1. NROSCI-BIOSC-MSNBIO 1070-2070
Respiration 2
October 30, 2019

2. Lung Volumes Clinically, measures of lung volumes can be useful.
A spirometer measures the volume of air moving during each breath.
It is useful to know the terms that refer to lung volumes, and their typical values.

3. Lung Volumes
The amount of air that moves in a single normal inspiration or expiration is called tidal volume (VT). In an average-sized male, this volume is approximately 500 ml.

4. Lung Volumes
• The amount of additional air that you can inspire following a normal tidal inspiration is called inspiratory reserve volume (IRV). In a normal male, this volume is ~ 3L.

5. Lung Volumes
• The term expiratory reserve volume (ERV) refers to the amount of additional air that can be exhaled after a normal expiration, and is about 1 L.

6. Lung Volumes
• The maximal amount of air that can normally be moved is called vital capacity, and is the summation of tidal volume, inspiratory reserve volume and expiratory reserve volume. Vital capacity is about 4.5 L.

7. Lung Volumes
• Even after a maximal expiration, some air is left in the lungs. This volume is called residual volume (RV), and is about 1.2 L.

8. Lung Volumes
• Total lung volume is the summation of vital capacity and reserve volume, and is about 5.7 L.

9. Pulmonary Ventilation
The term “total pulmonary ventilation” refers to the amount of air moved into and out of the lungs per minute. As you might imagine, total pulmonary ventilation is calculated by the following formula:
VT * Ventilation Rate = Total Pulmonary ventilation
• In an “average” male, tidal volume is 500 ml and Ventilation Rate is 12 breaths/min.
Thus:
Total pulmonary ventilation = 500 ml/breath * 12 breaths/min = 6000 ml/min

10. Pulmonary Ventilation
Total pulmonary ventilation is a misleading quantity, as not all of this volume reaches the exchange surface. Part of the air remains in the conducting passageways, which are referred to as dead space (because they are not involved in gas exchange). Thus, to determine total alveolar ventilation, dead space volume should be subtracted from tidal volume.
• In other words:
Alveolar Ventilation = Ventilation rate * (Tidal Volume - Dead Space Volume)
• In an “average” man, dead space volume = 150 ml,
so:
Alveolar Ventilation = 12 breaths/min * (500 ml/breath ml/breath) = 4200 ml/min

12. Alveolar Gas Exchange
During increases and decreases in alveolar ventilation, the partial pressure of oxygen and carbon dioxide in the alveoli can change markedly.
However, during normal tidal breathing, the partial pressures of these gases remains stable in the alveoli. This may seem contradictory, as you might expect the levels to change markedly between inspiration and expiration.

13. Alveolar Gas Exchange
• Two factors contribute to the maintenance of constant levels of oxygen and carbon dioxide in the alveoli:
- First, the amount of oxygen that enters an alveolus during each breath is approximately equal to the amount that enters the blood.
- Second, the amount of fresh air brought into the alveoli during each breath is only a fraction of the total air in the lungs.

14. Matching of Ventilation & Alveolar Blood Flow
Bringing oxygen into the alveoli does little good unless the circulatory system can pick-up the inspired gas. There is a precise matching between air and blood flow to the alveoli for this purpose.

15. Matching of Ventilation & Alveolar Blood Flow.
In the lungs, local factors are mainly responsible for this matching.
Arterioles in the lungs, unlike those in most other vascular beds, are not extensively regulated by the autonomic nervous system.

16. Matching of Ventilation & Alveolar Blood Flow
Pulmonary arterioles are mainly sensitive to local levels of oxygen.
When oxygen levels rise, the capillaries dilate to permit more gas exchange.
In contrast, the bronchiole smooth muscle is most affected by carbon dioxide levels.
When carbon dioxide levels rise, then the smooth muscle relaxes to permit more ventilation of the alveoli.

17. Matching of Ventilation & Alveolar Blood Flow

18. Matching of Ventilation & Alveolar Blood Flow
Furthermore, capillaries in the lungs are collapsible. Near the apex (top) of the lung, the capillaries are normally collapsed, and blood flow is diverted to the base of the lung where gravity causes hydrostatic pressure to be higher.
During exercise, when mean arterial pressure increases, the apex capillaries open, and gas exchange takes place in a larger area of the lung. This process is part of the reserve capacity of the lung.

19. How Much Gas is Exchanged?

20. How Much Gas is Exchanged?
Each day, a human:
Consumes 360L of oxygen (250 ml/min)
Generates 288 L of carbon dioxide (200 ml/min)
How Much Gas is Exchanged?

21. Gas Exchange in the Lungs
Simple diffusion governs the exchange of materials between the blood and alveoli
Diffusion is limited by the following conditions:
The rate of diffusion across membranes is directly proportional to the partial pressure (concentration) gradient.
The rate of diffusion across membranes is directly proportional to the available surface area.
The rate of diffusion across membranes is inversely proportional to the thickness of the membrane.
Diffusion is most rapid over short distances.

