Respiratory System

Respiration is defined as the movement of oxygen from the outside environment to the cells within tissue and the transport of carbon dioxide in the opposite direction. There are two lungs, the right and left, each divided into lobes. The lungs consist mainly of tiny air-containing sacs called alveoli (singular, alveolus), which number approximately 300 million in an adult. The alveoli are the sites of gas exchange with the blood. The airways are the tubes through which air flows from the external environment to the alveoli and back. Inspiration (inhalation) is the movement of air from the external environment through the airways into the alveoli during breathing. Expiration (exhalation) is air movement in the opposite direction. An inspiration and expiration constitute a respiratory cycle. During the entire respiratory cycle, the right ventricle of the heart pumps blood through the pulmonary arteries and arterioles and into the capillaries surrounding each alveolus. In a healthy adult at rest, approximately 4 L of fresh air enters and leaves the alveoli per minute, while 5L of blood, the cardiac output, flows through the pulmonary capillaries. During heavy exercise, the airflow can increase 20-fold, and the blood flow five to six fold.

During inspiration, air passes through the nose or the mouth (or both) into the pharynx, a passage common to both air and food. The pharynx branches into two tubes: the esophagus, through which food passes to the stomach, and the larynx, which is part of the airways. The larynx houses the vocal cords, two folds of elastic tissue stretched horizontally across its lumen. The flow of air past the vocal cords causes them to vibrate, producing sounds. The nose, mouth, pharynx, and larynx are collectively termed the upper airways. The larynx opens into a long tube, the trachea, which in turn branches into two bronchi (singular, bronchus), one of which enters each lung. Within the lungs, there are more than 20 generations of branchings, each resulting in narrower, shorter, and more numerous tubes. The walls of the trachea and bronchi contain rings of cartilage, which give them their cylindrical shape and support them. The first airway branches that no longer contain cartilage are termed bronchioles, which branch into the smaller, terminal bronchioles. Alveoli first begin to appear attached to the walls of the respiratory bronchioles. The number of alveoli increases

in the alveolar ducts, and the airways then end in grapelike clusters called alveolar sacs that consist entirely of alveoli. The bronchioles are surrounded by smooth muscle, which contracts or relaxes to alter bronchiolar radius, in much the same way that the radius of small blood vessels (arterioles) is controlled. The airways beyond the larynx can be divided into two zones. The conducting zone extends from the top of the trachea to the end of the terminal bronchioles. This zone contains no alveoli and does not exchange gases with the blood. The respiratory zone extends from the respiratory bronchioles down. This zone contains alveoli and is the region where gases exchange with the blood.

The alveoli are tiny, hollow sacs with open ends that are continuous with the lumens of the airways. Typically, a single alveolar wall separates the air in two adjacent alveoli. Most of the air-facing surfaces of the wall are lined by a continuous layer, one cell thick, of flat epithelial cells termed type I alveolar cells. Interspersed between these cells are thicker, specialized cells termed type II alveolar cells that produce a detergent-like substance called surfactant that, is important for preventing the collapse of the alveoli. The alveolar walls contain capillaries and a very small interstitial space, which consists of interstitial fluid and a loose meshwork of connective tissue. In many places, the interstitial space is absent altogether, and the basement membranes of the alveolar-surface epithelium and the capillary-wall endothelium fuse. Because of this unique anatomical arrangement, the blood within an alveolar-wall capillary is separated from the air within the alveolus by an extremely thin barrier (0.2 mm, compared with the 7mm diameter of an average red blood cell). The total surface area of alveoli in contact with capillaries is roughly the size of a tennis court. This extensive area and the thinness of the barrier permit the rapid exchange of large quantities of oxygen and carbon dioxide by diffusion. These are excellent examples of two of the general principles of physiology—that physiological processes require the transfer and balance of matter (in this case, oxygen and carbon dioxide) and energy between compartments; and that structure (in this case, the thinness of the diffusion barrier a nd the enormous surface area for gas exchange) is a determinant of—and has coevolved with—function (the transfer of oxygen and carbon dioxide between the alveolar air and the blood in the pulmonary capillaries). In some of the alveolar walls, pores permit the flow of air between alveoli. This route can be very important when the airway leading to an alveolus is occluded by disease, because some

air can still enter the alveolus by way of the pores between it and adjacent alveoli.

Alveolar air does not have the same concentrations of gases as atmospheric air. There are several reasons for the differences. First, alveolar air is only partially replaced by atmospheric air with each breath. Second, O2 is constantly being absorbed into the pulmonary blood from the alveolar air. Third, CO2 is constantly diffusing from the pulmonary blood into the alveoli. And fourth, dry atmospheric air that enters the respiratory passages is humidified even before it reaches the alveoli. By volume, dry air contains 78.09% nitrogen, 20.95% oxygen, 0.93% argon, 0.03% carbon dioxide and small amounts of other gases.

Nitrogen is a naturally occurring element that is essential for growth and reproduction of both animal and plants. It is found in amino acids, nucleic acid and biologically active molecules like alkaloids. Most of the living organisms cannot utilize elemental nitrogen directly but they can utilized nitrogen fixed compounds. Nitrogen fixation achieved through physical activity of lightning or biological activity of microbes.

Animal metabolism of nitrogen in proteins excreted as urea whereas in nucleic acid excreted as urea and uric acid. The characteristic odor of animal flesh decay is caused by the creation of long chain nitrogen containing amines such as putrescine and cadaverine which are breakdown product of ornithine and lysine respectively. Most decay eventually return nitrogen to the atmosphere.

