Human Physiology an Integrated Approach

Home , Chloride shift, Control of ventilation, Death zone, Hemoglobin

and Transport

Gas Exchange in the Lungs and Tissues 18 Lower Alveolar P Decreases Oxygen Uptake O2 Diff usion Problems Cause Hypoxia Gas Solubility Aff ects Diff usion Gas Transport in the Blood Hemoglobin Binds to Oxygen Oxygen Binding Obeys the Law of Mass Action Hemoglobin Transports Most Oxygen to the Tissues P Determines Oxygen-Hb Binding O2 Oxygen Binding Is Expressed As a Percentage Several Factors Aff ect Oxygen-Hb Binding Carbon Dioxide Is Transported in Three Ways Regulation of Ventilation Neurons in the Medulla Control Breathing Carbon Dioxide, Oxygen, and pH Infl uence Ventilation Protective Refl exes Guard the Lungs Higher Brain Centers Aff ect 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 buff ers Law of mass action Cerebrospinal fl uid Simple diff usion Autonomic and somatic motor neurons Structure of the brain stem Red blood cells and Giant liposomes hemoglobin of pulmonary Blood-brain barrier surfactant (40X)

633 Gas Exchange and Transport

he book Into Thin Air by Jon Krakauer chronicles an ill- RUNNING PROBLEM fated trek to the top of Mt. Everest. To reach the summit of TMt. Everest, climbers must pass through the “death zone” High Altitude located at about 8000 meters (over 26,000 ft ). Of the thousands of people who have attempted the summit, only about 2000 have been In 1981 a group of 20 physiologists, physicians, and successful, and more than 185 have died. What are the physiologi- climbers, supported by 42 Sherpa assistants, formed the American Medical Research Expedition to Mt. Everest. The cal challenges of climbing Mt. Everest (8850 m or 29,035 ft ), and purpose of the expedition was to study human physiology why did it take so many years before humans successfully reached at extreme altitudes, starting with the base camp at 5400 m the top? Th e lack of oxygen at high altitude is part of the answer. (18,000 ft) and continuing on to the summit at 8850 m (over Th e mechanics of breathing includes the events that cre- 29,000 ft). From the work of these scientists and others, we ate bulk fl ow of air into and out of the lungs. In this chapter we now have a good picture of the physiology of high-altitude focus on the two gases most signifi cant to human physiology, acclimatization. oxygen and carbon dioxide, and look at how they move between alveolar air spaces and the cells of the body. Th e process can be divided into two components: the exchange of gases between compartments, which requires diff usion across cell membranes, elevated concentrations of carbon dioxide. These two condi- and the transport of gases in the blood. Figure 18.1 presents tions are clinical signs, not diseases, and clinicians must gather an overview of the topics that we cover in this chapter. additional information to pinpoint their cause. Table 18.1 If the diff usion of gases between alveoli and blood is sig- lists several types of hypoxia and some typical causes. nifi cantly impaired, or if oxygen transport in the blood is inad- To avoid hypoxia and hypercapnia, the body uses sensors equate, hypoxia (a state of too little oxygen) results. Hypoxia that monitor arterial blood composition. Th ese sensors respond frequently (but not always!) goes hand in hand with hypercapnia , to three regulated variables: 1 Oxygen. Arterial oxygen delivery to the cells must be adequate to support aerobic respiration and ATP production. PULMONARY GAS EXCHANGE AND TRANSPORT 2 Carbon dioxide ( C O 2) is produced as a waste product during the citric acid cycle. Excretion of CO 2 by the lungs is CO2 O2 important for two reasons: high levels of CO2 are a central nervous system depressant, and elevated CO c a u s e s a Airways 2 state of acidosis (low pH) through the following reaction: + Δ Δ + + - Alveoli of lungs C O 2 H2O H2CO3 H HCO3 . 3 pH. Maintaining pH homeostasis is critical to prevent de- CO2 O2 naturation of proteins. The respiratory system monitors 6 CO 2 enters alveoli 1 Oxygen enters the at alveolar-capillary blood at alveolar- plasma pH and uses changes in ventilation to alter pH. interface. CO2 O2 capillary interface. Th is process is discussed later along with renal contribu- Pulmonary tions to pH homeostasis. circulation 2 Oxygen is transported in blood Th e normal values for these three parameters are given in dissolved in plasma Table 18.2 . In this chapter we will consider the mechanisms or bound to hemoglobin inside by which oxygen and CO2 move from the lungs to the cells and 5 CO2 is trans- RBCs. back again. ported dissolved, bound to hemoglobin, or – Systemic as HCO3 . CO2 circulation O2 Gas Exchange in the Lungs and Tissues 4 CO2 diffuses 3 Oxygen diffuses out of cells. into cells. Breathing is the bulk fl ow of air into and out of the lungs. Once CO O air reaches the alveoli, individual gases such as oxygen and CO Cells 2 2 2 Cellular diff use from the alveolar air space into the blood. Recall that dif- respiration fusion is movement of a molecule from a region of higher con- ATP determines Nutrients centration to one of lower concentration. metabolic CO2 production.

Fig. 18.1

634 Gas Exchange and Transport

Table Classifi cation of Hypoxias 18.1

Type Defi nition Typical Causes

Hypoxic hypoxia Low arterial P High altitude; alveolar hypoventilation; O2 decreased lung diffusion capacity; abnormal ventilation-perfusion ratio

Anemic hypoxia Decreased total amount of O2 bound to Blood loss; anemia (low [Hb] or altered hemoglobin H b O 2 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 Cyanide and other metabolic poisons have been poisoned

cells has a P of 100 mm Hg. Because P is lower in the cells, O2 O2 18 Table oxygen diff uses down its partial pressure gradient from plasma 18.2 Normal Blood Values in Pulmonary Medicine into cells. Once again, diff usion goes to equilibrium. As a result,

venous blood has the same PO2 as the cells it just passed.

Arterial Venous Conversely, PCO2 is higher in tissues than in systemic capillary blood because of CO2 production during metabolism P 95 mm Hg 40 mm Hg O2 ( Fig. 18.2 ). Cellular PCO2 in a person at rest is about 46 mm Hg, (85–100) compared to an arterial plasma PCO2 of 40 mm Hg. Th e gradient causes CO t o d i ff use out of cells into the capillaries. Diff usion P 40 mm Hg 46 mm Hg 2 CO2 goes to equilibrium, and systemic venous blood averages a P (35–45) CO2 of 46 mm Hg. pH 7.4 (7.38–7.42) 7.37 At the pulmonary capillaries, the process reverses.

Venous blood bringing waste CO2 from the cells has a PCO2 o f

46 mm Hg. Alveolar PCO2 is 40 mm Hg. Because PCO2 i s h i g h e r When we think of concentrations of solutions, units such in the plasma, CO2 moves from the capillaries into the alveoli. as moles/liter and milliosmoles/liter come to mind. However, By the time blood leaves the alveoli, it has a P CO2 of 40 mm Hg, respiratory physiologists commonly express plasma gas con- identical to the PCO2 of the alveoli. centrations in partial pressures to establish whether there is a In the sections that follow we will consider some of the concentration gradient between the alveoli and the blood. Gases other factors that aff ect the transfer of gases between the alveoli move from regions of higher partial pressure to regions of lower and the body’s cells. partial pressure. Figure 18.2 shows the partial pressures of oxygen and

CO2 in air, the alveoli, and inside the body. Normal alveolar PO2 Concept Check Answers: End of Chapter at sea level is about 100 mm Hg. Th e PO2 o f “ d e o x y g e n a t e d ” v e - nous blood arriving at the lungs is 40 mm Hg. Oxygen therefore 1. Cellular metabolism review: which of the following three metabolic pathways—glycolysis, the citric acid cycle, and the electron transport diff uses down its partial pressure (concentration) gradient from system—is directly associated with (a) O consumption and with the alveoli into the capillaries. Diff usion goes to equilibrium, 2 (b) CO 2 production? and the PO2 of arterial blood leaving the lungs is the same as in the alveoli: 100 mm Hg. 2. Why doesn’t the movement of oxygen from the alveoli to the plasma decrease the P of the alveoli? When arterial blood reaches tissue capillaries, the gradient O2 is reversed. Cells are continuously using oxygen for oxida- 3. If nitrogen is 78% of atmospheric air, what is the partial pressure of this tive phosphorylation. In the cells of a person at rest, intra- gas when the dry atmospheric pressure is 720 mm Hg? cellular PO2 averages 40 mm Hg. Arterial blood arriving at the

635 Gas Exchange and Transport

GASES DIFFUSE DOWN CONCENTRATION GRADIENTS RUNNING PROBLEM

Dry air = 760 mm Hg Hypoxia is the primary problem that people experience when ascending to high altitude. High altitude is considered PO = 160 mm Hg 2 anything above 1500 m (5000 ft), but most pathological PCO = 0.25 mm Hg 2 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.

Alveoli Q1: If water vapor contributes 47 mm Hg to the pressure of fully humidifi ed air, what is the P of inspired air P = 100 mm Hg O2 O2 reaching the alveoli at 2500 m, where dry atmospheric P = 40 mm Hg CO2 pressure is 542 mm Hg? How does this value for P O2 compare with that of fully humidifi ed air at sea level? O CO2 2

Pulmonary circulation Composition of the Inspired Air Th e fi rst requirement for adequate oxygen delivery to the tissues is adequate oxygen intake Venous blood Arterial blood from the atmosphere. Th e main factor that aff ects atmospheric P ≤ 40 mm Hg P = 100 mm Hg oxygen content is altitude. Th e partial pressure of oxygen in air O2 O2 P ≥ 46 mm Hg P = 40 mm Hg CO2 CO2 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 at-

mospheric pressure of about 628 mm Hg. Th e PO2 of dry air in Denver is 132 mm Hg, down from 160 mm Hg at sea level. For

Systemic fully humidifi ed atmospheric air reaching the alveoli, the PO2 i s circulation even lower: P 628 mm Hg - P 47 mm Hg) = 581 mm Hg * atm H2O 21% = PO of 122 mm Hg, down from 150 mm Hg at sea level. O 2 CO2 2 Notice that water vapor pressure is the same no matter what the Cells altitude, making its contribution to total pressure in the lungs

P ≤ 40 mm Hg more important as you go higher. O2 P ≥ 46 mm Hg CO2 Alveolar Ventilation Unless a person is traveling, altitude re- Aerobic metabolism consumes mains constant. If the composition of inspired air is normal but O2 and produces CO2. alveolar PO2 is low, then the problem must lie with alveolar ven- Fig. 18.2 tilation. 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 Lower Alveolar P Decreases Oxygen Uptake alveolar hypoventilation (Fig. 18.3 c) include decreased lung O2 compliance, increased airway resistance, or CNS depression that Many variables influence the efficiency of alveolar gas ex- slows ventilation rate and decreases depth. Common causes of change and determine whether arterial blood gases are normal CNS depression in young people include alcohol poisoning and ( Fig. 18.3 a). First, adequate oxygen must reach the alveoli. drug overdoses.

