Gas transport from airways to tissue

Reading assignment: Chapter 6, West

Lisa Ebihara MD-PhD, Department of Physiology and Biophysics

Topics to be covered:

• Oxygen transport in the blood
• Carbon dioxide transport in the blood
• Blood-tissue gas exchange

Main points that you should know:

1. The approximate P_O2 in air, alveoli, arterial blood and venous blood.
2. The approximate P_CO2 in air, alveoli, arterial blood and venous blood.
3. Amount of O₂ carried in physical solution in plasma.
4. The shape of O₂-Hb saturation curve and the physiology associated with this shape.
5. How to calculate O₂ content of blood from P_O2, Hb concentration, and O₂-Hb saturation curve.
6. Agents which shift position of O₂-Hb saturation curves and the advantages and disadvantages of such shifts.
7. Various ways CO₂ is carried by blood and relative importance of each.
8. The definition and physiological significance of the Haldane effect.
9. The forces involved in O₂ and CO₂ movement between tissues and blood.
10. The physiology involved in the Cl- shift in RBC’s.
11. Factors affecting O₂ extraction by tissues.

Oxygen transport in the blood

The amount of oxygen in blood or cells is usually expressed in terms of pressure of oxygen rather than concentration of oxygen. The pressure of oxygen in a liquid (i.e. blood) is equal to the pressure of oxygen in the surrounding air. Figure 1 shows the pressure of oxygen in the alveoli, arterial blood and venous blood.

Figure 1

The pressure and concentration of oxygen dissolved in blood are related as follows:

A few simple calculations can demonstrate the oxygen physically dissolved in blood is not sufficient to meet the body’s oxygen demands. The resting oxygen consumption of an adult is approximately 250 to 300 ml O₂/minute. If the tissues were able to remove the entire 0.3 ml O₂/100 ml blood flow they receive, the cardiac output would have to be about 83.3 liters/minute to meet the tissue demand for oxygen:

During exercise, the oxygen demand can increase to 4 liters/minute. Under such conditions, the cardiac output would have to be greater than 1000 liters/min. The maximum cardiac outputs attainable by normal adults are in the range of 25 liters/minute. Clearly, the physically dissolved oxygen in the blood cannot meet the metabolic demand for oxygen, even at rest.

SOLUTION – Blood contains a molecule, HEMOGLOBIN, which reversibly binds oxygen.

Hemoglobin is a globular protein consisting of 4 subunits. Each subunit consists of a polypeptide chain binding an iron containing heme group. Heme consists of a ferrous ion (Fe²⁺) chelated in a porphyrin ring. O₂ binds directly to the heme moiety housed within the helical structure of the globin polypeptide. Four oxygen molecules can bind to each hemoglobin molecule. Hemoglobin A (HbA), the major adult hemoglobin, consists of two α and two β subunits. More than 120 abnormal variants of normal adult hemoglobin have been demonstrated. The most common of these is hemoglobin S (sickle cell) which results from a single mutation, a change in residue 6 of the β chain of the hemoglobin from glycine to valine. Hemoglobin S tends to polymerize when it is in its deoxygenated form and changes the shape of the red blood cell from the normal biconcave disk to a sickle shape. A sickled cell is more fragile than a normal cell. In addition, the cells have a tendency to stick to one another, which increases blood viscosity and favors thrombosis.

The oxygen capacity of hemoglobin is defined as the maximum amount of O₂ that can be combined with Hb. One gram of Hb can combine with 1.39 ml O₂. Since normal blood contains approximately 15 gm Hb/100 ml blood. The oxygen carrying capacity of blood = (15 gm Hb/100 ml blood)(1.39 ml O₂/gm Hb) = 20.8 ml O₂/100 ml blood.

Figure 2. From JB West, Respiratory Physiology The Essentials, 7th ed. Lippincott, Williams & Wilkins

A key determinant of the actual amount of O₂ bound to blood is the O₂ saturation of hemoglobin (S_aO2).