22. Movement of O2 from Alveoli to Blood
The gas laws state that gases move from regions of higher partial pressure to regions of lower partial pressure. Also recall that the PO2 in the alveoli is near 100 mm Hg. The PO2 in the blood returning to the lungs is near 40 mm Hg. Thus, diffusion will cause oxygen to move from the alveolus to the blood.

23. Elimination of CO2
Carbon dioxide returning to the lungs from the systemic circulation has a partial pressure of ~45 mm Hg, whereas the partial pressure in the alveolus is ~40 mm Hg. Thus, diffusion causes CO2 to be eliminated from the blood.

24. Diffusion and Gas Exchange
Normally, diffusion between the alveolus and blood occurs rapidly and efficiently, because both oxygen and carbon dioxide are small molecules that are both lipid and water soluble.
Furthermore, the specializations that we discussed earlier (much of the surface area of the alveolus is covered with capillaries; the interstitial space is small) will serve to maximize the diffusion process.

25. Impairment of Gas Exchange
If the partial pressure of oxygen in an alveolus drops, then oxygenation of the blood will be impaired. This will occur if ventilation is impaired by diseases (e.g., asthma, which increases resistance in the bronchioles), or if atmospheric pressure drops (as occurs at high altitudes).

26. Impairment of Gas Exchange
For example, on the top of Mount Everest, atmospheric pressure is 253 mm Hg, and so the partial pressure of oxygen in the air is (0.21 * 253 = 53 mm Hg).
Because air inspired during each breath is only a fraction of air in lungs, the partial pressure of air in the alveolus would only be 35 mm Hg (a value less than that normally in venous blood).
It would thus be impossible for a person to achieve proper blood oxygenation if living on Mount Everest.

27. Impairment of Gas Exchange
The principles of diffusion also indicate that gas exchange between the alveoli and lungs will be impaired if there is a decrease in the surface area available for gas exchange, or if there is an increase in the diffusion distance between air and the blood.
Emphysema is associated with both the loss of alveoli and connective tissue from the lungs. As a result, surface area available for diffusion of oxygen into the blood is low, and PO2 in blood will be low.

28. Impairment of Gas Exchange
Diseases such as fibrosis can lead to a thickening of the alveoli, which will affect diffusion of gases into the blood, and PO2 will be low.

29. Impairment of Gas Exchange
Pulmonary edema, which results from left ventricular failure, will result in an expansion of fluid volume in the interstitial space of the lung and have the same effect (YOU SHOULD BE ABLE TO EXPLAIN WHY THIS OCCURS).

30. Impairment of Gas Exchange
Diseases such as asthma, in which alveolar ventilation decreases, will result in low PO2 in the alveoli, which translates to low PO2 in the blood.

31. Impairment of Gas Exchange
If too little oxygen is in the blood, then the cells will be deprived. This condition is referred to as hypoxia.
Often, hypoxia goes hand-in-hand with hypercapnia, or elevated concentrations of carbon dioxide.

32. Effects of Pulmonary Disease on Pulmonary Blood Flow
Hypoxia results in a constriction of pulmonary arterioles.
As a consequence:
The resistance in the pulmonary circulation (afterload) increases
Ejection fraction decreases for the right heart
End systolic volume increases.

33. Effects of Pulmonary Disease on Pulmonary Blood Flow
Normal cardiac return adds to the increased end systolic volume, such that end diastolic volume is also larger.
Hence, preload increases, and this induces larger right ventricular contractions.
In the left heart, diminished blood return through the pulmonary veins causes preload to drop, and thus left ventricular contractions are weaker.

34. Effects of Pulmonary Disease on Pulmonary Blood Flow
Accordingly, the Frank-Starling mechanism serves to equalize left and right ventricular cardiac output when hypoxia is moderate.
However, prolonged hypoxia results in more severe changes in pulmonary blood flow.

35. Effects of Pulmonary Disease on Pulmonary Blood Flow
Abbreviations:
eNOS: endothelial nitric oxide synthase
PGl2S: prostacyclin synthase (prostacyclin prevents clotting and causes vasodilation)
VEGF: vascular endothelial growth factor
SMC: smooth muscle cell
PAP: pulmonary artery pressure

36. Effects of Pulmonary Disease on Pulmonary Blood Flow
Sustained high pulmonary artery pressure results in a condition called pulmonary hypertension.
The right ventricular myocardium thickens due to the sustained intense contractions needed to overcome the afterload imposed by the pulmonary circulation.
Over time, the problem may become so severe that there is a mismatch in output from the left and right heart (congestive heart failure).
Blood accumulates in the veins, particularly in the legs, resulting in edema.