A decrease in alveolar PO2 means that less oxygen is available to enter the blood. Th ere can also be problems with the transfer Concept Check Answers: End of Chapter of gases between the alveoli and pulmonary capillaries. Finally, blood flow, or perfusion, of the alveoli must be adequate. If 4. At the summit of Mt. Everest, an altitude of 8850 m, atmospheric pressure is only 250 mm Hg. What is the P of dry atmospheric air atop Everest? If something impairs blood fl ow to the lung, then the body is un- O2 water vapor added to inhaled air at the summit has a partial pressure of able to acquire the oxygen it needs. Let’s look in more detail at 47 mm Hg, what is the P of the inhaled air when it reaches the alveoli? these factors. O2

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 Gas Exchange and Transport GAS EXCHANGE IN THE ALVEOLI

(a) Alveolar gas exchange Alveolar Gas Exchange

is influenced by

O2 reaching the aveoli

Gas diffusion Adequate Composition of Alveolar between alveoli perfusion inspired air ventilation and blood of alveoli

Rate and Surface Diffusion Airway Lung depth of area distance resistance compliance breathing

Barrier Amount of thickness fluid

(b) Cells form a diffusion barrier between lung and blood. 18

Surfactant Alveolar O2 CO2 Alveolar air space Alveoli epithelium Fused basement 0.1–1.5 μm membranes Nucleus of endothelial O CO Capillary cell 2 2

Plasma Capillary lumen RBC

Diffusion ∝ surface area × barrier permeability/distance2

Normal lung Emphysema Fibrotic lung disease Pulmonary edema Asthma

Destruction of alveoli Thickened alveolar membrane Fluid in interstitial space increases Increased airway resistance means less surface slows gas exchange. Loss diffusion distance. Arterial P decreases alveolar CO2 area for gas exchange. of lung compliance may may be normal due to higher ventilation. decrease alveolar ventilation. CO2 solubility in water. Bronchioles constricted P Exchange P PO O2 P P O2 2 O2 surface O2 normal normal normal normal normal low or low or low

Increased diffusion P normal PO low PO low P low O2 2 2 distance O2 P low O2 Fig. 18.3

637 Gas Exchange and Transport

D i ff usion Problems Cause Hypoxia BIOTECHNOLOGY If hypoxia is not caused by hypoventilation, then the problem usually lies with some aspect of gas exchange between alveoli The Pulse Oximeter

and blood. In these situations, alveolar PO2 may be normal, but the P of arterial blood leaving the lungs is low. Th e transfer of One important clinical indicator of the eff ectiveness of O2 gas exchange in the lungs is the concentration of oxygen in oxygen from alveoli to blood requires diff usion across the bar- arterial blood. Obtaining an arterial blood sample is diffi cult rier created by type I alveolar cells and the capillary endothe- for the clinician and painful for the patient because it means lium ( Fig. 18.3 b). fi nding an accessible artery. (Most blood is drawn from Th e exchange of oxygen and carbon dioxide across this dif- superfi cial veins rather than from arteries, which lie deeper fusion barrier obeys the same rules as simple diff usion across within the body). Over the years, however, scientists have a membrane. Th e diff usion rate is directly proportional to the developed instruments that quickly and painlessly measure available surface area, the concentration gradient of the gas, and blood oxygen levels through the surface of the skin on a the permeability of the barrier: fi nger or earlobe. One such instrument, the pulse oximeter , clips onto the skin and in seconds gives a digital reading of D i ff usion rate r arterial hemoglobin saturation. The oximeter works by mea- surface area : concentration gradient : barrier permeability suring light absorbance of the tissue at two wavelengths. Another instrument, the transcutaneous oxygen sensor , From the general rules for diff usion, we can add a fourth fac- measures dissolved oxygen using a variant of traditional gas- tor: diff usion distance. Diff usion is inversely proportional to the measuring electrodes. Both methods have limitations but are square of the distance or, in simpler terms—diff usion is most popular because they provide a rapid, noninvasive means of rapid over short distances estimating arterial oxygen content.

D i ff usion rate r 1 distance2 > Under most circumstances, diffusion distance, surface area, and barrier permeability in the body are constants and are maximized to facilitate diff usion. Gas exchange in the lungs is rapid, blood flow through pulmonary capillaries is slow, and diff usion reaches equilibrium in less than 1 second. Th is leaves the concentration gradient between alveoli and blood as the primary factor aff ecting gas exchange in healthy people. Th e factors of surface area, diff usion distance, and mem-

brane permeability do come into play with various diseases. Pathological changes that adversely aff ect 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 alveolar- capillary exchange barrier, and (3) an increase in the diff usion distance between the alveolar air space and the blood. tissue thickens the alveolar wall (Fig. 18.3 c). Diff usion of gases through this scar tissue is much slower than normal. However, Surface Area Physical loss of alveolar surface area can have because the lungs have a built-in reserve capacity, one-third of devastating eff ects in emphysema , a degenerative lung disease the exchange epithelium must be incapacitated before arterial

most oft en caused by cigarette smoking ( Fig. 18.3 c). Th e irri- PO2 falls signifi cantly. tating eff ect of smoke chemicals and tar in the alveoli activates alveolar macrophages that release elastase and other proteo- Diffusion Distance Normally the pulmonary diffusion dis- lytic enzymes. Th ese enzymes destroy the elastic fi bers of the tance is small because the alveolar and endothelial cells are thin lung and induce apoptosis of cells, breaking down the walls of and there is little or no interstitial fl uid between the two cell lay- the alveoli. The result is a high-compliance/low-elastic recoil ers (Fig. 18.3 b). However, in certain pathological states, excess lung with fewer and larger alveoli and less surface area for gas fl uid increases the diff usion distance between the alveolar air exchange. space and the blood. Fluid accumulation may occur inside the alveoli or in the interstitial compartment between the alveolar Diff usion Barrier Permeability Pathological changes in the epithelium and the capillary. alveolar-capillary diff usion barrier may alter its properties and In pulmonary edema, accumulation of interstitial fl uid in- slow gas exchange. For example, in fi brotic lung diseases, scar creases the diff usion distance and slows gas exchange (Fig. 18.3 c).

638 Gas Exchange and Transport

Normally, only small amounts of interstitial fl uid are present in RUNNING PROBLEM the lungs, the result of low pulmonary blood pressure and effective lymph drainage. However, if pulmonary blood pressure Acute mountain sickness is the mildest illness caused by rises for some reason, such as left ventricular failure or mitral altitude hypoxia. The primary symptom is a headache valve dysfunction, the normal fi ltration/reabsorption balance at that may be accompanied by dizziness, nausea, fatigue, or the capillary is disrupted. confusion. More severe illnesses are high-altitude pulmonary When capillary hydrostatic pressure increases, more fl uid edema ( HAPE) and high-altitude cerebral edema. HAPE is the fi lters out of the capillary. If fi ltration increases too much, the lym- major cause of death from altitude sickness. It is characterized phatics are unable to remove all the fl uid, and excess accumulates by high pulmonary arterial pressure, extreme shortness of in the pulmonary interstitial space, creating pulmonary edema. In breath, and sometimes a productive cough yielding a pink, severe cases, if edema exceeds the tissue’s ability to retain it, fl uid frothy fl uid. Treatment is immediate relocation to lower altitude and administration of oxygen. leaks from the interstitial space into the alveolar air space, fl ooding the alveoli. Normally the inside of the alveoli is a moist surface Q2: Why would someone with HAPE be short of breath? lined by a very thin (about 2–5 mm) layer of fl uid with surfactant (see Fig. 18.3 b). With alveolar fl ooding, this fl uid layer can be- Q3: Based on what you learned about the mechanisms for come much thicker and seriously impair gas exchange. Alveolar matching ventilation and perfusion in the lung, can fl ooding can also occur with leakage when alveolar epithelium is you explain why patients with HAPE have elevated pulmonary arterial blood pressure? damaged, such as from infl ammation or inhaling toxic gases. If hypoxia due to alveolar fl uid accumulation is severe and cannot be corrected by oxygen therapy, the condition may be called adult respiratory distress syndrome or ARDS. is equal to the movement of oxygen from the water back into 18 the air. Concept Concept CheckCheck Answers: End of Chapter We refer to the concentration of oxygen dissolved in the

water at any given PO2 a s t h e partial pressure of the gas in solution. 5. Why would left ventricular failure or mitral valve dysfunction cause In our example, therefore, if the air has a PO of 100 mm Hg, at elevated pulmonary blood pressure? 2 equilibrium the water also has a PO2 of 100 mm Hg. P Note that this does not mean that the concentration of 6. If alveolar ventilation increases, what happens to arterial O2? To arterial P P P oxygen is the same in the air and in the water! Th e concentra- CO2? To venous O2 and CO2? Explain your answers. tion 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 Gas Solubility Aff ects Diff usion numbers of gas molecules go into solution at a low gas partial pressure. With less soluble gases, even a high partial pressure may A fi nal factor that can aff ect gas exchange in the alveoli is the cause only a few molecules of the gas to dissolve in the liquid. solubility of the gas. Th e movement of gas molecules from air For example, when PO2 is 100 mm Hg in both the air and into a liquid is directly proportional to three factors: (1) the the water, air contains 5.2 mmol O L air, but water contains only 2> pressure gradient of the gas, (2) the solubility of the gas in the 0.15 mmol O L water (Fig. 18.4 c). As you can see, oxygen is not 2> liquid, and (3) temperature. Because temperature is relatively very soluble in water and, by extension, in any aqueous solution. constant in mammals, we can ignore its contribution in this Its low solubility was a driving force for the evolution of oxygen- discussion. carrying molecules in the aqueous solution we call blood. When a gas is placed in contact with water and there is a Now compare oxygen solubility with CO2 solubility pressure gradient, gas molecules move from one phase to the ( Fig. 18.4 d). Carbon dioxide is 20 times more soluble in water other. If gas pressure is higher in the water than in the gaseous than oxygen is. At a PCO2 of 100 mm Hg, the CO2 concentration phase, then gas molecules leave the water. If gas pressure is in air is 5.2 mmol CO L air, and its concentration in water is 3.0 2> higher in the gaseous phase than in water, then the gas dissolves mmol L water. So although P a n d P are both 100 mm Hg > O2 CO2 into the water. in the water, the amount of each gas that dissolves in the water is For example, consider a container of water exposed to air very diff erent. with a P of 100 mm Hg ( Fig. 18.4 a). Initially, the water has O2 Why is solubility important in physiology? Th e answer is no oxygen dissolved in it (water P = 0 mm Hg ). As the air stays O2 that oxygen’s low solubility in aqueous solutions means that very in contact with the water, some of the moving oxygen molecules little oxygen can be carried dissolved in plasma. Its low solubility in the air diff use into the water and dissolve (Fig. 18.4 b). Th is process continues until equilibrium is reached. At equilibrium ( Fig. 18.4 c), the movement of oxygen from the air into the water

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 O in solution (b) Oxygen dissolves. (c) At equilibrium, P in air and water are equal. Low O 2 O2 2 solubility means concentrations are not equal.

P = 100 mm Hg O2 [O ] = 5.20 mmol/L P = 100 mm Hg 2 O2

P = 100 mm Hg P = 0 mm Hg O2 O2 [O2] = 0.15 mmol/L

CO2 solubility

(d) When CO2 is at equilibrium at the same partial pressure FIGURE QUESTION (100 mm Hg), more CO2 dissolves. Physiologists also express dissolved gases in blood using the following equation:

PCO = 100 mm Hg α 2 [Gas]diss = [Pgas] [CO2] = 5.20 mmol/L α for oxygen is (0.03 mL O /L blood)/mm Hg P 2 O2 α for CO is (0.7 mL CO /L blood)/mm Hg P 2 2 CO2 PCO = 100 mm Hg 2 If arterial blood has a P of 95 mm Hg and a [CO ] = 3.00 mmol/L O2 2 P of 40 mm Hg, what are the oxygen and CO2 CO2 concentrations (in mL gas/L blood)?