Figure 2 shows the oxygen dissociation curve for hemoglobin. The sigmoidal shape is a result of a change in affinity of hemoglobin for oxygen as successive oxygen molecules bind. The flat part of the curve results from the saturation of binding sites.

The sigmoidal shape of the oxygen dissociation curve is advantagous because it insures that at P_O2’s found in peripheral tissues, Hb will give up its oxygen rather easily while at P_O2’s corresponding to those found in arterial blood, Hb will be completely saturated.

According to the O₂ dissociation curve, S_aO2 is about 97.5% when P_O2 = 100 mm Hg. In mixed venous blood that has a P_O2 of 40 mm Hg, S_aO2 is about 75%.

The O₂ content of blood (CO₂) = Amount of O₂ bound to Hb + amount of O₂ dissolved in plasma

or

C_O2=(S_O2x1.39x[Hb])+(.003xP_O2)

Assuming a blood hemoglobin concentration of 15 gm/100 ml blood, the oxygen content of arterial blood (P_O2 = 100 mm Hg) is

C_aO2=.975x1.39x15x.3=20.6mlO₂/100mlblood

The oxygen content of mixed venous blood (P_O2 = 40 mm Hg) is

C_v=.75x1.39x15x.3=15.9mlO₂/100mlblood

Therefore the total amount of oxygen being loaded into the blood/minute, assuming a cardiac output (CO) of 5 l/min, is

COx(C_aO2-C_v)=5L blood/min x 47 ml O₂/min = 236 ml O₂/min

Note that when the P_O2 is above 70 mm Hg, the curve is nearly flat. This is very important physiologically because it means that there is only a small decrease in the oxygen content of blood equilibrated with a P_O2 of 70 mm Hg instead of 100 mm Hg. In fact, the curve shows that at a P_aO2 of 70 mm Hg, hemoglobin is still 94.1% saturated with oxygen. This constitutes an important safety factor because a patient with a relatively low alveolar or arterial P_O2 (e.g. due to hypoventilation or intrapulmonary shunting) is still able to load oxygen into the blood with little difficulty. It should also be noted that since hemoglobin is ~97% saturated at a P_O2 of 100 mm Hg, raising the alveolar P_O2 does not lead to a significant increase the oxygen content of hemoglobin.

Figure 3. From JB West, Respiratory Physiology The Essentials, 7th ed. Lippincott, Williams & Wilkins.

Figure 3 shows the effects of anemia and polycythemia. The main point is that the oxygen carrying capacity of blood depends on the concentration of Hb.

Figure 3 also shows the effect of CO poisoning. CO interferes with O₂ transport of blood by binding with Hb at O₂ binding site to form carboxyhemoglobin (COHb). CO has an oxygen binding affinity that is 240 times higher than that of oxygen. Therefore even small amounts of CO can cause a drastic reduction in the oxygen carrying capacity of the blood.

CO bound to hemoglobin impairs peripheral tissue oxygenation by two main mechanisms:

1. CO directly decreases oxygen carrying capacity by decreasing the amount of Hb available for O₂ binding.
2. CO shifts the O₂ dissociation curve to the left.

An important point to note is that the P_aO2 is normal in carbon monoxide poisoning.

Figure 4. From JB West, Respiratory Physiology The Essentials, 7th ed. Lippincott, Williams & Wilkins.

There are several physiological factors that can affect the shape and position of the oxygen dissociation curve. These factors include pCO2, hydrogen ion concentration, temperature and 2,3-DPG. Figure 4 shows how these factors affect the oxygen dissociation curve. Factors that reduce the affinity of oxygen for hemoglobin shift the curve to the right and facilitate the unloading of oxygen in the peripheral tissues. Factors that increase the affinity of oxygen for hemoglobin shift the curve to the left and interfere with the unloading of oxygen in the peripheral tissues.

