of pulmonary arterioles causes blood to collect in the pulmonary arteries behind the constriction. This increases pulmonary arterial blood pressure. 4. How does adding erythrocytes to the blood help a person acclimatize to high altitude? 98% of arterial oxygen is carried bound to hemoglobin. Additional hemoglobin increases the oxygen-carrying capacity of the blood. 5. What does adding erythrocytes to the blood do to the viscosity of the blood? What effect will that change in viscosity have on blood flow? Adding cells increases blood viscosity. According to Poiseuille’s law, increased viscosity increases resistance to flow, so blood flow will decrease. 6. What happens to plasma pH during hyperventilation? Apply the law of mass action to the equation CO2 + H2O m H + + HCO3- . The amount of CO2 in the plasma decreases during hyperventilation, which means the equation shifts to the left. This shift decreases H+, which increases pH (alkalosis). 7. How does this change in pH affect oxygen binding at the lungs when PO2 is decreased? How does it affect unloading of oxygen at the cells? See Figure 18.9c. The left shift of the curve means that, at any given PO2, more O2 binds to hemoglobin. Less O2 will unbind at the tissues for a given PO2, but PO2 in the cells is probably lower than normal, and consequently there may be no change in unloading. 8. Why do you think periodic breathing occurs most often during sleep? Periodic breathing alternates periods of breath-holding (apnea) and hyperventilation. An awake person is more likely to make a conscious effort to breathe during the breath-holding spells, eliminating the cycle of periodic breathing. Test your understanding with: • Practice Tests • Running Problem Quizzes • A&PFlixTM Animations • PhysioExTM Lab Simulations • Interactive Physiology Animations www.masteringaandp.com Chapter Summary In this chapter, you learned why climbing Mt. Everest is such a respiratory challenge for the human body, and why people with emphysema experience the same respiratory challenges at sea level. The exchange and transport of oxygen and carbon dioxide in the body illustrate the mass flow of gases along concentration gradients. Homeostasis of these 656 blood gases demonstrates mass balance: the concentration in the blood varies according to what enters or leaves at the lungs and tissues. The law of mass action governs the chemical reactions through which hemoglobin binds O2, and carbonic anhydrase catalyzes the conversion of CO2 and water to carbonic acid. Gas Exchange and Transport Gas Exchange in the Lungs and Tissues Respiratory: Gas Exchange 1. Normal alveolar and arterial PO2 is about 100 mm Hg. Normal alveolar and arterial PCO2 is about 40 mm Hg. Normal venous PO2 is 40 mm Hg, and normal venous PCO2 is 46 mm Hg. (Fig. 18.2) 2. Body sensors monitor blood oxygen, CO2, and pH in an effort to avoid hypoxia and hypercapnia. 3. Both the composition of inspired air and the effectiveness of alveolar ventilation affect alveolar PO2. 4. Changes in alveolar surface area, in diffusion barrier thickness, and in fluid distance between the alveoli and pulmonary capillaries can all affect gas exchange efficiency and arterial PO2 . (Fig. 18.3) 5. The amount of a gas that dissolves in a liquid is proportional to the partial pressure of the gas and to the solubility of the gas in the liquid. Carbon dioxide is 20 times more soluble in aqueous solutions than oxygen is. (Fig. 18.4) Gas Transport in the Blood Respiratory: Gas Transport 6. Gas transport demonstrates mass flow and mass balance. The Fick equation relates blood oxygen content, cardiac output, and tissue oxygen consumption. (Fig. 18.6) 7. Oxygen is transported dissolved in plasma (62%) and bound to hemoglobin (798%). (Fig. 18.5) 8. The PO2 of plasma determines how much oxygen binds to hemoglobin. (Fig. 18.8) 9. Oxygen-hemoglobin binding is influenced by pH, temperature, and 2,3-diphosphoglycerate (2,3-DPG). (Fig. 18.9) 10. Venous blood carries 7% of its carbon dioxide dissolved in plasma, 23% as carbaminohemoglobin, and 70% as bicarbonate ion in the plasma. (Fig. 18.11) 11. Carbonic anhydrase in red blood cells converts CO2 to carbonic