Fig. 18.4

also means oxygen is slower to cross the increased diff usion dis- Gas Transport in the Blood tance present in pulmonary edema. Diffusion of oxygen into alveolar capillaries does not have time to come to equilibrium Now that we have described how gases enter and leave the before the blood has left the capillaries. Th e result is decreased capillaries, we turn our attention to oxygen and carbon dioxide transport in the blood. Gases that enter the capillaries arterial PO2 even though alveolar PO2 may be normal. Carbon dioxide, in contrast, is relatively soluble in body first dissolve in the plasma. But dissolved gases play only a fl uids, so increased diff usion distance may not signifi cantly af- small part in providing the cells with oxygen. The red blood fect CO2 exchange. In some cases of pulmonary edema, arterial cells, or erythrocytes , have a critical role in ensuring that gas transport between lung and cells is adequate to meet cell PO2 is low but arterial PCO2 is normal because of the different solubilities of the two gases. needs. Without hemoglobin in the red blood cells, the blood would be unable to transport sufficient oxygen to sustain life ( Fig. 18.5 ). Concept Check Answers: End of Chapter Oxygen transport in the circulation and oxygen con- 7. True or false? Plasma with a P of 40 mm Hg and a P of 40 mm Hg O2 CO2 sumption by tissues are excellent ways to illustrate the gen- has the same concentrations of oxygen and carbon dioxide. eral principles of mass flow and mass balance. Mass flow 8. A saline solution is exposed to a mixture of nitrogen gas and hydrogen is defined as amount of x moving per minute, where mass gas in which P = P . What information do you need to predict flow = concentration * volume flow. We can calculate the H2 N2 mass flow of oxygen traveling from lungs to the cells by us- whether equal amounts of H2 and N 2 dissolve in the solution? ing the oxygen content of the arterial blood * cardiac output.

640 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 Arterial O2 ARTERIAL BLOOD transport transport (mL O2/min) (mL O2/min) O dissolved in plasma (~ P ) < 2% 2 O2

Red blood cell

O2 O2 + Hb HbO2 > 98% Cellular oxygen consumption (Q ) O2 (mL O /min) Alveolus 2 Alveolar membrane Transport Capillary to cells Mass Balance endothelium Cells

Arterial O transport – Q = Venous O transport 2 O2 2

Rearranges to: O2 dissolved in plasma HbO2 Hb + O2 O2 Arterial O transport – Venous O transport = Q 18 2 2 O2

Used in cellular respiration Mass Flow

O2 transport = Cardiac output (CO) × O2 concentration (L blood/min) (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? Fick Equation

Fig. 18.5 Substitute the mass flow equation for 2O transport in the mass balance equation:

(CO × Arterial [O2] ) – (CO × Venous [O2] ) = QO If arterial blood contains, on average, 200 mL O L blood and 2 2 > the cardiac output is 5 L min: > Using algebra (AB) – (AC) = A(B – C):

mL O min to cells = 200 mL O L blood * 5 L blood min CO × ( Arterial [O2] – Venous [O2] ) = QO 2> 2> > 2 = 1000 mL O min delivered to tissues 2> Fig. 18.6

If we know the mass flow of oxygen in the venous blood leaving the cells, we can use the principle of mass balance Adolph Fick, the nineteenth-century physiologist who de- to calculate the uptake and consumption of oxygen by the cells rived Fick’s law of diff usion, combined the mass fl ow and mass

( Fig. 18.6 ): balance equations above to relate oxygen consumption (QO2), cardiac output (CO), and blood oxygen content. Th e result is the = Fick equation : Arterial O2 transport - cell use of O2 venous O2 transport

Q = CO * (arterial oxygen content - venous oxygen content) where oxygen transport is mass fl ow, mL O2 being transported O2 per minute. Th is equation rearranges to: The Fick equation can be used to estimate cardiac output or = oxygen consumption, assuming that arterial and venous blood Arterial O2 transport - venous O2 transport cell use of O2 gases can be measured.

641 Gas Exchange and Transport

Hemoglobin Binds to Oxygen Once arterial blood reaches the tissues, the exchange process that took place in the lungs reverses. Dissolved oxygen Oxygen transport in the blood has two components: the oxygen diff uses out of systemic capillaries into cells, and the resultant

that is dissolved in the plasma (the PO2 ) and oxygen bound to decrease in plasma PO2 disturbs the equilibrium of the oxygen- hemoglobin (Hb). In other words: hemoglobin binding reaction by removing oxygen from the left side of the equation. Th e equilibrium shift s to the left ac- Total blood O content = dissolved O + O bound to Hb 2 2 2 cording to the law of mass action, and the hemoglobin molecules release their oxygen stores, as represented in the bottom As you learned in the previous section, oxygen is only slightly half of Figure 18.5 . soluble in aqueous solutions, and less than 2% of all oxygen in Like oxygen loading at the lungs, this process of trans- the blood is dissolved. Th at means hemoglobin transports more ferring oxygen to the body’s cells takes place very rapidly and than 98% of our oxygen ( Fig. 18.5). goes to equilibrium. Th e P of the cells determines how much Hemoglobin, the oxygen-binding protein that gives red O2 oxygen is unloaded from hemoglobin. As cells increase their blood cells their color, binds reversibly to oxygen, as summa- metabolic activity, their P decreases, and hemoglobin releases rized in the equation O2 more oxygen to them. m Hb + O2 HbO2 Why is hemoglobin an effective oxygen carrier? The an- Hemoglobin Transports Most Oxygen swer lies in its molecular structure. Hemoglobin (Hb) is a tet- ramer with four globular protein chains ( globins ), each centered to the Tissues around an iron-containing heme group. Th e central iron atom To understand why we must have adequate amounts of hemo- of each heme group can bind reversibly with one oxygen mol- globin in our blood to survive, consider the following example. ecule. With four heme groups per hemoglobin molecule, one Assume that a person’s oxygen consumption at rest is about hemoglobin molecule has the potential to bind four oxygen 250 mL O min and the cardiac output is 5 L blood min. To 2> > molecules. Th e iron-oxygen interaction is a weak bond that can meet the cells’ needs for oxygen, the 5 L of blood min com- > be easily broken without altering either the hemoglobin or the ing to the tissues would need to contain at least 250 mL O2, o r oxygen. 50 mL O L blood. 2> Hemoglobin bound to oxygen is known as oxyhemo- Th e low solubility of oxygen means that only 3 mL of O2 globin , abbreviated HbO2. It would be more accurate to show will dissolve in the plasma fraction of 1 liter of arterial blood the number of oxygen molecules carried on each hemoglobin ( Fig. 18.7 a). Th e dissolved oxygen delivery to the cells is molecule— Hb(O2)1-4—but we use the simpler abbreviation because the number of bound oxygen molecules varies from one 3 mL O L blood * 5 L blood min = 15 mL O min 2> > 2> hemoglobin molecule to another. Th e cells use at least 50 mL O min, so the small amount of oxy- 2> Oxygen Binding Obeys the Law of Mass Action gen that dissolves in plasma cannot meet the needs of the tissues at rest. + m Th e hemoglobin binding reaction Hb O2 HbO2 o b e y s Now let’s consider the diff erence in oxygen delivery if he- the law of mass action. As the concentration of free O2 moglobin is available. At normal hemoglobin levels, red blood increases, more oxygen binds to hemoglobin and the equation cells carry about 197 mL O L blood (Fig. 18.7 b). 2> shift s to the right, producing more HbO2. If the concentration of O decreases, the equation shift s to the left . Hemoglobin re- = 2 Total blood O2 content dissolved O2 + O2 bound to Hb leases oxygen and the amount of oxyhemoglobin decreases. = 3 mL O L blood + 197 mL HbO L blood In the blood, the free oxygen available to bind to hemo- 2> 2> globin is dissolved oxygen, indicated by the P of plasma = 200 mL O L blood O2 2> ( Fig. 18.5 ). In the pulmonary capillaries, oxygen from the alveoli dissolves in plasma. Dissolved O then diff uses into the red If cardiac output remains 5 L min, hemoglobin-assisted oxygen 2 > blood cells, where it can binds to hemoglobin. Th e hemoglobin delivery to cells is 1000 mL min: > acts like a sponge, soaking up oxygen from the plasma until the reaction Hb + O m HbO reaches equilibrium. 200 mL O L blood * 5 L blood min = 1000 mL O min 2 2 2> > 2> Th e transfer of oxygen from alveolar air to plasma to red blood cells and onto hemoglobin occurs so rapidly that blood in Th is is four times the oxygen consumption needed by the tissues the pulmonary capillaries normally picks up as much oxygen as at rest. Th e extra serves as a reserve for times when oxygen de-

the PO2 of the plasma and the number of red blood cells permit. mand increases, such as with exercise.

642 Gas Exchange and Transport

HEMOGLOBIN INCREASES OXYGEN TRANSPORT

(a) Oxygen transport in blood without (b) Oxygen transport at normal (c) Oxygen transport at reduced P O2 hemoglobin. Alveolar P = arterial P P in blood with hemoglobin in blood with hemoglobin O2 O2 O2

P = 100 mm Hg P = 100 mm Hg P = 28 mm Hg O2 O2 O2

Alveoli O2 molecule

Arterial P = 100 mm Hg PO = 100 mm Hg P = 28 mmHg plasma O2 2 O2

Oxygen dissolves in plasma. Red blood cells with hemoglobin are carrying Red blood cells carrying 50% of 98% of their maximum load of oxygen. their maximum load of oxygen. 18 O2 content of plasma = 3 mL O2/L blood O2 content of plasma = 3 mL O2/L blood O2 content of plasma = 0.8 mL O2/L blood

O2 content of red O2 content of red O2 content of red blood cells = 0 blood cells = 197 mL O2/L blood blood cells = 99.5 mL O2/L blood

Total O2 carrying 3 mL O2/L blood Total O2 carrying 200 mL O2/L blood Total O2 carrying 100.3 mL O2/L blood capacity capacity capacity

Fig. 18.7

P O Determines Oxygen-Hb Binding EMERGING CONCEPTS 2 The amount of oxygen that binds to hemoglobin depends on

two factors: (1) the PO2 in the plasma surrounding the red blood Blood Substitutes cells and (2) the number of potential Hb binding sites available

Physiologists have been attempting to fi nd a substitute in the red blood cells ( Fig. 18.8 ). Plasma PO2 is the primary for blood ever since 1878, when an intrepid physician named factor determining what percentage of the available hemoglo- T. Gaillard Thomas transfused a patient with whole milk bin binding sites are occupied by oxygen, known as the percent in place of blood. (It helped but the patient died anyway.) saturation of hemoglobin. As you learned in previous sections, Although milk seems an unlikely replacement for blood, it arterial PO2 is established by (1) the composition of inspired air, has two important properties: proteins to provide colloid (2) the alveolar ventilation rate, and (3) the effi ciency of gas ex- osmotic pressure and molecules (emulsifi ed lipids) capable change from alveoli to blood. Figure 18.7 c shows what happens of binding to oxygen. In the development of hemoglobin to O transport when P decreases. substitutes, oxygen transport is the most diffi cult property 2 O2 Th e total number of oxygen-binding sites depends on the to mimic. A hemoglobin solution would seem to be the obvi- ous answer, but hemoglobin that is not compartmentalized number of hemoglobin molecules in red blood cells. Clini- in red blood cells behaves diff erently than hemoglobin that cally, this number can be estimated either by counting the red is compartmentalized. Investigators are making progress by blood cells and quantifying the amount of hemoglobin per polymerizing hemoglobin into larger, more stable molecules red blood cell (mean corpuscular hemoglobin) or by determin- and loading these hemoglobin polymers into phospholipid ing the blood hemoglobin content (g Hb dL whole blood). Any > liposomes. Perfl uorocarbon emulsions are also being tested pathological condition that decreases the amount of hemoglo- as oxygen carriers. To learn more about this research, read bin in the cells or the number of red blood cells adversely aff ects “Physiological properties of blood substitutes,” News Physiol the blood’s oxygen-transporting capacity. Sci 16(1): 38–41, 2001 Feb (http://nips.physiology.org ). 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 RUNNING PROBLEM bound to Hb depends on In most people arriving at high altitude, normal physiological responses kick in to help acclimatize the body to the chronic The amount of hypoxia. Within two hours of arrival, hypoxia triggers the Plasma O2 hemoglobin release of erythropoietin from the kidneys and liver. This hormone stimulates red blood cell production, and as a which determines which determines result, new erythrocytes appear in the blood within days.