Oxygen plays vital role in the breathing process and in the metabolism of the living organisms. Most of the organic compounds of living organisms contains oxygen in fixed format. During breathing, oxygen enter into human and it is transported through blood to tissue and then it reaches cells. In cells, oxygen plays vital role in cell respiration process in which oxygen converted into water.

Atmospheric air is composed almost entirely of nitrogen and O2; it normally contains almost no CO2 and little water vapor. However, as soon as the atmospheric air enters the respiratory passages, it is exposed to the fluids that cover the respiratory surfaces. Even before the air enters the alveoli, it becomes almost totally humidified. The partial pressure of water vapor at a normal body temperature of 37°C is 47 mm Hg, which is therefore the partial pressure of water vapor in the alveolar air. Because the total pressure in the alveoli cannot rise to more than the atmospheric pressure (760 mm Hg at sea level), this water vapor simply dilutes all the other gases in the inspired air. Humidification of the air dilutes the oxygen partial pressure at sea level from an average of 159 mm Hg in atmospheric air to 149 mm Hg in the humidified air, and it dilutes the nitrogen partial pressure from 597 to 563 mm Hg.

The average male functional residual capacity of the lungs (the volume of air remaining in the lungs at the end of normal expiration) measures about 2300 milliliters. Yet only 350 milliliters of new air is brought into the alveoli with each normal inspiration, and this same amount of old alveolar air is expired. Therefore, the volume of alveolar air replaced by new atmospheric air with each breath is only one seventh of the total, so multiple breaths are required to exchange most of the alveolar air. This slows rate of renewal of the alveolar air. In the first alveolus of the figure, excess gas is present in the alveoli but note that even at the end of 16 breaths the excess gas still has not been completely removed from the alveoli. The graph showed that the rate at which excess gas in the alveoli is normally removed, showing that with normal alveolar ventilation, about one half the gas is removed in 17 seconds. When a person’s rate of alveolar ventilation is only one-half normal, one half the gas is removed in 34 seconds, and when the rate of ventilation is twice normal, one half is removed in about 8 seconds.

Importance of the Slow Replacement of Alveolar Air. The slow replacement of alveolar air is of particular importance in preventing sudden changes in gas concentrations in the blood. This makes the respiratory control mechanism much more stable than it would be otherwise, and it helps prevent excessive increases and decreases in tissue oxygenation, tissue CO2 concentration, and tissue pH when respiration is temporarily interrupted.

Changes in intrapulmonary pressure occur as a result of changes in lung volume. This follows from Boyle’s law, which states that the pressure of a given quantity of gas is inversely proportional to its volume. An increase in lung volume during inspiration decreases intrapulmonary pressure to subatmospheric levels; air therefore goes in. A decrease in lung volume, conversely, raises the intrapulmonary pressure above that of the atmosphere, expelling air from the lungs. These changes in lung volume occur as a consequence of changes in thoracic volume.

According to Dalton’s law, the total pressure of a gas mixture (such as air) is equal to the sum of the pressures that each gas in the mixture would exert independently. The pressure that a particular gas in a mixture exerts independently is the partial pressure of that gas, which is equal to the product of the total pressure and the fraction of that gas in the mixture.

Dalton’s law can thus be restated as follows: The total pressure of the gas mixture is equal to the sum of the partial pressures of the constituent gases. Because oxygen constitutes about 21% of the atmosphere, for example, its partial pressure (abbreviated PO₂) is 21% of 760, or about 159 mmHg. Nitrogen constitutes about 78% of the atmosphere, so its partial pressure is equal to 0.78. 760 = 593 mmHg. These two gases thus contribute about 99% of the total pressure of 760 mmHg:

The enormous surface area of alveoli and the short diffusion distance between alveolar air and the capillary blood quickly help to bring oxygen and carbon dioxide in the blood and air into equilibrium. This function is further aided by the tremendous number of capillaries that surround each alveolus, forming an almost continuous sheet of blood around the alveoli. When a liquid and a gas, such as blood and alveolar air, are at equilibrium, the amount of gas dissolved in the fluid reaches a maximum value. According to Henry’s law, this value depends on (1) the solubility of the gas in the fluid, which is a physical constant; (2) the temperature of the fluid—more gas can be dissolved in cold water than warm water; and (3) the partial pressure of the gas. Because solubility is a constant and the temperature of the blood does not vary significantly, the concentration of a gas dissolved in a fluid (such as plasma) depends directly on its partial pressure in the gas mixture. When water—or plasma—is brought into equilibrium with air at a PO₂ of 100 mmHg, for example, the fluid will contain 0.3 ml of O₂ per 100 ml fluid at 37 ° C. If the PO₂ of the gas were reduced by half, the amount of dissolved oxygen would also be reduced by half.

Oxygen is continually being absorbed from the alveoli into the blood of the lungs, and new O2 is continually being breathed into the alveoli from the atmosphere. The more rapidly O2 is absorbed, the lower its concentration in the alveoli becomes; conversely, the more rapidly new O2 is breathed into the alveoli from the atmosphere, the higher its concentration becomes. Therefore, O2 concentration in the alveoli, as well as its partial pressure, is controlled by (1) the rate of absorption of O2 into the blood and (2) the rate of entry of new O2 into the lungs by the ventilatory process.