Effects of pH and PCO2

The effects of pH and P_CO2 are shown in Figure 4. Low pH or high P_CO2 shift the oxygen dissociation curve to the right. Conversely, high pH or low P_CO2 shift the curve to the left. Because high P_CO2’s are often associated with low pH, these effects often occur together. When oxygenated blood reaches the tissues, CO2 is added. The resulting fall in pH shifts the oxygen dissociation curve to the right (Bohr effect). This shift allows unloading of O2 at a higher end-capillary P_O2 than would otherwise be the case.

Effects of temperature

Increasing temperature shifts the curve to the right, a favorable adaptive response, given the increased cellular demand for O2 during fever or exercise. Hypothermia shifts the curve to the left.

Concentration of 2,3-DPG

2,3-DPG is an end product of red blood cell metabolism. The concentration of 2,3-DPG increases during hypoxemia due to a number of conditions including chronic exposure to high altitude, anemia and right-to-left shunts. High levels of 2,3-DPG shift the oxygen dissociation curve to the right and increase oxygen delivery to the peripheral tissues. Conversely, low levels of 2,3-DPG seen in certain pathological conditions such as septic shock shift the curve to the left. It is important to note that blood stored at blood banks for as little as one week has been consistently shown to have very low levels of 2,3-DPG.

Fetal hemoglobin (HbF)

HbF (α₂γ₂) has an oxygen dissociation curve that is shifted to the left. Synthesis of β chains normally begins about 6 weeks before birth, and HbA usually replaces almost all of the HbF by the time an infant is 4 months old. This is of significant advantage during fetal life because fetal P_O2’s are lower than adult P_O2’s. It also promotes the transport of oxygen across the placenta by maintaining the diffusion gradient.

A convenient way of measuring shifts in the oxygen dissociation curve is to measure the P₅₀ which is the value of P_aO2 at which hemoglobin is 50% saturated by oxygen.

Carbon dioxide transport in the blood

Carbon dioxide builds up in the peripheral tissues and diffuses out, across the capillary wall into the blood. The blood carries the CO₂ back to the lungs for elimination. Carbon dioxide is carried in the blood in 3 ways. A small amount, only about 5%, is dissolved in the blood plasma. A small amount (~5%) is carried chemically combined with hemoglobin (carbaminohemoglobin). Most of the CO₂ carried in the form of HCO3- .

Physically dissolved

Carbon dioxide is about 20 times as soluble in plasma as oxygen.

Its solubility coefficient is 0.06 ml CO₂/100 ml blood/mm Hg. Therefore the concentration of dissolved CO₂ in arterial blood is

[CO₂]=.06ml CO₂/100mlblood/mmHg x 40mmHg=2.4ml CO₂

About 5% of the total carbon dioxide content of the blood is physically dissolved in blood.

As Carbamino Compounds

Carbon dioxide can combine chemically with the terminal amine groups in blood proteins, forming carbamino compounds.

This reaction occurs rapidly: no enzymes are necessary. Note that a hydrogen ion is released when a carbamino compound is formed.

Because the protein found at highest concentration in blood is hemoglobin, most of the carbon dioxide transported in this manner is bound to hemoglobin and is called carbamino-hemoglobin.

About 5-10% of the total carbon dioxide in the blood is carried in this manner.

As bicarbonate ions

The remaining 80-90 % of the carbon dioxide transported in blood is carried in the form of bicarbonate ions.

Figure 5. From JB West, Respiratory Physiology The Essentials, 7th ed. Lippincott, Williams & Wilkins.

Figure 5 shows a diagram of the events that occur during CO₂ uptake in the peripheral tissues.

1. HCO3- is formed within the red blood cell by the following reaction:

This reaction occurs only in red blood cells because it requires the intracellular enzyme, carbonic anhydrase.

1. HCO3- diffuses out of the RBC in exchange for Cl- (chloride shift)
2. H+ ions remain in the RBC where they are buffered by deoxyhemoglobin. Deoxyhemoglobin is a better buffer for H+ than oxyhemoglobin.
3. A small amount of CO₂ combines with the terminal amino groups of hemoglobin to give carbamino-hemoglobin. Deoxyhemoglobin can bind more CO₂ than oxyhemoglobin.