% Saturation Total number of Q4: How does adding erythrocytes to the blood help a of Hb × Hb binding sites person acclimatize to high altitude?

calculated from Q5: What does adding erythrocytes to the blood do to the viscosity of the blood? What eff ect will that change in Hb content Number viscosity have on blood fl ow? per RBC × of RBCs

Fig. 18.8 librarian gives each of them four books (100% saturation), then the ideal replacement for blood loss, but in emergencies this is 400 books are carried to the new library. If the librarian gives

not always possible. Saline infusions can replace lost blood vol- three books to each student (decreased plasma PO2 ), then only ume, but saline (like plasma) cannot transport suffi cient quan- 300 books go to the new library, even though each student could tities of oxygen to support cellular respiration. Faced with this carry four. (Students carrying only three of a possible four books problem, researchers are currently testing artifi cial oxygen car- correspond to 75% saturation of hemoglobin.) If the librarian is riers to replace hemoglobin. In times of large-scale disasters, handing out four books per student but only 50 students show these hemoglobin substitutes would eliminate the need to iden- up (fewer hemoglobin molecules), then only 200 books get to tify a patient’s blood type before giving transfusions. the new library, even though the students are taking the maximum number of books they can carry.

Th e physical relationship between PO2 and how much oxy- Oxygen Binding Is Expressed As a Percentage gen binds to hemoglobin can be studied in vitro . Researchers expose samples of hemoglobin to various P levels and quan- As you just learned, the amount of oxygen bound to hemoglo- O2 titatively determine the amount of oxygen that binds. Oxy- bin at any given PO2 is expressed as the percent saturation of hemoglobin , where hemoglobin saturation curves, such as the ones shown in Figure 18.9 , are the result of these in vitro binding studies. (Amount of O bound maximum that could be bound) * 100 (Th ese curves are also called dissociation curves .) 2 > # = percent saturation of hemoglobin Th e shape of the Hb O2 saturation curve refl ects the properties of the hemoglobin molecule and its affi nity for oxygen. If all binding sites on all hemoglobin molecules are occupied by If you look at the curve, you find that at normal alveolar and oxygen molecules, the blood is 100% oxygenated, or saturated arterial PO2 (100 mm Hg), 98% of the hemoglobin is bound to with oxygen. If half the available binding sites are carrying oxy- oxygen (Fig. 18.9 a). In other words, as blood passes through the gen, the hemoglobin is 50% saturated, and so on. lungs under normal conditions, hemoglobin picks up nearly the

Th e relationship between plasma PO2 and percent satura- maximum amount of oxygen that it can carry. tion of hemoglobin can be explained with the following analogy. Notice that the curve is nearly fl at at PO2 levels higher than The hemoglobin molecules carrying oxygen are like students 100 mm Hg (that is, the slope approaches zero). At PO2 a b o v e moving books from an old library to a new one. Each student 100 mm Hg, even large changes in PO2 cause only minor changes (a hemoglobin molecule) can carry a maximum of four books in percent saturation. In fact, hemoglobin is not 100% saturated (100% saturation). Th e librarian in charge controls how many until the PO2 reaches nearly 650 mm Hg, a partial pressure far

books ( O2 molecules) each student will carry, just as plasma PO2 higher than anything we encounter in everyday life. determines the percent saturation of hemoglobin. The flattening of the saturation curve at higher PO2 a l s o Th e total number of books being carried depends on the means that alveolar PO2 can fall a good bit below 100 mm Hg 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 Fig. 18.9 ESSENTIALS

Oxygen-hemoglobin Binding Curves

Binding properties of adult and fetal hemoglobin

(a) The oxyhemoglobin saturation curve is determined in vitro (b) Maternal and fetal hemoglobin have different oxygen- in the laboratory. binding properties.

100 100 Fetal 90 90 hemoglobin 80 80 70 70 60 60 Maternal hemoglobin 50 50 40 40 30 30

Hemoglobin saturation, % 20 20 Hemoglobin saturation, % 10 10

0 20 40 60 80 100 0 20 40 60 80 100 120 P (mm Hg) Resting cell Alveoli O2 P (mm Hg) O2

Physical factors alter hemoglobin’s affinity for oxygen

7.4 P = 20 mm Hg 60 60 60 CO2 7.2 P = 40 mm Hg CO2 P = 80 mm Hg 40 40 40 CO2

20 20 20 Hemoglobin saturation, % Hemoglobin saturation, % Hemoglobin saturation, %

0 20406080100 0 20 40 60 80 100 0 20 40 60 80 100 P (mm Hg) P (mm Hg) PO (mm Hg) O2 O2 2

(f) Effect of the metabolic compound 2,3-DPG GRAPH QUESTIONS 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 P is hemoglobin 50% saturated with O ? 80 O2 2 2. At a P of 20 mm Hg, how much more oxygen is released at an exercising O2 No 2,3-DPG muscle cell whose pH is 7.2 than at a cell with a pH of 7.4? 60 Normal 2,3-DPG 3. What happens to oxygen release when the exercising muscle cell warms up? Added 2,3-DPG 40 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 saturation, % hemoglobin in fetal blood leaving the placenta is 80% saturated with oxygen. What is the P of that placental blood? O2

0 20 40 60 80 100 6. Blood in the vena cava of the fetus has a PO2 around 10 mm Hg. What is the percent O saturation of maternal hemoglobin at the same P ? P (mm Hg) 2 O2 O2

645 Gas Exchange and Transport

without signifi cantly lowering hemoglobin saturation. As long compatible with life). Look at the graph in Figure 18.c. At a PO2

as PO2 in the alveoli (and thus in the pulmonary capillaries) stays of 40 mm Hg (equivalent to a resting cell) and pH of 7.4, hemo-

above 60 mm Hg, hemoglobin is more than 90% saturated and globin is about 75% saturated. At the same PO2, if the pH falls to maintains near-normal levels of oxygen transport. However, 7.2, the percent saturation decreases to about 62%. Th is means

once PO2 falls below 60 mm Hg, the curve becomes steeper. Th e that hemoglobin molecules release 13% more oxygen at pH 7.2

steep slope means that a small decrease in PO2 causes a relatively than they do at pH 7.4. large release of oxygen. When does the body undergo shift s in blood pH? One sit-

For example, if PO2 falls from 100 mm Hg to 60 mm Hg, uation is with maximal exertion that pushes cells into anaerobic the percent saturation of hemoglobin goes from 98% to about metabolism. Anaerobic metabolism in exercising muscle fi bers 90%, a decrease of 8%. Th is is equivalent to a saturation change releases H+ into the cytoplasm and extracellular fl uid. As H+

of 2% for each 10 mm Hg change. If PO2 falls further, from 60 to concentrations increase, pH falls, the affi nity of hemoglobin for 40 mm Hg, the percent saturation goes from 90% to 75%, a de- oxygen decreases, and the HbO2 saturation curve shift s to the crease of 7.5% for each 10 mm Hg. In the 40–20 mm Hg range, right. More oxygen is released at the tissues as the blood be- the curve is even steeper. Hemoglobin saturation declines from comes more acidic (pH decreases). A shift in the hemoglobin 75% to 35%, a change of 20% for each 10 mm Hg change. saturation curve that results from a change in pH is called the What is the physiological signifi cance of the shape of the Bohr eff ect . saturation curve? In blood leaving systemic capillaries with a An additional factor that affects oxygen-hemoglobin

PO2 of 40 mm Hg (an average value for venous blood in a person binding is 2,3-diphosphoglycerate (2,3-DPG; also called at rest), hemoglobin is still 75% saturated, which means that at 2,3-bisphosphoglycerate or 2,3-BPG), a compound made from the cells it released only one-fourth of the oxygen it is capable of an intermediate of the glycolysis pathway. Chronic hypoxia (ex- carrying. Th e oxygen that remains bound serves as a reservoir tended periods of low oxygen) triggers an increase in 2,3-DPG that cells can draw on if metabolism increases. production in red blood cells. Increased levels of 2,3-DPG lower When metabolically active tissues use additional oxygen, the binding affi nity of hemoglobin and shift the HbO2 satura-

their cellular PO2 decreases, and hemoglobin releases additional tion curve to the right ( Fig. 18.9 f). Ascent to high altitude and

oxygen at the cells. At a PO2 of 20 mm Hg (an average value for anemia are two situations that increase 2,3-DPG production. exercising muscle), hemoglobin saturation falls to about 35%. Changes in hemoglobin’s structure also change its oxygen-

With this 20 mm Hg decrease in PO2 (40 mm Hg to 20 mm Hg), binding affi nity. For example, fetal hemoglobin (HbF ) has two hemoglobin releases an additional 40% of the oxygen it is ca- gamma protein chains in place of the two beta chains found in pable of carrying. Th is is another example of the built-in reserve adult hemoglobin. Th e presence of gamma chains enhances the capacity of the body. ability of fetal hemoglobin to bind oxygen in the low-oxygen environment of the placenta. Th e altered binding affi nity is re- Several Factors Aff ect Oxygen-Hb Binding fl ected by the diff erent shape of the fetal HbO2 s a t u r a t i o n c u r v e (Fig. 18.9 b). At any given placental PO2 , oxygen released by Any factor that changes the conformation of the hemoglobin maternal hemoglobin is picked up by the higher-affi nity fetal protein may aff ect its ability to bind oxygen. In humans, physi- hemoglobin for delivery to the developing fetus. Shortly aft er

ological changes in plasma pH, PCO2, and temperature all alter birth, fetal hemoglobin is replaced with the adult form as new the oxygen-binding affi nity of hemoglobin. Changes in binding red blood cells are made. affi nity are refl ected by changes in the shape of the HbO2 satura- Figure 18.10 summarizes all the factors that influence tion curve. the total oxygen content of arterial blood.

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. 18.9 c–e). When these factors change in the opposite direction, binding af- Concept CheckCheck Answers: End of Chapter fi nity increases, and the curve shift s to the left . Notice that when 9. Can a person breathing 100% oxygen at sea level achieve 100% the curve shift s in either direction, the changes are much more saturation of her hemoglobin? pronounced in the steep part of the curve. Physiologically, this means that oxygen binding at the lungs (in the 90–100 mm Hg 10. What eff ect does hyperventilation have on the percent saturation of arterial hemoglobin? PO2 range) is not greatly aff ected, but oxygen delivery at the tissues (in the 20–40 mm Hg range) is signifi cantly altered. 11. A muscle that is actively contracting may have a cellular P of 25 mm Hg. O2 Let’s examine one situation, the affinity shift that takes What happens to oxygen binding to hemoglobin at this low P ? W h a t O2 place when pH decreases from 7.4 (normal) to 7.2 (more acidic). is the P of the venous blood leaving the active muscle? O2 (Th e normal range for blood pH is 7.38–7.42, but a pH of 7.2 is

646 Gas Exchange and Transport

ARTERIAL OXYGEN

The total oxygen content of arterial blood depends on the amount of oxygen dissolved TOTAL ARTERIAL in plasma and bound to hemoglobin. O2 CONTENT

Oxygen dissolved in helps Oxygen plasma (P of plasma) bound to Hb O2 determine

is influenced by

Adequate Composition of Alveolar Oxygen diffusion % Saturation Total number of perfusion x inspired air ventilation between alveoli of Hb binding sites and blood of alveoli affected by

Rate and Diffusion Hb content Number Airway Lung Surface P pH Temperature 2,3-DPG CO2 x depth of resistance compliance area distance per RBC of RBCs breathing