The figure shows the effect of alveolar ventilation and rate of O2 absorption into the blood on the alveolar partial pressure of O2 (PO2). One curve represents O2 absorption at a rate of 250 ml/min, and the other curve represents a rate of 1000 ml/min. At a normal ventilatory rate of 4.2 L/min and an O2 consumption of 250 ml/min, the normal operating point in figure is point A. The figure also shows that when 1000 milliliters of O2 are being absorbed each minute, as occurs during moderate exercise, the rate of alveolar ventilation must increase fourfold to maintain the alveolar Po2 at the normal value of 104 mm Hg. Another effect shown in figure is that even an extreme increase in alveolar ventilation can never increase the alveolar PO2 above 149 mm Hg as long as the person is breathing normal atmospheric air at sea level pressure, because 149 mm Hg is the maximum PO2 in humidified air at this pressure. If the person breathes gases that contain partial pressures of O2 higher than 149 mm Hg, the alveolar PO2 can approach these higher pressures at high rates of ventilation.

Carbon dioxide is continually formed in the body and then carried in the blood to the alveoli, and it is continually removed from the alveoli by ventilation. The figure shows the effects on the alveolar partial pressure of CO2 (PCO2) of both alveolar ventilation and two rates of CO2

excretion, 200 and 800 ml/min. One curve represents a normal rate of CO2 excretion of 200 ml/min. At the normal rate of alveolar ventilation of 4.2 L/min, the operating point for alveolar PCO2 is at point A in figure (i.e., 40 mm Hg). Two other facts are also evident from figure:

First, the alveolar PCO2 increases directly in proportion to the rate of CO2 excretion, as represented by the fourfold elevation of the curve (when 800 milliliters of CO2 are excreted per minute). Second, the alveolar PCO2 decreases in inverse proportion to alveolar ventilation. Therefore, the concentrations and partial pressures of both O2 and CO2 in the alveoli are determined by the rates of absorption or excretion of the two gases and by the amount of alveolar ventilation.

Although at sea level nitrogen is physiologically inert, larger amounts of dissolved nitrogen under hyperbaric (highpressure) conditions have deleterious effects, possibly caused by the increased amounts of nitrogen dissolved in plasma membranes at the high partial pressures. Nitrogen narcosis resembles alcohol intoxication; depending on the depth of the dive, the diver may experience what Jacques Cousteau termed “rapture of the deep.” Dizziness and extreme drowsiness are other narcotizing effects.

The blood that enters the pulmonary capillaries is systemic venous blood pumped by the right ventricle to the lungs through the pulmonary arteries. Having come from the tissues, it has a relatively high PCO2 (46 mmHg in a healthy person at rest) and a relatively low PO2 (40 mmHg). The differences in the partial pressures of oxygen and carbon dioxide on the two sides of the alveolar-capillary membrane result in the net diffusion of oxygen from alveoli to blood and of carbon dioxide from blood to alveoli. (For simplicity, we are ignoring the small diffusion barrier provided by the interstitial space.) As this diffusion occurs, the PO2 in the pulmonary capillary blood increases and the PCO2 decreases. The net diffusion of these gases ceases when the capillary partial pressures become equal to those in the alveoli. In a healthy person, the rates at which oxygen and carbon dioxide diffuse are high enough and the blood flow through the capillaries slow enough that complete equilibrium is reached well before the blood reaches the end of the capillaries.

Thus, the blood that leaves the pulmonary capillaries to return to the heart and be pumped into the systemic arteries has essentially the same PO2 and PCO2 as alveolar air. (They are not exactly the same, for reasons given later.) Accordingly, the factors described in the previous section—atmospheric PO2, cellular oxygen consumption and carbon dioxide production, and alveolar ventilation—determine the alveolar gas pressures, which then determine the systemic arterial gas pressures. The diffusion of gases between alveoli and capillaries may be impaired in a number of ways, resulting in inadequate oxygen diffusion into the blood. For one thing, the total surface area of all of the alveoli in contact with pulmonary capillaries may be decreased. In pulmonary edema, some of the alveoli may become filled with fluid. Diffusion may also be impaired if the alveolar walls become severely thickened with connective tissue (fibrotic), as, for example, in the disease called diffuse interstitial fibrosis. In this disease, fibrosis may arise from infection, autoimmune disease, hypersensitivity to inspired substances, exposure to toxic airborne chemicals, and many other causes. Typical symptoms of these types of diffusion diseases are shortness of breath and poor oxygenation of blood. Pure diffusion problems of these types are restricted to oxygen and usually do not affect the elimination of carbon dioxide, which diffuses more rapidly than oxygen.

As the systemic arterial blood enters capillaries throughout the body, it is separated from the interstitial fluid by only the thin capillary wall, which is highly permeable to both oxygen and carbon dioxide. The interstitial fluid, in turn, is separated from the intracellular fluid by the plasma membranes of the cells, which are also quite permeable to oxygen and carbon dioxide. Metabolic reactions occurring within cells are constantly consuming oxygen and producing carbon dioxide. Therefore, intracellular PO2 is lower and PCO2 higher than in arterial blood. The lowest PO2 of all—less than 5 mmHg—is in the mitochondria, the site of oxygen utilization. As a result, a net diffusion of oxygen occurs from blood into cells and, within the cells, into the mitochondria, and a net diffusion of carbon dioxide occurs from cells into blood. In this manner, as blood flows through systemic capillaries, its PO2 decreases and its PCO2 increases. In summary, the supply of new oxygen to the alveoli and the consumption of oxygen in the cells create PO2 gradients that produce net diffusion of oxygen from alveoli to blood in the lungs and from blood to cells in the rest of the body. Conversely, the production of carbon dioxide by cells and its elimination from the alveoli via expiration create PCO2 gradients that produce net diffusion of carbon dioxide from cells to blood in the rest of the body and from blood to alveoli in the lungs.