acid, which dissociates into H + and HCO3- . The H + then binds to hemoglobin, and HCO3- enters the plasma using the chloride shift. Regulation of Ventilation Respiratory: Control of Respiration 12. Respiratory control resides in networks of neurons in the medulla and pons, influenced by input from central and peripheral sensory receptors and higher brain centers. (Fig. 18.13) 13. The medullary dorsal respiratory group (DRG) contains mostly inspiratory neurons that control somatic motor neurons to the diaphragm. The ventral respiratory group (VRG) includes the preBötzinger complex with its apparent pacemakers as well as neurons for inspiration and active expiration. (Fig. 18.14) 14. Peripheral chemoreceptors in the carotid and aortic bodies monitor PO2, PCO2, and pH. PO2 below 60 mm Hg triggers an increase in ventilation.(Fig. 18.17) 15. Carbon dioxide is the primary stimulus for changes in ventilation. Chemoreceptors in the medulla and carotid bodies respond to changes in PCO2.(Fig. 18.17) 16. Protective reflexes monitored by peripheral receptors prevent injury to the lungs from inhaled irritants. 17. Conscious and unconscious thought processes can affect respiratory activity. 18 Questions Level One Reviewing Facts and Terms 1. List five factors that influence the diffusion of gases between alveolus and blood. 2. More than % of the oxygen in arterial blood is transported bound to hemoglobin. How is the remaining oxygen transported to the cells? 3. Name four factors that influence the amount of oxygen that binds to hemoglobin. Which of these four factors is the most important? 4. Describe the structure of a hemoglobin molecule. What chemical element is essential for hemoglobin synthesis? 5. The networks for control of ventilation are found in the and of the brain. What do the dorsal and ventral respiratory groups of neurons control? What is a central pattern generator? 6. Describe the chemoreceptors that influence ventilation. What chemical is the most important controller of ventilation? 7. Describe the protective reflexes of the respiratory system. 8. What causes the exchange of oxygen and carbon dioxide between alveoli and blood or between blood and cells? 9. List five possible physical changes that could result in less oxygen reaching the arterial blood. Level Two Reviewing Concepts 10. Concept map: Construct a map of gas transport using the following terms. You may add other terms. • • • • • • • • alveoli arterial blood carbaminohemoglobin carbonic anhydrase chloride shift dissolved CO2 dissolved O2 hemoglobin • • • • • • • • hemoglobin saturation oxyhemoglobin PCO2 plasma PO2 pressure gradient red blood cell venous blood 11. In respiratory physiology, it is customary to talk of the PO2 of the plasma. Why is this not the most accurate way to describe the oxygen content of blood? 12. Compare and contrast the following pairs of concepts: (a) transport of O2 and CO2 in arterial blood (b) partial pressure and concentration of a gas dissolved in a liquid 13. Does HbO2 binding increase, decrease, or not change with decreased pH? 14. Define hypoxia, COPD, and hypercapnia. 15. Why did oxygen-transporting molecules evolve in animals? 16. Draw and label the following graphs: (a) the effect of ventilation on arterial PO2 (b) the effect of arterial PCO2 on ventilation 17. As the PO2 of plasma increases: (a) what happens to the amount of oxygen that dissolves in plasma? (b) what happens to the amount of oxygen that binds to hemoglobin? 657 Gas Exchange and Transport Level Three Problem Solving 20. Marco tries to hide at the bottom of a swimming hole by breathing in and out through two feet of garden hose, which greatly increases his anatomic dead space. What happens to the following parameters in his arterial blood, and why? (a) PCO2 (c) bicarbonate ion (b) PO2 (d) pH 21. Which person carries more oxygen in his blood? (a) one with Hb of 15 g >dL and arterial PO2 of 80 mm Hg (b) one with Hb of 12 g >dL and arterial PO2 of 100 mm Hg 22. What would happen to each of the following parameters in a person suffering from pulmonary edema? (a) arterial PO2 (b) arterial hemoglobin saturation (c) alveolar ventilation 23. In early research on the control of rhythmic breathing, scientists made the following observations. What hypotheses might the researchers have formulated from each observation? (a) Observation. If the brain stem is severed below the medulla, all respiratory movement ceases. (b) Observation. If the brain stem is severed above the level of the pons, ventilation is normal. (c) Observation. If the medulla is completely separated from the pons and higher brain centers, ventilation becomes irregular but a pattern of inspiration/expiration remains. 