Membrane Amount of thickness interstitial fluid Fig. 18.10 18 Carbon Dioxide Is Transported in Three Ways found concentrated in red blood cells. Let’s see how this happens. Dissolved CO2 in the plasma diff uses into red blood cells, Gas transport in the blood includes carbon dioxide removal where it may react with water in the presence of carbonic anhy- from the cells as well as oxygen delivery to cells, and hemoglo- drase to form carbonic acid ( H2CO3, top portion of Fig. 18.11 ). bin also plays an important role in CO2 transport. Carbon di- Carbonic acid then dissociates into a hydrogen ion and a bicar- oxide is a by-product of cellular respiration. It is more sol- bonate ion: uble in body fluids than oxygen is, but the cells produce far more CO2 than can dissolve in the plasma. Only about 7% of Carbonic the CO2 carried by venous blood is dissolved in the blood. Th e anhydrase m m + - remaining 93% diff uses into red blood cells, where 70% is con- CO2 + H2O H2CO3 H + HCO3 verted to bicarbonate ion, as explained below, and 23% binds to Carbonic hemoglobin (Hb CO2 ) . Figure 18.11 summarizes these three acid mechanisms of carbon dioxide transport in the blood. Wh y i s r e m o v i n g CO2 from the body so important? First, Because carbonic acid dissociates readily, we sometimes ignore elevated PCO2 (hypercapnia ) causes the pH disturbance known the intermediate step and summarize the reaction as: as acidosis. Extremes of pH interfere with hydrogen bond- m + - ing of molecules and can denature proteins. Abnormally high CO2 + H2O H + HCO3

PCO2 levels also depress central nervous system function, causing confusion, coma, or even death. For these reasons, CO2 i s Th is reaction is reversible. Th e rate in either direction depends a potentially toxic waste product that must be removed by the on the relative concentrations of the substrates and obeys the lungs. law of mass action. + - Th e conversion of carbon dioxide to H a n d HCO3 con-

C O 2 and Bicarbonate Ions As we just noted, about 70% of the tinues until equilibrium is reached. (Water is always in excess CO2 that enters the blood is transported to the lungs as bicar- in the body, so water concentration plays no role in the dy- - bonate ions (HCO3 ) dissolved in the plasma. Th e conversion of namic equilibrium of this reaction.) To keep the reaction go- - + - CO2 t o HCO3 serves two purposes: (1) it provides an additional ing, the products ( H a n d HCO3 ) must be removed from the - means of CO2 transport from cells to lungs, and (2) HCO3 i s cytoplasm of the red blood cell. If the product concentrations available to act as a buffer for metabolic acids, thereby are kept low, the reaction cannot reach equilibrium. Carbon helping stabilize the body’s pH. dioxide continues to move out of plasma into the red blood - How does CO2 t u r n i n t o HCO3 ? Th e rapid conversion de- cells, which in turn allows more CO2 t o d i ff use out of tissues pends on the presence of carbonic anhydrase (CA), an enzyme 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 VENOUS BLOOD capillaries. 1 CO2 2 Dissolved CO2 (7%) Cellular 2 Only 7% of the CO remains dissolved in plasma. Red blood cell 2 respiration 3 CO + Hb HbCO (23%) Cl– in 2 2 5 peripheral – – tissues CA HCO3 HCO3 in 3 Nearly a fourth of the CO2 binds to 4 CO2 + H2O H2CO3 plasma (70%) hemoglobin, forming carbaminohemoglobin. H+ + Hb HbH

Capillary 4 70% of the CO2 load is converted to bicarbonate and H+. Hemoglobin buffers H+. endothelium Cell membrane Transport – to lungs 5 HCO3 enters the plasma in exchange for Cl– (the chloride shift).

6 6 At the lungs, dissolved CO2 diffuses out of the plasma. Dissolved CO2 Dissolved CO2 CO2

– HbCO2 Hb + CO2 7 By the law of mass action, CO unbinds from Cl Alveoli 2 7 hemoglobin and diffuses out of the RBC. CA – – 8 HCO3 HCO3 H2CO3 H2O + CO2 in plasma + 8 The carbonic acid reaction reverses, pulling HbH H + Hb – HCO3 back into the RBC and converting it back to CO2.

KEY CA = carbonic anhydrase Fig. 18.11

+ - Two separate mechanisms remove free H a n d HCO3 . produced from the reaction of CO2 and water. In those cases, In the fi rst, bicarbonate leaves the red blood cell on an antiport excess H+ accumulates in the plasma, causing the condition protein. This transport process, known as the chloride known as respiratory acidosis . You will learn more about the - - shift, exchanges HCO3 f o r Cl . The anion exchange main- role of the respiratory system in maintaining pH homeostasis - tains the cell’s electrical neutrality. Th e transfer of HCO3 i n t o when you study acid-base balance. the plasma makes this buff er available to moderate pH changes caused by the production of metabolic acids. Bicarbonate is the Hemoglobin and CO Although most carbon dioxide that en- most important extracellular buff er in the body. 2 ters red blood cells is converted to bicarbonate ions, about 23% of the CO in venous blood binds directly to hemoglobin. At the Hemoglobin and H+ The second mechanism removes free 2 cells, when oxygen leaves its binding sites on the hemoglobin H + from the red blood cell cytoplasm. Hemoglobin within the molecule, CO binds with free hemoglobin at exposed amino red blood cell acts as a buff er and binds hydrogen ions in the 2 groups ( -NH ), forming carbaminohemoglobin: reaction 2

+ + m H + Hb m HbH CO2 Hb HbCO2 (carbaminohemoglobin)

+ + Hemoglobin’s buff ering of H is an important step that prevents Th e presence of CO2 a n d H facilitates formation of carbami-

large changes in the body’s pH. If blood PCO2 is elevated much nohemoglobin because both these factors decrease hemoglo- above normal, the hemoglobin buff er cannot soak up all the H + bin’s binding affi nity 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 Dry air = 760 mm Hg hyperventilation, which begins on arrival. Hyperventilation P = 160 mm Hg enhances alveolar ventilation, but this may not help elevate O2 P = 0.25 mm Hg arterial P levels signifi cantly when atmospheric P is low. CO2 O2 O2 However, hyperventilation does lower plasma P . CO2

Q6: What happens to plasma pH during hyperventilation? (Hint: Apply the law of mass action to fi gure out what Alveoli happens to the balance between CO and H+ + HCO - ) . P = 100 mm Hg 2 3 O2 P = 40 mm Hg CO2 Q7: How does this change in pH aff ect oxygen binding at CO O the lungs when P is decreased? How does it aff ect 2 2 O2 unloading of oxygen at the cells? CO2 transport O2 transport – Pulmonary HCO3 = 70% HbO2 > 98% circulation HbCO2 = 23% Dissolved O2 < 2%

Dissolved CO2 = 7% (~PO2)

C O 2 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 ). Th e PCO2 o f t h e a l v e o l i is lower than that of venous blood in the pulmonary capillaries. 18 Therefore, CO2 diffuses down its pressure gradient—in other Venous blood Arterial blood words, out of plasma into the alveoli—and the plasma PCO2 b e - gins to fall. P ≤ 40 mm Hg PO = 100 mm Hg O2 Systemic 2 ≥ P = 40 mm Hg PCO 46 mm Hg circulation CO Th e decrease in plasma PCO2 allows dissolved CO2 to dif- 2 2 fuse out of the red blood cells. As CO2 levels in the red blood - cells decrease, the equilibrium of the CO2 - HCO3 r e a c t i o n i s CO2 O2 disturbed, shift ing toward production of more CO2. Removal + Cells of CO2 c a u s e s H to leave the hemoglobin molecules, and the - P ≤ 40 mm Hg chloride shift reverses: Cl returns to the plasma in exchange O2 - - ≥ PCO 46 mm Hg for HCO3 moving back into the red blood cells. The HCO3 2 and newly released H + re-form into carbonic acid, which is Fig. 18.12 then converted into water and CO2 . Th is CO2 is then free to diffuse out of the red blood cell and into the alveoli. hemoglobin. At the lungs, the process reverses as CO2 d i ff uses Figure 18.12 shows the combined transport of CO2 out of the pulmonary capillaries and into the alveoli. and O2 in the blood. At the alveoli, O2 d i ff uses down its pressure gradient, moving from the alveoli into the plasma and then To understand fully how the respiratory system coordi- from the plasma into the red blood cells. Hemoglobin binds to nates delivery of oxygen to the lungs with transport of oxygen in the circulation, we now consider the central nervous system O2 , increasing the amount of oxygen that can be transported to the cells. control of ventilation.

At the cells, the process reverses. Because PO2 is lower in cells than in the arterial blood, O d i ff uses from the plasma into 2 Concept Check Answers: End of Chapter the cells. Th e decrease in plasma PO2 causes hemoglobin to release O2 , making additional oxygen available to enter cells. 12. How would an obstruction of the airways aff ect alveolar ventilation, arterial P , and the body’s pH? Carbon dioxide from aerobic metabolism simultaneously CO2 leaves cells and enters the blood, dissolving in the plasma. From there, CO2 enters red blood cells, where most is converted to - + - HCO3 a n d H . T h e HCO3 is returned to the plasma in exchange for a Cl- while the H + binds to hemoglobin. A frac- Regulation of Ventilation tion of the CO2 that enters red blood cells also binds directly to 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 sponta- The neural control of breathing is one of the few “black neously. Instead, skeletal muscle contraction must be initiated boxes” left in systems-level physiology. Although we know the by somatic motor neurons, which in turn are controlled by the major regions of the brain stem that are involved, the details central nervous system. remain elusive and controversial. Th e brain stem network that In the respiratory system, contraction of the diaphragm controls breathing behaves like a central pattern generator, with and other muscles is initiated by a spontaneously fi ring network intrinsic rhythmic activity that probably arises from pacemaker of neurons in the brain stem ( Fig. 18.13 ). Breathing occurs au- neurons with unstable membrane potentials. tomatically throughout a person’s life but can also be controlled Some of our understanding of how ventilation is con- voluntarily, up to a point. Complicated synaptic interactions trolled has come from observing patients with brain dam- between neurons in the network create the rhythmic cycles of age. Other information has come from animal experiments in inspiration and expiration, infl uenced continuously by sensory which neural connections between major parts of the brain + input, especially that from chemoreceptors for CO2 , O2 , a n d H . stem are severed, or sections of brain are studied in isolation. Ventilation pattern depends in large part on the levels of those Research on CNS respiratory control is diffi cult because of the three substances in the arterial blood and extracellular fl uid. 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 CO2 O and pH control 2 16

15 Higher Medullary Carotid and aortic 1 brain chemoreceptors chemoreceptors centers 14 2 13 3 4 Limbic Afferent sensory system neurons 12 5

7 Medulla oblongata and pons 8 11

Somatic Somatic 10 motor neurons motor neurons (inspiration) (expiration)

Scalene and External Internal Abdominal Inspiration Expiration Diaphragm sternocleidomastoid intercostals intercostals muscles muscles

KEY FIGURE QUESTION Match the numbers on the Stimuli Integrating centers figure to the boxes of the map. Sensors Efferent neurons Fig. 18.13 Afferent neurons Targets

650 Gas Exchange and Transport but in recent years scientists have developed better techniques Neural networks in the brain stem control ventilation. for studying the system. Th e 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. Th is model states that: 1 Respiratory neurons in the medulla control inspiratory and expiratory muscles. 2 Neurons in the pons integrate sensory information and interact with medullary neurons to infl uence ventilation. 3 The rhythmic pattern of breathing arises from a neural Higher network with spontaneously discharging neurons. brain centers 4 Ventilation is subject to continuous modulation by various chemoreceptor- and mechanoreceptor-linked refl exes and by higher brain centers. Pons