The oxygen is present in two forms: (1) dissolved in the plasma and erythrocyte cytosol and (2) reversibly combined with hemoglobin molecules in the erythrocytes. As predicted by Henry’s law, the amount of oxygen dissolved in blood is directly proportional to the PO2 of the blood. Because the solubility of oxygen in water is relatively low, only 3 mL can be dissolved in 1 L of blood at the normal arterial PO2 of 100 mmHg. The other 197 mL of oxygen in a liter of arterial blood—more than 98% of the oxygen content in the liter—is transported in the erythrocytes, reversibly combined with hemoglobin. Each hemoglobin molecule is a protein made up of four subunits bound together. Each subunit consists of a molecular group known as heme and a polypeptide attached to the heme. The four polypeptides of a hemoglobin molecule are collectively called globin. Each of the four heme groups in a hemoglobin molecule contains one atom of iron (Fe²⁺), to which molecular oxygen binds. Because each iron atom can bind one molecule of oxygen, a single hemoglobin molecule can bind four oxygen molecules. However, for simplicity, the equation for the reaction between oxygen and hemoglobin is usually written in terms of a single polypeptide–heme subunit of a hemoglobin molecule:

Therefore, hemoglobin can exist in one of two forms—deoxyhemoglobin (Hb) and oxyhemoglobin (HbO2). In a blood sample containing many hemoglobin molecules, the fraction of all the hemoglobin in the form of oxyhemoglobin is expressed as the percent hemoglobin saturation:

For example, if the amount of oxygen bound to hemoglobin is 40% of the maximal capacity, the sample is said to be 40% saturated. The denominator in this equation is also termed the oxygen-carrying capacity of the blood.

Let us now apply this analysis to capillaries of the lungs and tissues. The plasma and erythrocytes entering the lungs have a PO2 of 40 mmHg. As we can see from Figure 13.26, hemoglobin saturation at this PO2 is 75%. The alveolar PO2-105 mmHg-is higher than the blood PO2 and so oxygen diffuses from the alveoli into the plasma. This increases plasma PO2 and induces diffusion of oxygen into the erythrocytes, increasing erythrocyte PO2 and causing increased combination of oxygen and hemoglobin. Most of the oxygen diffusing into the blood from the alveoli does not remain dissolved but combines with hemoglobin. Therefore, the blood PO2 normally remains less than the alveolar PO2 until hemoglobin is virtually 100% saturated. This maintains the diffusion gradient of oxygen movement into the blood during the very large transfer of oxygen.

In the tissue capillaries, the process is reversed. Because the mitochondria of all cells are utilizing oxygen, the cellular PO2 is less than the PO2 of the surrounding interstitial fluid. Therefore, oxygen is continuously diffusing into the cells. This causes the interstitial fluid PO2 to always be less than the PO2 of the blood flowing through the tissue capillaries, so net diffusion of oxygen occurs from the plasma within the capillary into the interstitial fluid. As a result, plasma PO2 becomes lower than erythrocyte PO2, and oxygen diffuses out of the erythrocyte into the plasma. The decrease in erythrocyte PO2 causes the dissociation of oxygen from hemoglobin, thereby liberating oxygen, which then diffuses out of the erythrocyte. The net result is a transfer, purely by diffusion, of large quantities of oxygen from hemoglobin to plasma to interstitial fluid to the mitochondria of tissue cells. In most tissues under resting conditions, hemoglobin is still 75% saturated as the blood leaves the tissue capillaries. This fact underlies an important local mechanism by which cells can obtain more oxygen whenever they increase their activity. For example, an exercising muscle consumes more oxygen, thereby lowering its intracellular and interstitial PO2. This increases the blood-to-cell PO2 gradient. As a result, the rate of oxygen diffusion from blood to cells increases. In turn, the resulting decrease in erythrocyte PO2 causes additional dissociation of hemoglobin and oxygen. In this manner, the extraction of oxygen from blood in an exercising muscle is much greater than the usual 25%. In addition, an increased blood flow to the muscles, called active hyperemia, also contributes greatly to the increased oxygen supply.

Carbon dioxide is a waste product that has toxicity in part because it generates H⁺. Large changes in H⁺ concentration, if not buffered, would lead to significant changes in pH, thus altering the tertiary structure of proteins, including enzymes. In a resting person, metabolism generates about 200 mL of carbon dioxide per minute. When arterial blood flows through tissue capillaries, this volume of carbon dioxide diffuses from the tissues into the blood. Carbon dioxide is much more soluble in water than is oxygen, so blood carries more dissolved carbon dioxide than dissolved oxygen. Even so, only about 10% of the carbon dioxide entering the blood dissolves in the plasma and the cytosol of the erythrocytes. In order to transport all of the CO2 produced in the tissues to the lung, much of the CO2 in the blood must be carried in other forms. Another 25% to 30% of the carbon dioxide molecules entering the blood react reversibly with the amino groups of hemoglobin to form carbaminohemoglobin. For simplicity, this reaction with hemoglobin is written as

This reaction is aided by the fact that deoxyhemoglobin, formed as blood flows through the tissue capillaries, has a greater affinity for carbon dioxide than does oxyhemoglobin. The remaining 60% to 65% of the carbon dioxide molecules entering the blood in the tissues is converted to HCO3^-:

The first reaction in equation 13–11 is rate limiting and is very slow unless catalyzed in both directions by the enzyme carbonic anhydrase. This enzyme is present in the erythrocytes but not in the plasma, so this reaction occurs mainly in the erythrocytes. In contrast, carbonic acid dissociates very rapidly into HCO3^-and H⁺ without any enzyme assistance. Once formed, most of the HCO3^- moves out of the erythrocytes into the plasma via a transporter that exchanges one HCO3^- for one chloride ion (this is called the “chloride shift,” which maintains electroneutrality). HCO3^- leaving the erythrocyte favors the balance of the reaction

The reactions also explain why, as mentioned earlier, the H⁺ concentration in tissue capillary blood and systemic venous blood is higher than that in arterial blood and increases as metabolic activity increases. The fate of this H⁺ will be discussed in the next section. Because carbon dioxide undergoes these various fates in blood, it is customary to add up the amounts of dissolved carbon dioxide, HCO3^-, and carbon dioxide in carbaminohemoglobin to arrive at the total-blood carbon dioxide, which is measured as a component of routine blood chemistry testing. The opposite events occur as systemic venous blood flows through the lung capillarie. Because the blood PCO2 is higher than alveolar PCO2, a net diffusion of CO2 from blood into alveoli occurs. This loss of CO2 from the blood decreases the blood PCO2 and drives the reactions to the left. HCO3^- and H⁺ combine to produce H2CO3, which then dissociates to CO2 and H2O. Similarly, HbCO2 generates Hb and free CO2. Normally, as fast as CO2 is generated from HCO3^- and H⁺ and from HbCO2, it diffuses into the alveoli. In this manner, the CO2 that was delivered into the blood in the tissues is now delivered into the alveoli, from where it is eliminated during expiration.

As blood flows through the tissues, a fraction of oxyhemoglobin loses its oxygen to become deoxyhemoglobin, while simultaneously a large quantity of carbon dioxide enters the blood and undergoes the reactions that generate HCO3^- and H⁺. Deoxyhemoglobin has a much greater affinity for H⁺than does oxyhemoglobin, so it binds (buffers) most of the H⁺. When deoxyhemoglobin binds H⁺, it is abbreviated HbH.

In this manner, only a small amount of the H⁺ generated in the blood remains free. This explains why venous blood (pH 5 7.36) is only slightly more acidic than arterial blood (pH 5 7.40). As the venous blood passes through the lungs, this reaction is reversed. Deoxyhemoglobin becomes converted to oxyhemoglobin and, in the process, releases the H⁺ it picked up in the tissues. The H⁺ reacts with HCO3^- to produce carbonic acid, which, under the influence of carbonic anhydrase, dissociates to form carbon dioxide and water. The carbon dioxide diffuses into the alveoli to be expired. Normally, all the H⁺ that is generated in the tissue capillaries from the reaction of carbon dioxide and water recombines with HCO3^- to form carbon dioxide and water in the pulmonary capillaries. Therefore, none of this H⁺ appears in the arterial blood.

Not only would arterial PCO2 increase as a result, but so would arterial H⁺ concentration. Increased arterial H⁺ concentration due to carbon dioxide retention is termed respiratory acidosis. Conversely, hyperventilation would decrease arterial PCO2 and H⁺concentration, producing respiratory alkalosis.

As a result of catalysis by carbonic anhydrase within the red blood cells, large amounts of carbonic acid are produced as blood passes through the systemic capillaries. The buildup of carbonic acid concentrations within the red blood cells favors the dissociation of these molecules into hydrogen ions (protons, which contribute to the acidity of a solution) and HCO₃⁻ (bicarbonate), as shown by this equation: H2 CO3 → H⁺ + HCO3⁻ The hydrogen ions (H+) released by the dissociation of carbonic acid are largely buffered by their combination with deoxyhemoglobin within the red blood cells. Although the unbuffered hydrogen ions are free to diffuse out of the red blood cells, more bicarbonate diffuses outward into the plasma than does H+. As a result of the “trapping” of hydrogen ions within the red blood cells by their attachment to hemoglobin and the outward diffusion of bicarbonate, the inside of the red blood cell gains a net positive charge. This attracts chloride ions (Cl−), which move into the red blood cells as HCO3− moves out. This exchange of anions as blood travels through the tissue capillaries is called the chloride shift.

The unloading of oxygen is increased by the bonding of H+ (released from carbonic acid) to oxyhemoglobin. This is the Bohr effect, and results in increased conversion of oxyhemoglobin to deoxyhemoglobin. Now, deoxyhemoglobin bonds H+ more strongly than does oxyhemoglobin, so the act of unloading its oxygen improves the ability of hemoglobin to buffer the H+ released by carbonic acid. Removal of H + from solution by combining with hemoglobin (through the law of mass action), in turn, favors the continued production of carbonic acid and thereby improves the ability of the blood to transport carbon dioxide. Thus, carbon dioxide increases oxygen unloading, and oxygen unloading improves carbon dioxide transport.

When blood reaches the pulmonary capillaries, deoxyhemoglobin is converted to oxyhemoglobin. Because oxyhemoglobin has a weaker affinity for H+ than does deoxyhemoglobin, hydrogen ions are released within the red blood cells. This attracts HCO3− from the plasma, which combines with H+ to form carbonic acid: H+ + HCO3− → H2CO3. Under conditions of lower PCO2, as occurs in the pulmonary capillaries, carbonic anhydrase catalyzes the conversion of carbonic acid to carbon dioxide and water:

In summary, the carbon dioxide produced by the cells is converted within the systemic capillaries, mostly through the action of carbonic anhydrase in the red blood cells, to carbonic acid. With the buildup of carbonic acid concentrations in the red blood cells, the carbonic acid dissociates into bicarbonate and H+, which results in the chloride shift. A reverse chloride shift operates in the pulmonary capillaries to convert carbonic acid to H2O and CO2 gas, which is eliminated in the expired breath. The PCO2, carbonic acid, H+, and bicarbonate concentrations in the systemic arteries are thus maintained relatively constant by normal ventilation. This is required to maintain the acid-base balance of the blood.