Figure 6

In the lungs all reactions occur in reverse (Figure 6).

1. HCO3- enters red blood cells in exchange for Cl-.
2. 
3. CO₂ diffuses out of the blood into the alveoli and is expired by the lung.

Figure 7. From JB West, Respiratory Physiology The Essentials, 7th ed. Lippincott, Williams & Wilkins.

Figure 7 shows the CO₂ dissociation curve. The CO₂ dissociation curve is much more linear than the O₂ dissociation curve within the physiological range of P_CO2’s.

When blood is oxygenated in the lung, oxyhemoglobin (HbO₂) is formed. HbO₂ is a stronger acid than reduced Hb and causes a fall in pH that shifts the CO₂ dissociation curve to the right (Figure 7). This shift facilitates unloading of CO₂ in the lungs, both from bicarbonate and from carbamino compounds, and is called the Haldane effect. Conversely, when blood is deoxygenated in the peripheral tissues it becomes a better proton acceptor. This allows blood to load more CO₂ in the peripheral tissues.

Blood-tissue gas exchange

Oxygen and carbon dioxide travel from the blood across the capillary walls into the tissue by DIFFUSION. The diffusion constant for CO₂ is about 20 times large than that for O₂. For this reason, diffusion of carbon dioxide from the peripheral tissue to the blood is rarely the rate limiting step in CO₂ transport and will not be considered further.

Rate of oxygen transport = J = KA[C_cap-C_cell]/x

where K is a constant, A is surface area of capillaries, x is distance between a given region of tissue and its nearest capillary, and C_cap and C_cell are concentrations of oxygen in capillary and tissue cell.

This is simply FICK’S LAW OF DIFFUSION

Figure 8. From JB West, Respiratory Physiology The Essentials, 7th ed. Lippincott, Williams & Wilkins.

The passage of oxygen is driven by the difference in oxygen concentration between the blood and the tissue.

Tissue hypoxia can result from a number of factors including:

1. decrease in arterial P_O2 (hypoxic hypoxia)
2. reduced ability of blood to carry oxygen (anemic hypoxia)
3. reduction in blood flow, either generalized as in shock or localized (circulatory hypoxia)
4. interference with the ability of tissues to utilize available oxygen (histotoxic hypoxia)

Hypoxic hypoxia

Conditions that cause this condition include hypoventilation and high altitudes, diffusion impairment, right-to-left shunts and ventilation-perfusion mismatch. These conditions will be discussed in detail in the next lecture.

Anemic hypoxia

This condition is caused by a decrease in functioning hemoglobin, which can be the result of decreased hemoglobin or erythrocyte production, the production of abnormal hemoglobin, pathologic destruction of erythrocytes, or interference with the chemical combination of oxygen and hemoglobin. Carbon monoxide poisoning, for example, results from the greater affinity of hemoglobin for carbon monoxide than for oxygen. Methemoglobinemia is a condition in which the iron in hemoglobin has been altered from Fe²⁺ to the Fe³⁺ form, which does not combine with oxygen. Anemic hypoxia results in a decreased oxygen content when both alveolar and arterial P_O2 are normal. Venous PO2 and oxygen content are decreased. Administration of high F_IO2’s are of little value except possibly in the case of carbon monoxide poisoning.

Hypoperfusion hypoxia

This results from low blood flow. Raising the F_IO2 is of little value because the blood flowing to the tissues is already oxygenated normally.

Histotoxic hypoxia

This condition refers to a poisoning of the cellular machinery that uses oxygen to produce energy. Cyanide, for example, binds to cytochrome oxidase in the respiratory chain and effectively blocks oxidative phosphorylation. Alveolar P_O2 and arterial P_O2 and oxygen content may be normal or elevated. Mixed venous P_O2 is increased due to decreased oxygen utilization by the tissues.