37. Effects of Pulmonary Disease on Pulmonary Blood Flow
Iloprost:
Synthetic
prostacyclin

38. Transport of O2 in the Blood and Exchange with Tissues
Blood in the pulmonary veins has a slightly lower PO2 than blood in the lung capillaries. This is because some capillaries in the lung perfuse tissues which are not gas-exchanging surfaces.
Simple diffusion explains the exchange of gases between the body tissues and the blood in the systemic capillaries. Typically, PO2 in the blood falls to about 40 mm Hg after passing through systemic capillaries.
Tissue PO2 is both influenced by the rate of oxygen transport and the rate at which oxygen is used by the tissues.
Carbon dioxide, a major waste product of cells, is picked-up by the blood in the systemic capillaries and transported to the lungs for elimination. Carbon dioxide can diffuse about 20X as fast as oxygen, and thus there is almost the same PCO2 in the systemic veins as in the cells.

39. Ductus Arteriosus and Foramen Ovale
In the developing fetus, two shunts divert blood away from the lungs.
The foramen ovale is a shunt between the left atrium and right atrium.
In addition, ductus arteriosus is a blood vessel connecting the pulmonary artery to the proximal descending aorta.
Between the two, coupled with the extremely high resistance of the pulmonary circulation, practically no blood enters the lungs.

40. Ductus Arteriosus and Foramen Ovale
Since practically no blood is moving from the lungs to the left atrium, left atrial pressure is extremely low in the fetus.
Thus, the pressure gradient favors the movement of blood from the right to the left atrium.

41. Ductus Arteriosus and Foramen Ovale
Pressures in the pulmonary artery and aorta are nearly equal in the fetus, or pressure is slightly higher in the pulmonary artery.
This is due to relatively weak contractions of the developing left ventricle, as well as the fact that preload to the left ventricle is relatively low.
Thus, blood moves from from the pulmonary artery to the descending aorta through ductus arteriosus.

42. Ductus Arteriosus and Foramen Ovale
The trajectory of blood flow from the inferior vena cava favors movement through foramen ovale into the left atrium.
The trajectory of blood flow from the superior vena cava favors movement through the tricuspid valve into the right ventricle, and then through ductus arteriosus to the descending aorta and placenta.

43. Ductus Arteriosus and Foramen Ovale
At birth, the shunts must close immediately to permit the normal circulation to commence.
Once the fetus is born and begins to breathe, pulmonary circulatory resistance drops precipitously.
Blood thus begins to flow through the pulmonary circulation instead of ductus arteriosus, as resistance in the ductus arteriosus is higher.

44. Ductus Arteriosus and Foramen Ovale
High pO2 after birth acts as a paracrine to cause constriction of smooth muscle in ductus arteriosus
The patency of ductus arteriosus is also dependent on prostaglandins that are produced in part by the placenta.
The prostaglandins inhibit the contraction of smooth muscle within the wall of ductus arteriosus.
The prostaglandin levels drop at birth, causing the ductus to collapse as smooth muscle within contracts.

45. Ductus Arteriosus and Foramen Ovale
As blood from the lungs returns to the left atrium, pressure in the left atrium exceeds that in the right atrium.
This causes a flap of tissue to press against the foramen ovale, blocking the flow of blood between the atria.
Within a few weeks, a full closure of the opening occurs.

48. Transport of O2 by Blood
Normally, about 97% of the oxygen carried in the blood is bound to hemoglobin in the red blood cells. The other 3% is dissolved in the plasma. Thus, hemoglobin greatly increases the oxygen-carrying capacity of blood.
The amount of oxygen that binds to hemoglobin depends on two factors: the PO2 of the plasma and the number of free hemoglobin oxygen binding sites.
Dissolved oxygen in the plasma diffuses into the red blood cells, where it is rapidly bound by hemoglobin. This rapid removal of oxygen from the plasma helps to ensure that diffusion from the alveoli to the plasma occurs very efficiently. O2
Alveolus
Plasma
RBC O2

49. Hemoglobin
Each hemoglobin molecule can bind 4 oxygen molecules, to form oxyhemoglobin.
The oxygen-hemoglobin dissociation curve shows the relationship between PO2 and binding of oxygen to hemoglobin.
If PO2 > 60 mm Hg, then hemoglobin will still be almost totally saturated with oxygen.
In other words, even moderate pulmonary problems that compromise alveolar ventilation won’t have a serious effect on the amount of oxygen in the blood.

50. Hemoglobin
When blood reaches the systemic capillaries, and PO2 of the plasma drops, then oxygen will tend to dissociate from the hemoglobin. Note, however, even at typical tissue levels of PO2, hemoglobin still carries about 75% of the oxygen that it is capable of moving.
This “reserve” helps to assure that more oxygen can be released if a tissue shows a tremendous amount of metabolic activity. For example, PO2 in the plasma of capillaries of exercising muscle is frequently near 20 mm Hg.