1. The tidal volume is the volume of air inspired or expired with each normal breath; it amounts to about 500 milliliters in the average adult male.

2. The inspiratory reserve volume is the extra volume of air that can be inspired over and above the normal tidal volume when the person inspires with full force; it is usually equal to about 3000 milliliters.

3. The expiratory reserve volume is the maximum extra volume of air that can be expired by forceful expiration after the end of a normal tidal expiration; this volume normally amounts to about 1100 milliliters.

4. The residual volume is the volume of air remaining in the lungs after the most forceful expiration; this volume averages about 1200 milliliters.

In describing events in the pulmonary cycle, it is sometimes desirable to consider two or more of the volumes together. Such combinations are called pulmonary capacities. The important pulmonary capacities, which can be described as follows:

1. The inspiratory capacity equals the tidal volume plus the inspiratory reserve volume. This capacity is the amount of air (about 3500 milliliters) a person can breathe in, beginning at the normal expiratory level and distending the lungs to the maximum amount.

2. The functional residual capacity equals the expiratory reserve volume plus the residual volume. This capacity is the amount of air that remains in the lungs at the end of normal expiration (about 2300 milliliters).

3. The vital capacity equals the inspiratory reserve volume plus the tidal volume plus the expiratory reserve volume. This capacity is the maximum amount of air a person can expel from the lungs after first filling the lungs to their maximum extent and then expiring to the maximum extent (about 4600 milliliters).

4. The total lung capacity is the maximum volume to which the lungs can be expanded with the greatest possible effort (about 5800 milliliters); it is equal to the vital capacity plus the residual volume.

All pulmonary volumes and capacities are usually about 20 to 25 percent less in women than in men, and they are greater in large and athletic people than in small and asthenic people.

Spirometry is only one of many measurement procedures that the pulmonary physician uses daily. Many of these measurement procedures depend heavily on mathematical computations. To simplify these calculations, as well as the presentation of pulmonary function data, several abbreviations and symbols have become standardized. Using these symbols, we present here a few simple algebraic exercises showing some of the interrelations among the pulmonary volumes and capacities; the student should think through and verify these interrelations.

Table : Average Pulmonary Volumes and Capacities for a Healthy, Young Adult Man
Pulmonary Volumes and Capacities	Normal Values (ml)
Volumes
Tidal volume	500
Inspiratory reserve volume	3000
Expiratory volume	1100
Residual volume	1200
Capacities
Inspiratory capacity	3500
Functional residual capacity	2300
Vital capacity	4600
Total lung capacity	5800

During respiration, the volume and functioning of lungs, represented by different volume and capacity. Volume represents a particular state whereas capacity refers to the combination of different volumes.

The carbon dioxide released during fuel metabolism reacts with water by the action of enzyme carbonic anhydrase to form carbonic acid [H2CO3]. Carbonic acid is a weak acid that partially dissociated into bicarbonate ion [HCO-3] and H+ ion.

As base is added and H+ removed, carbonic acid dissociates into hydrogen ion and bicarbonate ions, and dissolved CO2 reacts with water to replenish the carbonic acid levels. When CO2 levels increased, it forms more amount of carbonic acid which inturn dissociated into hydrogen ion and bicarbonate ions. Thus bicarbonate buffer functions as buffer system.

Phosphoric acid dissociates into H+ ions and dihydrogen phosphate [H2PO4-] ions with pKa of 2.15. Dihydrogen phosphate [H2PO4-] ion dissociates into H+ ions and Monohydrogen phosphate [HPO42-] ions with pKa of 7.2 whereas Monohydrogen phosphate ions dissociates into hydrogen ion and phosphate PO43- anions with pKa of 12.4. From the dissociation constant values, it was clearly understood that phosphate act as effective buffer in blood (pH = 7.4).

But, phosphate concentration is very low in blood, thus, phosphate buffer, plays major role as a intracellular bufer in red blood cell and other types of cells where their concentration higher than blood and interstitial fluid. The sodium salts of phoshoric acid also act as buffer system.

Plasma proteins actually responsible for protein buffer system. The buffering capacity of proteins depends upon the pK inonizable group of aminoacid side chains. Histidine amino acid plays vital role as buffering agent because its imidazole group pK value is 6.7 and it is the more effective contributor for protein buffer system. The plasma proteins responsible for the 2% buffering capacity of plasma.

Hemoglobin present in erythrocytes also plays important role as buffering agent. It mainly buffers the acids produced during gaseous transport between lungs and tissues.

At tissue levels, H⁺ ions released from carbonic acid binds with hemoglobin and helps in the transport of CO₂ as HCO₃. In lungs, as hemoglobin combines with oxygen, it releases H⁺ ions, which inturn binds with HCO₃^- to form carbonic acid. Carbonic acid then dissociates into CO₂ and water. Then, CO₂ is exhaled.

The body pH is maintained by buffer system along with the functions of Kidney and Lungs. The role of kidney and lungs in the maintenance of pH is as follows.

