Oxygen and Carbon Dioxide Transport

Diffusion of Gases From Regions of Higher to Lower Partial Pressure in the Lungs

The process of gas diffusion is passive and similar whether diffusion occurs in a gaseous or liquid state. The rate of diffusion of a gas through a liquid is described by Graham’s law, which states that the rate is directly proportional to the solubility coefficient of the gas and inversely proportional to the square root of its molecular weight. Calculation of the diffusion properties for O ₂ and CO ₂ reveals that CO ₂ diffuses approximately 20 times faster than O ₂ . Rates of O ₂ diffusion from the lungs into blood and from blood into tissue, and vice versa for CO ₂ , are predicted by Fick’s law of gas diffusion ( Fig. 24.2 ). Fick’s law states that gas diffusion across a permeable membrane ( $\dot{V}$ ) is proportional to the diffusion coefficient for the gas (D), the surface area of the membrane (A), and the pressure gradient across the membrane (P ₁ − P ₂ ). It is inversely proportional to the thickness of the membrane (T). The ratio of surface area (A) x diffusion coefficient (D) to membrane thickness (T) (or A•D/T) represents the conductance of a gas from the alveolus to the blood. The diffusing capacity of the lung (D _L ) is its conductance (A•D/T) when considered for the entire lung; thus, with Fick’s equation, D _L can be calculated as follows:

where V ˙ _gas = gas diffusion.

Fick’s law of diffusion could be used to assess the diffusion properties of O ₂ in the lungs, except that the capillary partial pressure of oxygen cannot be measured. This limitation can be overcome with the use of carbon monoxide (CO) rather than O ₂ . Because CO has low solubility in the capillary membrane, the rate of CO equilibrium across the capillary is slow, and the partial pressure of CO in capillary blood remains close to 0. In contrast, the solubility of CO in blood is high. Thus, the only limitation for diffusion of CO is the alveolar-capillary membrane, and thus CO is a useful gas for calculating D _L . The capillary partial pressure (P ₂ in Eq. 24.1 ) is essentially 0 for CO, and therefore D _L can be measured from the diffusion of carbon monoxide ( $\dot{V}\text{CO}$ ) and the average partial pressure of Co in the alveolus (P ₁ ); that is,

where D _L co = diffusion capacity of the lung for carbon monoxide.

Assessment of D _L co has become a classic measurement of the diffusion barrier of the alveolar-capillary membrane. It is useful in the differential diagnosis of certain obstructive lung diseases, such as emphysema. Although exposure to high levels of carbon monoxide gas can be toxic, in gas diffusion testing the total CO exposure is negligible.

Oxygen and Carbon Dioxide Exchange in the Lung Is Perfusion Limited

Different gases have different solubility factors. Gases that are insoluble in blood (i.e., anesthetic gases such as nitrous oxide and ether) do not chemically combine with proteins in blood and equilibrate rapidly between alveolar gas and blood. The equilibration occurs in less time than the 0.75 to 1.0 seconds that the red blood cell spends in the capillary bed (the capillary transit time). The diffusion of insoluble gases between alveolar gas and blood is considered perfusion limited because the partial pressure of gas in the blood leaving the capillary has reached equilibrium with alveolar gas and is limited only by the amount of blood perfusing the alveolus. In contrast, a gas that is diffusion limited, such as CO, has low solubility in the alveolar-capillary membrane but high solubility in blood because of its high affinity for hemoglobin (Hgb). These features prevent the equilibration of CO between alveolar gas and blood during the red blood cell transit time.

The high affinity of CO for Hgb enables large amounts of CO to be taken up in blood with little or no appreciable increase in its partial pressure. Gases that are chemically bound to Hgb do not exert a partial pressure in blood. Like CO, both CO ₂ and O ₂ have relatively low solubility in the alveolar-capillary membrane but high solubility in blood because of their ability to bind to Hgb. However, their rate of equilibration is sufficiently rapid for complete equilibration to occur during the transit time of the red blood cell within the capillary. Equilibration for O ₂ and CO ₂ usually occurs within 0.25 seconds. Thus, O ₂ and CO ₂ transfer is normally perfusion limited. The partial pressure of a gas that is diffusion limited (i.e., CO) does not reach equilibrium with the alveolar pressure over the time that it spends in the capillary ( Fig. 24.3 ). Although CO ₂ has a greater rate of diffusion in blood than O ₂ does, it has a lower membrane-blood solubility ratio and consequently takes approximately the same amount of time to reach equilibration in blood.

Diffusion limitation for O ₂ and CO ₂ would occur if red blood cells spent less than 0.25 seconds in the capillary bed. This is occasionally the case in very fit athletes during vigorous exercise and in healthy subjects who exercise at high altitude.

Hemoglobin

Hgb is the major transport molecule for O ₂ . The Hgb molecule is a protein with two major components: four nonprotein heme groups, each containing iron in the reduced ferric (Fe ⁺⁺⁺ ) form, which is the site of O ₂ binding; and a globin portion consisting of four polypeptide chains. Normal adults have two α-globin chains and two β-globin chains (HgbA), whereas children younger than 6 months of age have predominantly fetal Hgb (HgbF), which consists of two α chains and two γ chains. This difference in the structure of HgbF increases its affinity for O ₂ and aids in the transport of O ₂ across the placenta. In addition, HgbF is not inhibited by 2,3-diphosphoglycerate (2,3-DPG), a product of glycolysis; thus O ₂ uptake is further enhanced.

Binding of O ₂ to Hgb alters the ability of Hgb to absorb light. This effect of O ₂ on Hgb is responsible for the change in color between oxygenated arterial blood (bright red) and deoxygenated venous blood (dark red-bluish). Binding and dissociation of O ₂ with Hgb occur in milliseconds, thus facilitating O ₂ transport because red blood cells spend only 0.75 seconds in the capillaries. There are approximately 280 million Hgb molecules per red blood cell, which provides an efficient mechanism to transport O ₂ . Myoglobin, a protein in striated muscle similar in structure and function to Hgb, has only one subunit of the Hgb molecule. It aids in the transfer of O ₂ from blood to muscle cells and in the storage of O ₂ , which is especially critical in O ₂ -deprived conditions.

Abnormalities of the Hgb molecule occur with mutations in the amino acid sequence (i.e., sickle cell disease) or in the spatial arrangement of the globin polypeptide chains and result in abnormal function. Compounds such as CO, nitrites (nitric oxide), and cyanides can oxidize the iron molecule in the heme group and change it from the reduced ferrous state (Fe ⁺⁺ ) to the ferric state (Fe ⁺⁺⁺ ), which reduces the ability of O ₂ to bind to Hgb.