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Gas Transport from Airways to Tissues

Page history last edited by PBworks 14 years, 5 months ago

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 PO2 in air, alveoli, arterial blood and venous blood.
  2. The approximate PCO2 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 PO2, 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:

 

Concentration = Pressure x Solubility

 

[OO2] = PO2 x solubility of O2 in blood (HENRY’S LAW)

 

Solubility of O2 in blood = .003 ml O2/100 ml blood/mm Hg

 

[OO2] = 100 mm Hg x .003 ml O2/100 ml blood/mm Hg = .3 ml O2/100 ml blood

 

BUT – BIG PROBLEM – Oxygen is poorly soluble in water (and plasma)

 

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:

(250 ml O2/min)/(0.3ml O2/100ml blood)= 83.3liters/min

 

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 (SaO2).

 

SaO2=((oxygen bound to hemoglobin)/(O2 carrying capacity))x100%

 

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 PO2’s found in peripheral tissues, Hb will give up its oxygen rather easily while at PO2’s corresponding to those found in arterial blood, Hb will be completely saturated.

 

According to the O2 dissociation curve, SaO2 is about 97.5% when PO2 = 100 mm Hg. In mixed venous blood that has a PO2 of 40 mm Hg, SaO2 is about 75%.

 

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

 

or

 

CO2=(SO2x1.39x[Hb])+(.003xPO2)

 

Assuming a blood hemoglobin concentration of 15 gm/100 ml blood, the oxygen content of arterial blood (PO2 = 100 mm Hg) is

 

CaO2=.975x1.39x15x.3=20.6mlO2/100mlblood

 

The oxygen content of mixed venous blood (PO2 = 40 mm Hg) is

 

Cv=.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(CaO2-Cv)=5L blood/min x 47 ml O2/min = 236 ml O2/min

 

Note that when the PO2 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 PO2 of 70 mm Hg instead of 100 mm Hg. In fact, the curve shows that at a PaO2 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 PO2 (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 PO2 of 100 mm Hg, raising the alveolar PO2 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 PaO2 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 PCO2 are shown in Figure 4. Low pH or high PCO2 shift the oxygen dissociation curve to the right. Conversely, high pH or low PCO2 shift the curve to the left. Because high PCO2’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 PO2 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 PO2’s are lower than adult PO2’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 PaO2 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. 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 PCO2’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[Ccap-Ccell]/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 Ccap and Ccell 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 PO2 (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 PO2 are normal. Venous PO2 and oxygen content are decreased. Administration of high FIO2’s are of little value except possibly in the case of carbon monoxide poisoning.

 

Hypoperfusion hypoxia

 

This results from low blood flow. Raising the FIO2 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 PO2 and arterial PO2 and oxygen content may be normal or elevated. Mixed venous PO2 is increased due to decreased oxygen utilization by the tissues.

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