The kidney maintains pH by excreting either acidic or basic urine. Excretion of acidic urine increases pH whereas basic urine excretion decreases pH in extracellular. Large amount of H+ ions are secreted into the tubular lumen by tubular epithelial cells. If they are removed in urine, it will increase pH of extracellular fluid. Large amount of bicarbonate ions are also continuously secreted in the renal tubules, if they are excreted in urine, then it reduces pH by retaining H+ ions. If more hydrogen ions removed than bicarbonate ions then there will be a net loss of acid whereas if more bicarbonate ions are filtered than hydrogen ions are secreted, then there will be a net loss of base. These functions achieved by mainly three components namely bicarbonate buffer system, phosphate buffer system and ammonia. The role of these components as follows:

The bicarbonate ions freely filtered through glomerulus, combines with hydrogen ions and forms carbonic acid which inturn dissociates into carbon dioxide and water. The carbon dioxide then diffused into tubular cells where it again combines with water to form carbonic acid in the presence of enzme carbonic anhydrase. Thus bicarbonate ions are reabsorbed. This pattern of H+ ion secretion occurs in proximal convoluted tube, ascending loop of henle and early part of distal convoluted tube.

After the absorption of available bicarbonate ions in tubular filtrate, remaining hydrogen ions interact with HPO^2-₄ or NaHPO-₄and forms H₂PO-₄or NaH₂PO₄ which can be excreted in urine. Thus, hydrogen ions removed from extracellular fluid.

Ammonia produced from glutamine in tubular epithelial cells, can freely diffused into tubular lumen. This ammonia then combines with hydrogen ions to form ammonium ions which can be easily excreted in urine. Thus, hydrogen ions are removed from extracellular fluid.

The second line of defense against maintenance of pH is the control of extracellular concentrations of CO₂ by the lungs. An increase in ventilation removes CO₂ from extracellular fluid which inturn reduces hydrogen ion concentration. Conversely, decreased ventilation increases CO₂, thus increasing hydrogen ion concentration in the extracellular fluid. Both bicarbonate buffer system and hemoglobin buffer system of erythrocytes are important for the maintenance of pH by lungs. In general, the overall buffering capacity of respiratory system is one to two times add great as than the other chemical buffer system comibined of extracellular fluid.

Respiratory regulation of acid-base balance is a physiological type of buffer system because it acts rapidly and keeps the H⁺ concentration from changing too much until the slowly responding kidneys can eliminate the imbalance. In general, the overall buffering power of the respiratory system is one to two times as great as the buffering power of all other chemical buffers in the extracellular fluid combined. That is, one to two times as much acid or base can normally be buffered by this mechanism as by the chemical buffers.

Defective acid-base balance leads to acid-base disorders which are of mainly two types namely acidosis and alkalosis. These disorders arised mainly due to the alterations in bicarbonate ions and carbonic acid levels.

Increased level of carbonic acid or decreased level of bicarbonate ion results in acidosis. It will be of two types namely respiratory acidosis and metabolic acidosis.

Role of lungs in the elevation of carbonic acid is referred as respiratory acidosis. The rise in arterial PCO₂ due to decreased ventilation causes respiratory acidosis. The CO₂ retained is in equilibrium with carbonic acid which inturn equilibrium with bicarbonate and hydrogen ion. Thus hydrogen ion concentration increased and pH decreased in extracellular fluid. This inturn, promotes secretion of hydrogen ions in tubular lumen.

Metabolic abnormalities results in acidosis called as metabolic acidosis. When acids stronger than HHb and the other buffer acids are added to blood, metabolic acidosis is produced and when the H+ level falls as a result of addition of alkali or removal of acid, metabolic acidosis results. The hydrogen and bicarbonate ions combined to form carbonic acid. The carbonic acid converted into carbon dioxide and water then carbondioxie is excreted via lungs. In metabolic acidosis, an excess of hydrogen ion over bicarbonate ions occurs in tubular fluid primarily due to decreased filtration of bicarbonate ions. This decreased filtrations of bicarbonate ions is caused mainly by a decrease in extracellular concentrations of bicarbonate ions. The primary compensations for metabolic acidosis are increased ventilations and increased reabsorption of bicarbonate ions.

Decreased level of carbonic acid or increased level of bicarbonate ion results in alkalosis. It will be of two types namely respiratory alkalosis and metabolic alkalosis.

Role of lungs in the decrease of carbonic acid is refferred as respiratory alkalosis. The decrease in arterial PCO₂ due to hyperventilation causes respiratory alkalosis. The CO₂ removed is in equilibrium with carbonic acid which inturn equilibrium with bicarbonate and hydrogen ion. Thus hydrogen ion concentration decreased and pH increased in extracellular fluid. This inturn, decreases secretion of hydrogen ions in tubular lumen.

Metabolic abnormalities result in alkalosis called as metabolic alkalosis. In metabolic alkalosis, plasma bicarbonate ions and pH increased. This is partly compensated by reduction in respiration rate which increases PCO₂ and helps to return the extracellular pH toward normal. In addition,the increase in bicarbonate concentration in the extracellular fluid leads to the increase in filtered load of bicarbonate ions in tubular fluid over hydrogen ions. The excess bicarbonate ions excreted in urine without reabsorption due to lack of hydrogen ions. Thus by decreased ventilation and increased bicarbonate ions excretions, the raise in bicarbonate ions compensated.

