Transport of oxygen
Oxygen is poorly soluble in plasma, so that less than 2 percent of oxygen is transported dissolved in plasma. The vast majority of oxygen is bound to hemoglobin, a protein contained within red cells. Hemoglobin is composed of four iron-containing ring structures (hemes) chemically bonded to a large protein (globin). Each iron atom can bind and then release an oxygen molecule. Enough hemoglobin is present in normal human blood to permit transport of about 0.2 millilitre of oxygen per millilitre of blood. The quantity of oxygen bound to hemoglobin is dependent on the partial pressure of oxygen in the lung to which blood is exposed. The curve representing the content of oxygen in blood at various partial pressures of oxygen, called the oxygen-dissociation curve, is a characteristic S-shape because binding of oxygen to one iron atom influences the ability of oxygen to bind to other iron sites. In alveoli at sea level, the partial pressure of oxygen is sufficient to bind oxygen to essentially all available iron sites on the hemoglobin molecule.
Not all of the oxygen transported in the blood is transferred to the tissue cells. The amount of oxygen extracted by the cells depends on their rate of energy expenditure. At rest, venous blood returning to the lungs still contains 70 to 75 percent of the oxygen that was present in arterial blood; this reserve is available to meet increased oxygen demands. During extreme exercise the quantity of oxygen remaining in venous blood decreases to 10 to 25 percent. At the steepest part of the oxygen-dissociation curve (the portion between 10 and 40 millimetres of mercury partial pressure), a relatively small decline in the partial pressure of oxygen in the blood is associated with a relatively large release of bound oxygen.
Hemoglobin binds not only to oxygen but to other substances such as hydrogen ions (which determine the acidity, or pH, of the blood), carbon dioxide, and 2,3-diphosphoglycerate (2,3-DPG; a salt in red blood cells that plays a role in liberating oxygen from hemoglobin in the peripheral circulation). These substances do not bind to hemoglobin at the oxygen-binding sites. However, with the binding of oxygen, changes in the structure of the hemoglobin molecule occur that affect its ability to bind other gases or substances. Conversely, binding of these substances to hemoglobin affects the affinity of hemoglobin for oxygen. (Affinity denotes the tendency of molecules of different species to bind to one another.) Increases in hydrogen ions, carbon dioxide, or 2,3-DPG decrease the affinity of hemoglobin for oxygen, and the oxygen-dissociation curve shifts to the right. Because of this decreased affinity, an increased partial pressure of oxygen is required to bind a given amount of oxygen to hemoglobin. A rightward shift of the curve is thought to be of benefit in releasing oxygen to the tissues when needs are great in relation to oxygen delivery, as occurs with anemia or extreme exercise. Reductions in normal concentrations of hydrogen ions, carbon dioxide, and 2,3-DPG result in an increased affinity of hemoglobin for oxygen, and the curve is shifted to the left. This displacement increases oxygen binding to hemoglobin at any given partial pressure of oxygen and is thought to be beneficial if the availability of oxygen is reduced, as occurs at extreme altitude.
Temperature changes affect the oxygen-dissociation curve similarly. An increase in temperature shifts the curve to the right (decreased affinity; enhanced release of oxygen); a decrease in temperature shifts the curve to the left (increased affinity). The range of body temperature usually encountered in humans is relatively narrow, so that temperature-associated changes in oxygen affinity have little physiological importance.
Transport of carbon dioxide
Transport of carbon dioxide in the blood is considerably more complex. A small portion of carbon dioxide, about 5 percent, remains unchanged and is transported dissolved in blood. The remainder is found in reversible chemical combinations in red blood cells or plasma. Some carbon dioxide binds to blood proteins, principally hemoglobin, to form a compound known as carbamate. About 88 percent of carbon dioxide in the blood is in the form of bicarbonate ion. The distribution of these chemical species between the interior of the red blood cell and the surrounding plasma varies greatly, with the red blood cells containing considerably less bicarbonate and more carbamate than the plasma.
Less than 10 percent of the total quantity of carbon dioxide carried in the blood is eliminated during passage through the lungs. Complete elimination would lead to large changes in acidity between arterial and venous blood. Furthermore, blood normally remains in the pulmonary capillaries less than a second, an insufficient time to eliminate all carbon dioxide.