24. A hospitalized patient with severe chronic obstructive lung disease has a PCO2 of 55 mm Hg and a PO2 of 50 mm Hg. To elevate his blood oxygen, he is given pure oxygen through a nasal tube. The patient immediately stops breathing. Explain why this might occur. 25. You are a physiologist on a space flight to a distant planet. You find intelligent humanoid creatures inhabiting the planet, and they willingly submit to your tests. Some of the data you have collected are described below. 100 Pigment saturation, % 90 80 70 60 50 40 30 20 10 20 40 60 80 PO2 (mm Hg) 100 The graph above shows the oxygen saturation curve for the oxygen-carrying molecule in the blood of the humanoid named Bzork. 658 Bzork’s normal alveolar PO2 is 85 mm Hg. His normal cell PO2 is 20 mm Hg, but it drops to 10 mm Hg with exercise. (a) What is the percent saturation for Bzork’s oxygen-carrying molecule in blood at the alveoli? In blood at an exercising cell? (b) Based on the graph above, what conclusions can you draw about Bzork’s oxygen requirements during normal activity and during exercise? 26. The next experiment on Bzork involves his ventilatory response to different conditions. The data from that experiment are graphed below. Interpret the results of experiments A and C. PO2 = 50 mm Hg PO = 85 mm Hg 2 Alveolar ventilation 18. If a person is anemic and has a lower-than-normal level of hemoglobin in her red blood cells, what is her arterial PO2 compared to normal? 19. Create reflex pathways (stimulus, receptor, afferent path, and so on) for the chemical control of ventilation, starting with the following stimuli: (a) Increased arterial PCO2 (b) Arterial PO2 = 55 mm Hg Be as specific as possible regarding anatomical locations. Where known, include neurotransmitters and their receptors. A B PO2 = 85 mm Hg C Subject drank seven beers Plasma PCO2 27. The alveolar epithelium is an absorptive epithelium and is able to transport ions from the fluid lining of alveoli into the interstitial space, creating an osmotic gradient for water to follow. Draw an alveolar epithelium and label apical and basolateral surfaces, the airspace, and interstitial fluid. Arrange the following proteins on the cell membrane so that the epithelium absorbs sodium and water: aquaporins, Na + -K + -ATPase, epithelial Na + channel (ENaC). (Remember: Na + concentrations are higher in the ECF than in the ICF.) Level Four Quantitative Problems 28. You are given the following information on a patient. Blood volume = 5.2 liters Hematocrit = 47% Hemoglobin concentration = 12 g>dL whole blood Total amount of oxygen carried in blood = 1015 mL Arterial plasma PO2 = 100 mm Hg You know that when plasma PO2 is 100 mm Hg, plasma contains 0.3 mL O2 >dL, and that hemoglobin is 98% saturated. Each hemoglobin molecule can bind to a maximum of four molecules of oxygen. Using this information, calculate the maximum oxygencarrying capacity of hemoglobin (100% saturated). Units will be mL O2/g Hb. 29. Adolph Fick, the nineteenth-century physiologist who derived Fick’s law of diffusion, also developed the Fick equation that relates oxygen consumption, cardiac output, and blood oxygen content: O2 consumption = cardiac output : (arterial oxygen content - venous oxgen content) A person has a cardiac output of 4.5 L >min, an arterial oxygen content of 105 mL O2 >L blood, and a vena cava oxygen content of 50 mL O2 >L blood. What is this person’s oxygen consumption? 