At any given PO2, other factors influence the degree of hemoglobin saturation. These include blood PCO2, H1 concentration, temperature, the concentration of a substance produced by erythrocytes called 2,3-diphosphoglycerate (DPG) (also known as bisphosphoglycerate [BPG]), and the presence of a special kind of hemoglobin usually only found in the fetal blood. An increase in DPG concentration, temperature, and acidity causes the dissociation curve to shift to the right. This means that at any given PO2, hemoglobin has less affinity for oxygen. In contrast, a decrease in DPG concentration, temperature, or acidity causes the dissociation curve to shift to the left, such that at any given PO2, hemoglobin has a greater affinity for oxygen. The effects of increased PCO2, H⁺ concentration, and temperature are continuously exerted on the blood in tissue capillaries, because each of these factors is greater in tissue capillary blood than in arterial blood. The PCO2 is increased because of the carbon dioxide entering the blood from the tissues. For reasons to be described later, the H⁺ concentration is increased because of the increased PCO2 and the release of metabolically produced acids such as lactic acid. The temperature is increased because of the heat produced by tissue metabolism. Hemoglobin exposed to this increased blood PCO2, H⁺ concentration, and temperature as it passes through the tissue capillaries has a decreased affinity for oxygen. Therefore, hemoglobin gives up even more oxygen than it would have if the decreased tissue capillary PO2 had been the only operating factor. The more metabolically active a tissue, the greater its PCO2, H⁺concentration, and temperature will be. At any given PO2, this causes hemoglobin to release more oxygen during passage through the tissue’s capillaries and provides the more active cells with additional oxygen. Here, then, is another local mechanism that increases oxygen delivery to tissues with increased metabolic activity. Carbon dioxide and H⁺ do so by combining with the globin portion of hemoglobin and altering the conformation of the hemoglobin molecule. Therefore, these effects are a form of allosteric modulation. Increased temperature also decreases hemoglobin’s affinity for oxygen by altering its conformation.

DPG, which is produced during glycolysis, reversibly binds with hemoglobin, allosterically causing it to have a lower affinity for oxygen (see Figure 13.29). Erythrocytes have no mitochondria and, therefore, rely exclusively on glycolysis. Consequently, erythrocytes contain large quantities of DPG, which is present in only trace amounts in cells with mitochondria. The net result is that whenever DPG concentrations increase, there is enhanced unloading of oxygen from hemoglobin as blood flows through the tissues. Such an increase in DPG concentration is triggered by a variety of conditions associated with inadequate oxygen supply to the tissues and helps to maintain oxygen delivery. For example, the increase in DPG is important during exposure to high altitude when the PO2 of the blood is decreased, because DPG increases the unloading of oxygen in the tissue capillaries. Finally, the fetus has a unique form of hemoglobin called fetal hemoglobin. Fetal hemoglobin contains subunits that are coded for by different genes than those that are expressed postnatally. These subunits alter the shape of the final protein and result in a hemoglobin molecule that has a higher affinity for oxygen than adult hemoglobin. That is, fetal hemoglobin binds considerably more oxygen than adult hemoglobin at any given PO2. This allows an increase in oxygen uptake across the placental diffusion barrier. Therefore, although fetal arterial PO2 is much lower than that in the air-breathing newborn, fetal hemoglobin allows adequate oxygen uptake in the placenta to supply the developing fetus.

Carbon monoxide is a colorless, odorless gas that is a product of the incomplete combustion of hydrocarbons, such as gasoline. It is a common cause of sickness and death due to poisoning, both intentional and accidental. Its most striking pathophysiological characteristic is its extremely high affinity—210 times that of oxygen—for the oxygen-binding sites in hemoglobin. For this reason, it reduces the amount of oxygen that combines with hemoglobin in pulmonary capillaries by competing for these sites. It also exerts a second deleterious effect: It alters the hemoglobin molecule shifting the oxygen–hemoglobin dissociation curve to the left, thereby decreasing the unloading of oxygen from hemoglobin in the tissues. The situation is worsened because persons suffering from carbon monoxide poisoning do not show any reflex increase in their ventilation.

The dynamics of the reaction of hemoglobin with O2 make it a particularly suitable O2 carrier. Hemoglobin is a protein made up of four subunits, each of which contains a heme moiety attached to a polypeptide chain. In normal adults, most of the hemoglobin molecules contain two α and two β chains. Heme is a porphyrin ring complex that includes one atom of ferrous iron. Each of the four iron atoms in hemoglobin can reversibly bind one O2 molecule. The iron stays in the ferrous state, so that the reaction is oxygenation (not oxidation). It has been customary to write the reaction of hemoglobin with O2 as Hb + O2 à HbO2. Because it contains four deoxyhemoglobin (Hb) units, the hemoglobin molecule can also be represented as Hb4, and it actually reacts with four molecules of O2 to form Hb4O8.

The reaction is rapid, requiring less than 0.01 s. The deoxygenation of Hb4O8 is also very rapid. The quaternary structure of hemoglobin determines its affinity for O2. In deoxyhemoglobin, the globin units are tightly bound in a tense (T) configuration, which reduces the affinity of the molecule for O2. When O2 is first bound, the bonds holding the globin units are released, producing a relaxed (R) configuration, which exposes more O2 binding sites. The net result is a 500-fold increase in O2 affinity. In tissues, these reactions are reversed, resulting in O2 release. The transition from one state to another has been calculated to occur about 108 times in the life of a red blood cell. The oxygen-hemoglobin dissociation curve relates percentage saturation of the O2 carrying power of hemoglobin (abbreviated as SaO2) to the Po2. This curve has a characteristic sigmoid shape due to the T–R configuration interconversion. Combination of the first heme in the Hb molecule with O2 increases the affinity of the second heme for O2, and oxygenation of the second increases the affinity of the third, and so on, so that the affinity of Hb for the fourth O2 molecule is many times that for the first. Especially note that small changes at low Po2 lead to large changes in SaO2.