PRG NTS Neurons in the Medulla Control Breathing Medullary chemo- Classic descriptions of how the brain controls ventilation di- receptors vided the brain stem into various control centers. More recent monitor CO . 2 18 descriptions, however, are less specifi c about assigning function Sensory input to particular “centers” and instead look at complex interactions from CN IX, X DRG (mechanical and between neurons in a network. We know that respiratory neu- chemosensory) rons are concentrated bilaterally in two areas of the medulla Medulla oblongata. Figure 18.14 shows these areas on the left side of pre-Bötzinger the brain stem. One area called the nucleus tractus solitarius complex (NTS) contains the dorsal respiratory group (DRG) of neurons VRG that control mostly muscles of inspiration. Output from the Output to expiratory, Output DRG goes via the phrenic nerves to the diaphragm and via some inspiratory, primarily to pharynx, larynx, and inspiratory the intercostal nerves to the intercostal muscles. In addition, tongue muscles muscles the NTS receives sensory information from peripheral chemo- and mechanoreceptors through the vagus and glossopharyngeal nerves (cranial nerves X and IX). KEY Respiratory neurons in the pons receive sensory infor- PRG = Pontine respiratory group VRG = Ventral respiratory group mation from the DRG and in turn infl uence the initiation and DRG = Dorsal respiratory group NTS = Nucleus tractus solitarius termination of inspiration. The pontine respiratory groups Fig. 18.14 (previously called the pneumotaxic center) and other pontine neurons provide tonic input to the medullary networks to help coordinate a smooth respiratory rhythm. nerve and other motor nerves ( Fig. 18.15 ). During quiet Th e ventral respiratory group (VRG) of the medulla has breathing, a pacemaker initiates each cycle, and inspiratory neu- multiple regions with diff erent functions. One area known as the rons gradually increase stimulation of the inspiratory muscles. pre-Bötzinger complex contains spontaneously fi ring neurons Th is increase is sometimes called ramping because of the shape that may act as the basic pacemaker for the respiratory rhythm. of the graph of inspiratory neuron activity. A few inspiratory Other areas control muscles used for active expiration or for neurons fi re to begin the ramp. Th e fi ring of these neurons re- greater-than-normal inspiration, such as occurs during vigorous cruits other inspiratory neurons to fi re in an apparent positive exercise. In addition, nerve fi bers from the VRG innervate mus- feedback loop. As more neurons fi re, more skeletal muscle fi bers cles of the larynx, pharynx, and tongue to keep the upper airways are recruited. Th e rib cage expands smoothly as the diaphragm open during breathing. Inappropriate relaxation of these muscles contracts. during sleep contributes to obstructive sleep apnea , a sleeping dis- At the end of inspiration, the inspiratory neurons abruptly order associated with snoring and excessive daytime sleepiness. stop fi ring, and the respiratory muscles relax. Over the next few Th e integrated action of the respiratory control networks seconds, passive expiration occurs because of elastic recoil of can be seen by monitoring electrical activity in the phrenic the inspiratory muscles and elastic lung tissue. However, some

651 Gas Exchange and Transport

NEURAL ACTIVITY DURING QUIET BREATHING

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.

Rapid positive feedback loop Number of active inspiratory neurons

Inspiration shuts off

0.5

0 Tidal volume (liters) Inspiration Passive expiration Inspiration 2 sec 3 sec 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 expira- stimulus for changes in ventilation. Oxygen and plasma pH play tion, suggesting that perhaps muscles in the upper airways con- lesser roles. tract to slow the fl ow of air out of the respiratory system. The chemoreceptors for oxygen and carbon dioxide are Many neurons of the VRG remain inactive during quiet strategically associated with the arterial circulation. If too little respiration. Th ey function primarily during forced breathing, oxygen is present in arterial blood destined for the brain and when inspiratory movements are exaggerated, and during active other tissues, the rate and depth of breathing increase. If the rate expiration. In forced breathing, increased activity of inspiratory of CO2 production by the cells exceeds the rate of CO2 r e m o v a l

neurons stimulates accessory muscles, such as the sternocleido- by the lungs, arterial PCO2 increases, and ventilation is intensi- mastoids. Contraction of these accessory muscles enhances ex- fi ed to match CO2 removal to production. Th ese homeostatic

pansion of the thorax by raising the sternum and upper ribs. refl exes operate constantly, keeping arterial PO2 a n d PCO2 w i t h i n With active expiration, expiratory neurons from the VRG a narrow range. activate the internal intercostal and abdominal muscles. Th ere Peripheral chemoreceptors located in the carotid and

seems to be some communication between inspiratory and ex- aortic arteries sense changes in the PO2, pH, and PCO2 o f t h e piratory neurons, as inspiratory neurons are inhibited during plasma ( Fig. 18.13 ). Th ese carotid and aortic bodies are close active expiration. to the locations of the baroreceptors involved in refl ex control of blood pressure. Central chemoreceptors in the brain respond to changes in the concentration of CO2 in the cerebro- Carbon Dioxide, Oxygen, and spinal fl uid. Th ese central receptors lie on the ventral surface of pH Infl uence Ventilation the medulla, close to neurons involved in respiratory control. Sensory input from central and peripheral chemoreceptors Peripheral Chemoreceptors When specialized glomus cells modifi es the rhythmicity of the control network to help main- {glomus , a ball-shaped mass} in the carotid and aortic bodies are

tain blood gas homeostasis. Carbon dioxide is the primary activated by a decrease in PO2 or pH or by an increase in PCO2 ,

652 Gas Exchange and Transport they trigger a refl ex increase in ventilation. Under most normal causes exocytosis of neurotransmitter onto the sensory neuron. circumstances, oxygen is not an important factor in modulat- In the carotid and aortic bodies, neurotransmitters initiate ac- ing ventilation because arterial PO2 must fall to less than 60 mm tion potentials in sensory neurons leading to the brain stem re-

Hg before ventilation is stimulated. Th is large decrease in PO2 i s spiratory networks, signaling them to increase ventilation. equivalent to ascending to an altitude of 3000 m. (For reference, Because the peripheral chemoreceptors respond only to

Denver is located at an altitude of 1609 m). However, any condi- dramatic changes in arterial PO2 , arterial oxygen concentrations tion that reduces plasma pH or increases PCO2 will activate the do not play a role in the everyday regulation of ventilation. How- carotid and aortic glomus cells and increase ventilation. ever, unusual physiological conditions, such as ascending to high Th e details of glomus cell function remain to be worked altitude, and pathological conditions, such as chronic obstructive out, but the basic mechanism by which these chemoreceptors pulmonary disease (COPD), can reduce arterial PO2 t o l e v e l s t h a t respond to low oxygen is similar to the mechanism you learned are low enough to activate the peripheral chemoreceptors. for insulin release by pancreatic beta cells or taste transduction in taste buds. Central Chemoreceptors Th e most important chemical con- In all three examples, a stimulus inactivates K+ c h a n n e l s , troller of ventilation is carbon dioxide, mediated both through causing the receptor cell to depolarize ( Fig. 18.16 ). Depo- the peripheral chemoreceptors just discussed and through cen- larization opens voltage-gated Ca2+ c h a n n e l s , a n d Ca2+ e n t r y tral chemoreceptors located in the medulla ( Fig. 18.17 ). Th ese receptors set the respiratory pace, providing continuous input

into the control network. When arterial P CO2 increases, CO2 crosses the blood-brain barrier and activates the central chemo- GLOMUS CELLS receptors. Th ese receptors signal the control network to increase The carotid body oxygen sensor releases neurotransmitter the rate and depth of ventilation, thereby enhancing alveolar 18 when P decreases. O2 ventilation and removing CO2 from the blood. Although we say that the central chemoreceptors monitor Blood vessel Low P CO2, they actually respond to pH changes in the cerebrospinal O2 fl uid (CSF). Carbon dioxide that diff uses across the blood-brain barrier into the CSF is converted to carbonic acid, which dissociates to bicarbonate and H+. Experiments indicate that the H + 1 Low PO 2 2 K+ channels close produced by this reaction is what initiates the chemoreceptor refl ex, rather than the increased level of CO2 . Note, however, that pH changes in the plasma do not usu- Cell ally influence the central chemoreceptors directly. Although 3 + depolarizes plasma PCO enters the CSF readily, plasma H crosses the Glomus cell 2 in carotid blood-brain barrier very slowly and therefore has little direct ef- body fect on the central chemoreceptors.

When plasma PCO2 increases, the chemoreceptors initially respond strongly by increasing ventilation. However, if PCO 2+ 2 5 Ca remains elevated for several days, ventilation falls back toward enters 4 Voltage-gated Ca2+ normal rates as the chemoreceptor response adapts by mecha- channel opens nisms that are not clear. Fortunately for people with chronic lung diseases, the response of peripheral chemoreceptor to low arterial P remains intact over time, even though the central 6 Exocytosis of O2 neurotransmitters chemoreceptor response adapts to high PCO2 .

In some situations, low PO2 becomes the primary chemi- Receptor on cal stimulus for ventilation. For example, patients with severe sensory neuron chronic lung disease, such as COPD, have chronic hypercapnia and hypoxia. Th eir arterial P may rise to 50–55 mm Hg Action potential CO2

(normal is 35–45) while their PO2 falls to 45–50 mm Hg (normal 75–100). Because these levels are chronic, the chemorecep-

tor response adapts to the elevated PCO2. Most of the chemical 7 Signal to medullary stimulus for ventilation in this situation then comes from low centers to increase P , sensed by the carotid and aortic chemoreceptors. If these ventilation O2 patients are given too much oxygen, they may stop breathing Fig. 18.16 because their chemical stimulus for ventilation is eliminated.

653 Gas Exchange and Transport

CHEMORECEPTOR RESPONSE

+ Central chemoreceptors monitor CO2 in cerebrospinal fluid. Carotid and aortic chemoreceptors monitor CO2, O2, and H .

Plasma KEY P CO2 CA = carbonic anhydrase –

Cerebral capillary + – CO2 H + HCO3 Blood-brain P H+ barrier CO2 (in plasma)

+ – CO2 + H2O H2CO3 H + HCO3 CA Cerebrospinal Stimulates fluid Plasma P peripheral O2 chemoreceptors <60 mm Hg in carotid and aortic bodies Central – Medulla chemoreceptor oblongata at brain Respiratory control Sensory centers neurons

Ventilation

Plasma P O2 Negative feedback Plasma P CO2 Fig. 18.17

Th e central chemoreceptors respond to decreases in arte- Th e irritant receptors send signals through sensory neurons to

rial PCO2 as well as to increases. If alveolar PCO2 falls, as it might integrating centers in the CNS that trigger bronchoconstric-

during hyperventilation, plasma PCO2 and cerebrospinal fluid tion. Protective reflex responses also include coughing and

PCO2 follow suit. As a result, central chemoreceptor activity de- sneezing. clines, and the control network slows the ventilation rate. When Th e Hering-Breuer infl ation refl ex was fi rst described in the ventilation decreases, carbon dioxide begins to accumulate in late 1800s in anesthetized dogs. In these animals, if tidal volume

alveoli and the plasma. Eventually, the arterial PCO2 r i s e s a b o v e exceeded a certain volume, stretch receptors in the lung signaled the threshold level for the chemoreceptors. At that point, the re- the brain stem to terminate inspiration. However, this refl ex is ceptors fi re, and the control network again increases ventilation. diffi cult to demonstrate in adult humans and does not operate during quiet breathing and mild exertion. Studies on human in- fants, however, suggest that the Hering-Breuer infl ation refl ex Protective Refl exes Guard the Lungs may play a role in limiting their ventilation volumes. In addition to the chemoreceptor reflexes that help regulate ventilation, the body has protective reflexes that respond to Higher Brain Centers Aff ect physical injury or irritation of the respiratory tract and to over- infl ation of the lungs. eTh major protective refl ex isbroncho- Patterns of Ventilation constriction, mediated through parasympathetic neurons that Conscious and unconscious thought processes also aff ect respi- innervate bronchiolar smooth muscle. Inhaled particles or nox- ratory activities. Higher centers in the hypothalamus and cere- ious gases stimulate irritant receptors in the airway mucosa. brum can alter the activity of the brain stem control network

654 Gas Exchange and Transport to change ventilation rate and depth. Voluntary control of RUNNING PROBLEM ventilation falls into this category. Higher brain center control is not a requirement for ventilation, however. Even if the brain The hyperventilation response to hypoxia creates a peculiar stem above the pons is severely damaged, essentially normal re- breathing pattern called periodic breathing , in which the spiratory cycles continue. person goes through a 10–15-second period of breath- Respiration can also be aff ected by stimulation of portions holding followed by a short period of hyperventilation. of the limbic system. For this reason, emotional and autonomic Periodic breathing occurs most often during sleep. activities such as fear and excitement may aff ect the pace and Q8: Based on your understanding of how the body controls depth of respiration. In some of these situations, the neural ventilation, why do you think periodic breathing occurs pathway goes directly to the somatic motor neurons, bypassing most often during sleep? the control network in the brain stem. Although we can temporarily alter our respiratory perfor- mance, we cannot override the chemoreceptor refl exes. Holding your breath is a good example. You can hold your breath vol- Breathing is intimately linked to cardiovascular function. untarily only until elevated PCO2 in the blood and cerebrospinal fl uid activates the chemoreceptor refl ex, forcing you to inhale. The integrating centers for both functions are located in the Small children having temper tantrums sometimes attempt brain stem, and interneurons project between the two networks, to manipulate parents by threatening to hold their breath until allowing signaling back and forth. Th e cardiovascular, respira- they die. However, the chemoreceptor refl exes make it impos- tory, and renal systems all work together to maintain fl uid and sible for the children to carry out that threat. Extremely strong- acid-base homeostasis. willed children can continue holding their breath until they turn 18 blue and pass out from hypoxia, but once they are unconscious, normal breathing automatically resumes.