30. Describe what happens to the oxygen-hemoglobin saturation curve in Figure 18.9a when blood hemoglobin falls from 15 g >dL blood to 10 g>dL blood. Gas Exchange and Transport Answers Answers to Concept Check Questions 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. (a) electron transport system (b) citric acid cycle The PO2 of the alveoli is constantly being replenished by fresh air. 720 mm Hg * 0.78 N2 = 561.6 mm Hg Air is 21% oxygen. Therefore, for dry air on Everest, PO2 = 0.21 * 250 mm Hg = 53 mm Hg. Correction for PH2O : PO2 = (250 mm Hg 47 mm Hg) * 21 = (203 mm Hg) * 0.21 = 43 mm Hg. Blood pools in the lungs because the left heart is unable to pump all the blood coming into it from the lungs. Increased blood volume in the lungs increases pulmonary blood pressure. When alveolar ventilation increases, arterial PO2 increases because more fresh air enters the alveoli. Arterial PCO2 decreases because the low PCO2 of fresh air dilutes alveolar PCO2. The CO2 pressure gradient between venous blood and the alveoli increases, causing more CO2 to leave the blood. Venous PO2 and PCO2 do not change because these pressures are determined by oxygen consumption and CO2 production in the cells. False. Plasma is essentially water, and Figure 18.4 shows that CO2 is more soluble in water than O2. The other factor that affects how much of each gas dissolves in the saline solution is the solubility of the gas in that solution. Yes. Hemoglobin reaches 100% saturation at 650 mm Hg. At sea level, atmospheric pressure is 760 mm Hg, and if the “atmosphere” is 100% oxygen, then PO2 is 760 mm Hg. The flatness at the top of the PO2 curve tells you that hyperventilation causes only a minimal increase in percent saturation of arterial Hb. 11. As the PO2 falls, more oxygen is released. The PO2 of venous blood leaving the muscle is 25 mm Hg, same as the PO2 of the muscle. 12. An airway obstruction would decrease alveolar ventilation and increase arterial PCO2. Elevated arterial PCO2 would increase the H + concentration in the arterial blood and decrease pH. Answers to Figure and Graph Questions Figure 18.4: Oxygen is 2.85 mL >L blood and CO2 is 28 mL>L blood. Figure 18.5: O2 crosses five cell membranes: two of the alveolar cell, two of the capillary endothelium, and one of the red blood cell. Figure 18.9: 1. (a) When PO2 is 20 mm Hg, Hb saturation is 34%. (b) Hemoglobin is 50% saturated with oxygen at a PO2 of 28 mm Hg. 2. When pH falls from 7.4 to 7.2, Hb saturation decreases by 13%, from about 37% saturation to 24%. 3. When an exercising muscle cell warms up, Hb releases more oxygen. 4. Loss of 2,3-DPG is not good because then hemoglobin binds more tightly to oxygen at the PO2 values found in cells. 5. The PO2 of placental blood is about 28 mm Hg. 6. At a PO2 of 10 mm Hg, maternal blood is only about 8% saturated with oxygen. Figure 18.13: 1. pons; 2. ventral respiratory group; 3. medullary chemoreceptor; 4. sensory neuron; 5. carotid chemoreceptor; 6. somatic motor neuron (expiration); 7. aortic chemoreceptor; 8. internal intercostals; 9. abdominal muscles; 10. diaphragm; 11. external intercostals; 12. scalenes and sternocleidomastoids; 13. somatic motor neuron (inspiration); 14. dorsal respiratory group; 15. limbic system; 16. higher brain centers (emotions and voluntary control) Figure 18.15: One breath takes 5 seconds, so there are 12 breaths>min. 18 Answers to Review Questions Level One Reviewing Facts and Terms 1. Pressure gradients, solubility in water, alveolar capillary perfusion, blood pH, temperature. 2. 98%. Remainder is dissolved in plasma. 3. PO2, temperature, pH, and the amount of hemoglobin available for binding (most important). 4. Four globular protein chains, each wrapped around a central heme group with iron. 5. Medulla and pons. Dorsal—neurons for inspiration; ventral—neurons for inspiration and active expiration. Central pattern generator—group of neurons that interact spontaneously to control rhythmic contraction of certain muscle groups. 6. Medullary chemoreceptors increase ventilation when PCO2 increases. Carotid and aortic chemoreceptors respond to PCO2, pH, and PO2 6 60 mm Hg. PCO2 is most important. 7. They include irritant-mediated bronchoconstriction and the cough reflex. 