Carbon dioxide enters blood in the tissues because its local partial pressure is greater than its partial pressure in blood flowing through the tissues. As carbon dioxide enters the blood, it combines with water to form carbonic acid (H2CO3), a relatively weak acid, which dissociates into hydrogen ions (H+) and bicarbonate ions (HCO3-). Blood acidity is minimally affected by the released hydrogen ions because blood proteins, especially hemoglobin, are effective buffering agents. (A buffer solution resists change in acidity by combining with added hydrogen ions and, essentially, inactivating them.) The natural conversion of carbon dioxide to carbonic acid is a relatively slow process; however, carbonic anhydrase, a protein enzyme present inside the red blood cell, catalyzes this reaction with sufficient rapidity that it is accomplished in only a fraction of a second. Because the enzyme is present only inside the red blood cell, bicarbonate accumulates to a much greater extent within the red cell than in the plasma. The capacity of blood to carry carbon dioxide as bicarbonate is enhanced by an ion transport system inside the red blood cell membrane that simultaneously moves a bicarbonate ion out of the cell and into the plasma in exchange for a chloride ion. The simultaneous exchange of these two ions, known as the chloride shift, permits the plasma to be used as a storage site for bicarbonate without changing the electrical charge of either the plasma or the red blood cell. Only 26 percent of the total carbon dioxide content of blood exists as bicarbonate inside the red blood cell, while 62 percent exists as bicarbonate in plasma; however, the bulk of bicarbonate ions is first produced inside the cell, then transported to the plasma. A reverse sequence of reactions occurs when blood reaches the lung, where the partial pressure of carbon dioxide is lower than in the blood.
Hemoglobin acts in another way to facilitate the transport of carbon dioxide. Amino groups of the hemoglobin molecule react reversibly with carbon dioxide in solution to yield carbamates. A few amino sites on hemoglobin are oxylabile, that is, their ability to bind carbon dioxide depends on the state of oxygenation of the hemoglobin molecule. The change in molecular configuration of hemoglobin that accompanies the release of oxygen leads to increased binding of carbon dioxide to oxylabile amino groups. Thus, release of oxygen in body tissues enhances binding of carbon dioxide as carbamate. Oxygenation of hemoglobin in the lungs has the reverse effect and leads to carbon dioxide elimination.
Only 5 percent of carbon dioxide in the blood is transported free in physical solution without chemical change or binding, yet this pool is important, because only free carbon dioxide easily crosses biologic membranes. Virtually every molecule of carbon dioxide produced by metabolism must exist in the free form as it enters blood in the tissues and leaves capillaries in the lung. Between these two events, most carbon dioxide is transported as bicarbonate or carbamate.
Gas exchange in the lung
The introduction of air into the alveoli allows the removal of carbon dioxide and the addition of oxygen to venous blood. Because ventilation is a cyclic phenomenon that occurs through a system of conducting airways, not all inspired air participates in gas exchange. A portion of the inspired breath remains in the conducting airways and does not reach the alveoli where gas exchange occurs. This portion is approximately one-third of each breath at rest but decreases to as little as 10 percent during exercise, due to the increased size of inspired breaths.
In contrast to the cyclic nature of ventilation, blood flow through the lung is continuous, and almost all blood entering the lungs participates in gas exchange. The efficiency of gas exchange is critically dependent on the uniform distribution of blood flow and inspired air throughout the lungs. In health, ventilation and blood flow are extremely well matched in each exchange unit throughout the lungs. The lower parts of the lung receive slightly more blood flow than ventilation because gravity has a greater effect on the distribution of blood than on the distribution of inspired air. Under ideal circumstances, partial pressures of oxygen and carbon dioxide in alveolar gas and arterial blood are identical. Normally there is a small difference between oxygen tensions in alveolar gas and arterial blood because of the effect of gravity on matching and the addition of a small amount of venous drainage to the bloodstream after it has left the lungs. These events have no measurable effect on carbon dioxide partial pressures because the difference between arterial and venous blood is so small.