RUNNING PROBLEM CONCLUSION

High Altitude On May 29, 1953, Edmund Hillary and Tenzing Norgay of To learn more about diff erent types of mountain the British Everest Expedition were the fi rst humans to sickness, see the International Society for Mountain Medicine reach the summit of Mt. Everest. They carried supplemental ( www.ismmed.org/np_altitude_tutorial.htm ); “High altitude oxygen with them, as it was believed that this feat was medicine,” Am Fam Physician 1998 Apr. 15 (www.aafp.org/ impossible without it. In 1978, however, Reinhold Messner afp/980415ap/harris.html ); and “High-altitude pulmonary and Peter Habeler achieved the “impossible.” On May 8, edema” (www.emedicine.com/MED/topic1956.htm ). they struggled to the summit using sheer willpower and no In this running problem you learned about normal extra oxygen. In Messner’s words, “I am nothing more than and abnormal responses to high altitude. Check your a single narrow gasping lung, fl oating over the mists and understanding of the physiology behind this respiratory summits.” Learn more about these Everest expeditions by challenge by comparing your answers with the doing a Google search for Hillary Everest or Messner Everest. information in the following table.

Question Facts Integration and Analysis

What is the P of inspired air Water vapor contributes a partial pressure Correction for water vapor: 1. O2 reaching the alveoli when dry of 47 mm Hg to fully humidifi ed air. Oxygen 542 - 47 = 495 mm Hg * 21% P O2 atmospheric pressure is 542 mm Hg? is 21% of dry air. Normal atmospheric = 104 mm Hg P . In humidifi ed air at sea O2 How does this value for P compare pressure at sea level is 760 mm Hg. level, P = 150 mm Hg. O2 O2 with the P value for fully humidifi ed O2 air at sea level?

2. Why would someone with HAPE be Pulmonary edema increases the diff usion Slower oxygen diff usion means less oxygen short of breath? distance for oxygen. reaching the blood, which worsens the normal hypoxia of altitude.

655 Gas Exchange and Transport

RUNNING PROBLEM CONCLUSION (continued)

Question Facts Integration and Analysis

3. Based on mechanisms for Low oxygen levels constrict pulmonary Constriction of pulmonary arterioles causes matching ventilation and perfusion in arterioles. blood to collect in the pulmonary arteries the lung, why do patients with HAPE behind the constriction. This increases have elevated pulmonary arterial pulmonary arterial blood pressure. blood pressure?

4. How does adding erythrocytes to 98% of arterial oxygen is carried bound to Additional hemoglobin increases the the blood help a person acclimatize hemoglobin. oxygen-carrying capacity of the blood. to high altitude?

5. What does adding erythrocytes to Adding cells increases blood viscosity. According to Poiseuille’s law, increased the blood do to the viscosity of the viscosity increases resistance to fl ow, so blood? What eff ect will that change in blood fl ow will decrease. viscosity have on blood fl ow?

6. What happens to plasma pH during Apply the law of mass action to the The amount of CO2 in the plasma decreases + - hyperventilation? equation CO2 + H2O m H + HCO3 . 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 aff ect See Figure 18.9 c. The left shift of the curve means that, at any oxygen binding at the lungs when given P , more O binds to hemoglobin. O2 2 P is decreased? How does it aff ect Less O will unbind at the tissues for a given O2 2 unloading of oxygen at the cells? P , but P in the cells is probably lower O2 O2 than normal, and consequently there may be no change in unloading.

8. Why do you think periodic Periodic breathing alternates periods An awake person is more likely to make breathing occurs most often during of breath-holding (apnea) and a conscious eff ort to breathe during the sleep? hyperventilation. breath-holding spells, eliminating the cycle of periodic breathing.

Test your understanding with: • Practice Tests • PhysioExTM Lab Simulations • Running Problem Quizzes • Interactive Physiology TM • A&PFlix Animations Animations www.masteringaandp.com

Chapter Summary

In this chapter, you learned why climbing Mt. Everest is such a respira- blood gases demonstrates mass balance : the concentration in the blood tory challenge for the human body, and why people with emphysema varies according to what enters or leaves at the lungs and tissues. Th e experience the same respiratory challenges at sea level. Th e exchange law of mass action governs the chemical reactions through which he-

and transport of oxygen and carbon dioxide in the body illustrate the moglobin binds O2 , and carbonic anhydrase catalyzes the conversion of mass fl ow of gases along concentration gradients. Homeostasis of these CO 2 and water to carbonic acid.

656 Gas Exchange and Transport

Gas Exchange in the Lungs and Tissues 9. Oxygen-hemoglobin binding is infl uenced by pH, temperature, and 2,3-diphosphoglycerate (2,3-DPG). ( Fig. 18.9 ) Respiratory:Respiratory: Gas ExchangeExchange 10. Venous blood carries 7% of its carbon dioxide dissolved in plasma, 23% as carbaminohemoglobin, and 70% as bicarbonate ion in the

1. Normal alveolar and arterial PO2 is about 100 mm Hg. Normal al- plasma. ( Fig. 18.11 ) veolar and arterial PCO is about 40 mm Hg. Normal venous PO i s 2 2 11. Carbonic anhydrase in red blood cells converts CO2 to carbonic acid, + - + 40 mm Hg, and normal venous PCO is 46 mm Hg. ( Fig. 18.2 ) 2 which dissociates into H and HCO3 . Th e H then binds to hemo- - 2. Body sensors monitor blood oxygen, CO2, and pH in an eff ort to globin, and HCO3 enters the plasma using the chloride shift . avoid hypoxia and hypercapnia . 3. Both the composition of inspired air and the eff ectiveness of alveo- Regulation of Ventilation

lar ventilation aff ect alveolar PO2 . 4. Changes in alveolar surface area, in diff usion barrier thickness, Respiratory:Respiratory: Control of Respiration and in fl uid distance between the alveoli and pulmonary capillar- 12. Respiratory control resides in networks of neurons in the medulla ies can all affect gas exchange efficiency and arterial PO2 . ( Fig. 18.3 ) and pons, infl uenced by input from central and peripheral sensory 5. Th e amount of a gas that dissolves in a liquid is proportional to the receptors and higher brain centers. (Fig. 18.13 ) partial pressure of the gas and to the solubility of the gas in the liq- 13. The medullary dorsal respiratory group (DRG) contains mostly uid. Carbon dioxide is 20 times more soluble in aqueous solutions inspiratory neurons that control somatic motor neurons to the than oxygen is. ( Fig. 18.4 ) diaphragm. Th e ventral respiratory group (VRG) includes the pre- Bötzinger complex with its apparent pacemakers as well as neurons Gas Transport in the Blood for inspiration and active expiration. (Fig. 18.14 ) 14. Peripheral chemoreceptors in the carotid and aortic bodies monitor P , P , and pH. P below 60 mm Hg triggers an increase in Respiratory:Respiratory: Gas Transport O2 CO2 O2 ventilation.( Fig. 18.17 ) 18 6. Gas transport demonstrates mass fl ow and mass balance. Th e Fick 15. Carbon dioxide is the primary stimulus for changes in ventilation. equation relates blood oxygen content, cardiac output, and tissue Chemoreceptors in the medulla and carotid bodies respond to oxygen consumption. ( Fig. 18.6 ) changes in PCO2 .( Fig. 18.17 ) 7. Oxygen is transported dissolved in plasma (62%) and bound to he- 16. Protective refl exes monitored by peripheral receptors prevent injury moglobin (798%). ( Fig. 18.5 ) to the lungs from inhaled irritants.

8. Th e PO2 of plasma determines how much oxygen binds to hemoglo- 17. Conscious and unconscious thought processes can aff ect respiratory bin. ( Fig. 18.8 ) activity.

Questions

Level One Reviewing Facts and Terms • alveoli • hemoglobin saturation 1. List fi ve factors that infl uence the diff usion of gases between alveo- • arterial blood • oxyhemoglobin

lus and blood. • carbaminohemoglobin • PCO2 2. More than % of the oxygen in arterial blood is trans- • carbonic anhydrase • plasma • chloride shift • P ported bound to hemoglobin. How is the remaining oxygen trans- O2 ported to the cells? • dissolved CO2 • pressure gradient • dissolved O • red blood cell 3. Name four factors that infl uence the amount of oxygen that binds to 2 • hemoglobin • venous blood hemoglobin. Which of these four factors is the most important? 11. In respiratory physiology, it is customary to talk of the P of the 4. Describe the structure of a hemoglobin molecule. What chemical O2 plasma. Why is this not the most accurate way to describe the oxy- element is essential for hemoglobin synthesis? gen content of blood? 5. Th e networks for control of ventilation are found in the 12. Compare and contrast the following pairs of concepts: and of the brain. What do the dorsal and ventral respiratory groups of neurons control? What is a central pattern generator? (a) transport of O2 and CO2 in arterial blood (b) partial pressure and concentration of a gas dissolved in a liquid 6. Describe the chemoreceptors that influence ventilation. What chemical is the most important controller of ventilation? 13. D o e s HbO2 binding increase, decrease, or not change with decreased pH? 7. Describe the protective refl exes of the respiratory system. 14. D e fi ne hypoxia, COPD, and hypercapnia. 8. What causes the exchange of oxygen and carbon dioxide between alveoli and blood or between blood and cells? 15. Why did oxygen-transporting molecules evolve in animals? 9. List fi ve possible physical changes that could result in less oxygen 16. Draw and label the following graphs: reaching the arterial blood. (a) the eff ect of ventilation on arterial PO2

(b) the eff ect of arterial PCO2 on ventilation Level Two Reviewing Concepts 17. As the PO2 of plasma increases: 10. Concept map: Construct a map of gas transport using the following (a) what happens to the amount of oxygen that dissolves in plasma? terms. You may add other terms. (b) what happens to the amount of oxygen that binds to hemoglobin?