8. Partial pressure gradients 9. Decreased atmospheric PO2, decreased alveolar perfusion, loss of hemoglobin, increased thickness of respiratory membrane, decreased respiratory surface area, increased diffusion distance. Level Two Reviewing Concepts 10. Start with Figure 18.10. 11. Most oxygen is bound to hemoglobin, not dissolved in the plasma. 12. (a) Most O2 is transported bound to hemoglobin, but most CO2 is converted to bicarbonate. (b) Concentration is amount of gas per volume of solution, measured in units such as moles per liter. While solution partial pressure and concentration are proportional, concentration is affected by the gas solubility, and therefore is not the same as partial pressure. 13. decrease 14. Hypoxia—low oxygen inside cells. COPD—chronic obstructive pulmonary disease (includes chronic bronchitis and emphysema). Hypercapnia— elevated CO2. 15. Oxygen is not very soluble in water, and the metabolic requirement for oxygen in most multicellular animals would not be met without an oxygentransport molecule. 16. (a) x-axis—ventilation in L>min; y-axis—arterial PO2, in mm Hg. See Figure 18.9. (b) x-axis—arterial PCO2 in mm Hg; y-axis—ventilation in L>min. As arterial PCO2 increases, ventilation increases. There is a maximum ventilation rate, and the slope of the curve decreases as it approaches this maximum. 17. (a) increases (b) increases 659 Gas Exchange and Transport 18. Normal, because PO2 depends on the PO2 of the alveoli, not on how much Hb is available for oxygen transport. 19. (a) See Figure 18.17. (b) See Figure 18.13. Level Three Problem Solving 20. Increased dead space decreases alveolar ventilation. (a) increases (b) decreases (c) increases (d) decreases 21. Person (a) has slightly reduced dissolved O2 but at PO2 = 80, Hb saturation is still about 95%. If oxygen content is 197 mL O2>L at PO2 = 100 and 98% saturation, then oxygen content at PO2 = 80 mm Hg and 95% saturation is 190 mL O2>L blood 1197 * 10.95/0.9822, with Hb constant. Person (b) has reduced hemoglobin of 12 g>dL, but it is still 98% saturated. So, oxygen content would be 157.6 mL O2>L blood 1197 * 112/1522. The increased PO2 did not compensate for the decreased hemoglobin content. 22. (a) decrease (b) decrease (c) decrease 23. (a) Respiratory movements originate above the level of the cut, which could include any area of the brain. (b) Ventilation depends upon signals from the medulla and/or pons. (c) Respiratory rhythm is controlled by the medulla alone, but other important aspects of respiration depend upon signals originating in the pons or higher. 24. With chronic elevated PCO2, the chemoreceptor response adapts, and CO2 is no longer a chemical drive for ventilation. The primary chemical signal for ventila- tion becomes low oxygen (below 60 mm Hg). Thus, when the patient is given O2, there is no chemical drive for ventilation, and the patient stops breathing. 25. (a) Alveoli—96%; exercising cell—23% (b) At rest Bzork only uses about 20% of the oxygen that his hemoglobin can carry. With exercise, his oxygen consumption increases, and his hemoglobin releases more than 3>4 of the oxygen it can carry. 26. All three lines show that as PCO2 increases, ventilation increases. Line A shows that a decrease in PCO2 potentiates this increase in ventilation (when compared to line B). Line C shows that ingestion of alcohol lessens the effect of increasing PCO2 on ventilation. Because alcohol is a CNS-depressant, we can hypothesize that the pathway that links increased PCO2 and increased ventilation is integrated in the CNS. 27. Apical—faces airspace; basolateral—faces interstitial fluid. Apical side has ENaC and aquaporins; basolateral side has aquaporins and Na+-K+-ATPase. Na+ enters the cell through ENaC, then is pumped out the basolateral side. (Cl- follows to maintain electrical neutrality.) Translocation of NaCl allows water to follow by osmosis. Level Four Quantitative Problems 28. 1.65 mL O2>gm Hb 29. 247.5 mL O2>min 30. Nothing. The percent saturation of Hb is unchanged at any given PO2. However, with less Hb available, less oxygen will be transported. Photo Credits CO: Jorge Bernardino de la Serna, MEMPHYS-Center for Biomembrane Physics, University of Southern Denmark 660 Biotechnology: Photomick/iStockphoto.com.