657 Gas Exchange and Transport

18. If a person is anemic and has a lower-than-normal level of hemoglo- Bzork’s normal alveolar PO2 is 85 mm Hg. His normal cell PO2 i s

bin in her red blood cells, what is her arterial PO2 compared to normal? 20 mm Hg, but it drops to 10 mm Hg with exercise. 19. Create refl ex pathways (stimulus, receptor, aff erent path, and so on) for (a) What is the percent saturation for Bzork’s oxygen-carrying the chemical control of ventilation, starting with the following stimuli: molecule in blood at the alveoli? In blood at an exercising cell? (b) Based on the graph above, what conclusions can you draw (a) Increased arterial PCO2 = about Bzork’s oxygen requirements during normal activity and (b) Arterial PO2 55 mm Hg Be as specific as possible regarding anatomical locations. Where during exercise? known, include neurotransmitters and their receptors. 26. Th e next experiment on Bzork involves his ventilatory response to diff erent conditions. Th e data from that experiment are graphed be- Level Three Problem Solving low. Interpret the results of experiments A and C. 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 P = 50 mm Hg O2 his anatomic dead space. What happens to the following parameters PO = 85 mm Hg in his arterial blood, and why? 2 (a) P (c) bicarbonate ion CO2 A (b) PO2 (d) pH B P = 85 mm Hg 21. Which person carries more oxygen in his blood? O2 (a) one with Hb of 15 g dL and arterial P of 80 mm Hg > O2 C Subject drank (b) one with Hb of 12 g dL and arterial P of 100 mm Hg > O2 seven beers 22. What would happen to each of the following parameters in a person Alveolar ventilation suff ering from pulmonary edema?

(a) arterial PO2 (b) arterial hemoglobin saturation Plasma P (c) alveolar ventilation CO2 23. In early research on the control of rhythmic breathing, scientists 27. Th e alveolar epithelium is an absorptive epithelium and is able to made the following observations. What hypotheses might the re- transport ions from the fl uid lining of alveoli into the interstitial searchers have formulated from each observation? space, creating an osmotic gradient for water to follow. Draw an (a) Observation. If the brain stem is severed below the medulla, all alveolar epithelium and label apical and basolateral surfaces, the respiratory movement ceases. airspace, and interstitial fl uid. Arrange the following proteins on (b) Observation. If the brain stem is severed above the level of the the cell membrane so that the epithelium absorbs sodium and wa- pons, ventilation is normal. ter: aquaporins, Na+ - K + -ATPase, epithelial Na+ channel (ENaC). (c) Observation. If the medulla is completely separated from the (Remember: Na+ concentrations are higher in the ECF than in the pons and higher brain centers, ventilation becomes irregular ICF.) but a pattern of inspiration/expiration remains. 24. A hospitalized patient with severe chronic obstructive lung disease Level Four Quantitative Problems

has a PCO2 of 55 mm Hg and a PO2 of 50 mm Hg. To elevate his blood 28. You are given the following information on a patient. oxygen, he is given pure oxygen through a nasal tube. Th e patient Blood volume = 5.2 liters immediately stops breathing. Explain why this might occur. Hematocrit = 47% 25. You are a physiologist on a space fl ight to a distant planet. You fi nd Hemoglobin concentration = 12 g dL whole blood intelligent humanoid creatures inhabiting the planet, and they will- > = ingly submit to your tests. Some of the data you have collected are Total amount of oxygen carried in blood 1015 mL = described below. Arterial plasma PO2 100 mm Hg You know that when plasma P is 100 mm Hg, plasma contains 100 O2 0.3 mL O dL, and that hemoglobin is 98% saturated. Each he- 90 2> moglobin molecule can bind to a maximum of four molecules of 80 oxygen. Using this information, calculate the maximum oxygen- 70 carrying capacity of hemoglobin (100% saturated). Units will be 60 mL O2/g Hb. 50 29. Adolph Fick, the nineteenth-century physiologist who derived 40 Fick’s law of diff usion, also developed the Fick equation that relates oxygen consumption, cardiac output, and blood oxygen content: 30 = : O 2 consumption cardiac output (arterial oxygen content Pigment saturation, % 20 - venous oxgen content) 10 A person has a cardiac output of 4.5 L min, an arterial oxygen con- > tent of 105 mL O L blood, and a vena cava oxygen content of 50 20 40 60 80 100 2> mL O2 L blood. What is this person’s oxygen consumption? PO (mm Hg) > 2 30. Describe what happens to the oxygen-hemoglobin saturation curve in Figure 18.9 a when blood hemoglobin falls from 15 g dL blood to The graph above shows the oxygen saturation curve for the > 10 g dL blood. oxygen-carrying molecule in the blood of the humanoid named Bzork. >

658 Gas Exchange and Transport

Answers

11. As the PO falls, more oxygen is released. Th e PO of venous blood Answers to Concept Check Questions 2 2 leaving the muscle is 25 mm Hg, same as the PO2 of the muscle. 12. An airway obstruction would decrease alveolar ventilation and in- 1. (a) electron transport system (b) citric acid cycle + crease arterial PCO2 . Elevated arterial PCO2 would increase the H

2 . Th e PO2 of the alveoli is constantly being replenished by fresh air. concentration in the arterial blood and decrease pH. = 3. 720 mm Hg * 0.78 N2 561.6 mm Hg = * 4. Air is 21% oxygen. Th erefore, 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. Answers to Figure and Graph Questions 5. Blood pools in the lungs because the left heart is unable to pump all Figure 18.4 : Oxygen is 2.85 mL L blood and CO is 28 mL L blood. the blood coming into it from the lungs. Increased blood volume > 2 > in the lungs increases pulmonary blood pressure. Figure 18.5 : O2 crosses fi ve cell membranes: two of the alveolar cell, two of the capillary endothelium, and one of the red blood cell. 6. When alveolar ventilation increases, arterial PO2 increases because Figure 18.9 : 1. (a) When PO2 is 20 mm Hg, Hb saturation is 34%. more fresh air enters the alveoli. Arterial PCO2 decreases because (b) Hemoglobin is 50% saturated with oxygen at a PO2 of 28 mm the low PCO2 of fresh air dilutes alveolar PCO2. The CO2 pressure gradient between venous blood and the alveoli increases, causing 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 more CO2 to leave the blood. Venous PO2 and PCO2 do not change because these pressures are determined by oxygen consumption muscle cell warms up, Hb releases more oxygen. 4. Loss of 2,3-DPG is not good because then hemoglobin binds more tightly to oxy- and CO2 production in the cells. gen at the P values found in cells. 5. Th e P of placental blood is 7. False. Plasma is essentially water, and Figure 18.4 shows that CO O2 O2 2 about 28 mm Hg. 6. At a P of 10 mm Hg, maternal blood is only 18 is more soluble in water than O . O2 2 about 8% saturated with oxygen. 8 . Th e other factor that aff ects how much of each gas dissolves in the Figure 18.13 : 1. pons; 2. ventral respiratory group; 3. medullary chemo- saline solution is the solubility of the gas in that solution. receptor; 4. sensory neuron; 5. carotid chemoreceptor; 6. somatic 9. Yes. Hemoglobin reaches 100% saturation at 650 mm Hg. At sea motor neuron (expiration); 7. aortic chemoreceptor; 8. internal level, atmospheric pressure is 760 mm Hg, and if the “atmosphere” intercostals; 9. abdominal muscles; 10. diaphragm; 11. external in- is 100% oxygen, then P is 760 mm Hg. O2 tercostals; 12. scalenes and sternocleidomastoids; 13. somatic motor

10. Th e fl atness at the top of the PO2 curve tells you that hyperventi- neuron (inspiration); 14. dorsal respiratory group; 15. limbic sys- lation causes only a minimal increase in percent saturation of tem; 16. higher brain centers (emotions and voluntary control) arterial Hb. Figure 18.15 : One breath takes 5 seconds, so there are 12 breaths min. >

Answers to Review Questions

Level One Reviewing Facts and Terms Level Two Reviewing Concepts 1. Pressure gradients, solubility in water, alveolar capillary perfusion, blood 10. Start with Figure 18.10 . pH, temperature. 11. Most oxygen is bound to hemoglobin, not dissolved in the plasma.

2. 98%. Remainder is dissolved in 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, 3 . PO2, temperature, pH, and the amount of hemoglobin available for binding (most important). measured in units such as moles per liter. While solution partial pressure and concentration are proportional, concentration is affected by the gas solubil- 4. Four globular protein chains, each wrapped around a central heme group ity, and therefore is not the same as partial pressure. with iron. 13. decrease 5. Medulla and pons . Dorsal—neurons for inspiration; ventral—neurons for inspiration and active expiration. Central pattern generator—group of neurons 14. Hypoxia—low oxygen inside cells. COPD—chronic obstructive pulmonary that interact spontaneously to control rhythmic contraction of certain muscle disease (includes chronic bronchitis and emphysema). Hypercapnia— groups. elevated CO2 . 15. Oxygen is not very soluble in water, and the metabolic requirement for 6. Medullary chemoreceptors increase ventilation when PCO2 increases. Carotid 6 oxygen in most multicellular animals would not be met without an oxygen- and aortic chemoreceptors respond to PCO2, pH, and PO2 60 mm Hg. PCO2 is most important. transport molecule. 7. They include irritant-mediated bronchoconstriction and the cough reflex. 16. (a) x -axis—ventilation in L min; y -axis—arterial P , in mm Hg. See Figure > O2 8. Partial pressure gradients 18.9 . (b) x-axis—arterial P in mm Hg; y -axis—ventilation in L min. As CO2 > arterial P increases, ventilation increases. There is a maximum ventilation 9. Decreased atmospheric PO2, decreased alveolar perfusion, loss of hemoglo- CO2 bin, increased thickness of respiratory membrane, decreased respiratory rate, and the slope of the curve decreases as it approaches this maximum. surface area, increased diffusion distance. 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 tion becomes low oxygen (below 60 mm Hg). Thus, when the patient is given is available for oxygen transport. O2, there is no chemical drive for ventilation, and the patient stops breathing. 19. (a) See Figure 18.17 . (b) See Figure 18.13 . 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 Level Three Problem Solving > oxygen it can carry. 20. Increased dead space decreases alveolar ventilation. (a) increases (b) de- 26. All three lines show that as P increases, ventilation increases. Line A shows creases (c) increases (d) decreases CO2 that a decrease in P potentiates this increase in ventilation (when compared 21. Person (a) has slightly reduced dissolved O but at P = 80, Hb saturation CO2 2 O2 to line B). Line C shows that ingestion of alcohol lessens the effect of increasing is still about 95%. If oxygen content is 197 mL O L at P = 100 and 98% 2> O2 P on ventilation. Because alcohol is a CNS-depressant, we can hypothesize saturation, then oxygen content at P = 80 mm Hg and 95% saturation CO2 O2 that the pathway that links increased P and increased ventilation is inte- is 190 mL O L blood 197 * 0.95/0.98 , with Hb constant. Person (b) CO2 2> 1 1 22 grated in the CNS. has reduced hemoglobin of 12 g dL, but it is still 98% saturated. So, oxygen > 27. Apical—faces airspace; basolateral—faces interstitial fluid. Apical side has content would be 157.6 mL O L blood 197 * 12/15 . The increased P 2> 1 1 22 O2 ENaC and aquaporins; basolateral side has aquaporins and Na +-K+ -ATPase. did not compensate for the decreased hemoglobin content. Na+ enters the cell through ENaC, then is pumped out the basolateral side. 22. (a) decrease (b) decrease (c) decrease ( Cl- follows to maintain electrical neutrality.) Translocation of NaCl allows 23. (a) Respiratory movements originate above the level of the cut, which could water to follow by osmosis. 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 Level Four Quantitative Problems alone, but other important aspects of respiration depend upon signals origi- 28. 1.65 mL O gm Hb nating in the pons or higher. 2> 29. 247.5 mL O min 24. With chronic elevated P , the chemoreceptor response adapts, and CO is no 2> CO2 2 30. Nothing. The percent saturation of Hb is unchanged at any given P . How- longer a chemical drive for ventilation. The primary chemical signal for ventila- O2 ever, with less Hb available, less oxygen will be transported.

Photo Credits

CO: Jorge Bernardino de la Serna, MEMPHYS-Center for Biomembrane Biotechnology: Photomick/iStockphoto.com. Physics, University of Southern Denmark

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