52. Effects of pH on Hemoglobin (Bohr Effect)
Increasing H+ in the blood (lowering pH) shifts the oxygen- hemoglobin dissociation curve to the right, so hemoglobin sheds oxygen more easily to the tissues.

53. Effects of Temperature on Hemoglobin
Increasing temperature shifts the oxygen- hemoglobin dissociation curve to the right, so hemoglobin sheds oxygen more easily to the tissues

55. Fetal Hemoglobin
Fetal hemoglobin has a higher affinity for oxygen than maternal hemoglobin, a necessary adaptation for getting O2 across the placenta.

56. Effects of 2,3 DPG on Hemoglobin
Oxygen-hemoglobin binding is also affected by 2,3- phosphoglycerate (2,3-DPG), a compound made from the intermediate of the glycolysis pathway.
Through mechanisms that are not well understood, chronic hypoxia (as during anemia or high altitude exposure) leads to an increase in 2,3-DPG production by red blood cells.
This compound shifts the oxygen-hemoglobin dissociation curve to the right, thereby causing more oxygen to be released at a particular PO2 level.

57. Carbon Monoxide Poisoning
Carbon monoxide combines with hemoglobin in a similar manner as does oxygen, but does so about 250x more effectively. As a result, only a small amount of CO in the atmosphere will displace the oxygen from hemoglobin, and the amount of oxygen carried by the blood will be greatly reduced.

58. Carbon Monoxide Poisoning
In terms of the Hb-O2 dissociation curve, the maximum height will be reduced by the presence of CO, as the toxic gas is occupying binding sites on the hemoglobin. Furthermore, CO affects the manner in which the unoccupied sites bind to oxygen, causing a small left-shift in the curve. This impairs unloading of oxygen from hemoglobin in the tissues.

59. Carbon Monoxide Poisoning
Patients with CO poisoning are placed in a hyperbaric chamber (an extremely high PO2 environment) so that oxygen can compete with CO and drive CO out of the blood.

60. Carbon Monoxide Poisoning
Nitric oxide (which is used as a chemical signaling agent in the body) also very effectively binds to hemoglobin.
In fact, its binding is about 200,000 times as effective as that of oxygen.
Fortunately, nitric oxide is not typically found in the environment (it is a by product of burning of fuel by automobile engines but is removed by catalytic converters).
It is interesting that we use such a lethal substance as a paracrine factor.

61. CO2 Transport
Only about 7% of carbon dioxide is found in the plasma of venous blood.
The other 93% is either bound to hemoglobin or in the form of bicarbonate.

62. CO2 Transport
The conversion of carbon dioxide to bicarbonate is useful, as it :
Increases the capacity of the blood to carry this molecule and
Tends to stabilize blood pH (bicarbonate is a buffer).

63. CO2 Transport
The conversion of carbon dioxide to bicarbonate is catalyzed by the enzyme carbonic anhydrase. The end result is H+ and HCO3-.
The hydrogen ion binds to hemoglobin (a buffer),
The bicarbonate is transported out of the red blood cell in exchange for chloride ion. This process is called the chloride shift.

64. CO2 Transport
Note that the ability of hemoglobin to bind H+ is essential, or the blood would become very acidic.
The process goes in reverse in the lungs.

65. Summary of Gas Transport

66. Blood Flow and Gas Exchange
The release of oxygen and vasodilator substances from erythrocytes are coupled: an increase in O2 release is associated with more vasodilator release.
As such, tissues utilizing considerable oxygen will receive increased blood flow, as nearby arterioles will dilate.

67. Blood Flow and Gas Exchange
NO is continuosly produced by endothelial cells. Some of the NO reacts with O2 to form the nitrite anion (NO2-), which can be taken up by the erythrocytes.
The deoxygenated hemoglobin can function as a nitrite reductase that regenerates NO from nitrite. NO O2
NO2

68. Blood Flow and Gas Exchange
As such, NO production by erythrocytes is coupled to how much oxygen they have released to surrounding tissues.
ATP is produced in the erythrocyte by glycolysis and is released in response to off-loading of O2. How O2 dissociation from hemoglobin activates this process is still not known. The release of ATP triggers the release of NO from endothelial cells.

69. Blood Flow and Gas Exchange
Through these mechanisms, the off-loading of O2 from erythrocytes leads to local vasodilation, and thus delivery of more erythrocytes to the area utilizing O2.
During exercise, this mechanism enhances oxygen delivery to working muscle.

70. Measurement of Oxygen Delivery to Tissues: the Fick Principle
The Fick Principle is based on the idea that delivery of oxygen (or any substance) to a tissue is the difference between the concentration of that substance in arterial and venous blood.

71. Measurement of Oxygen Delivery to Tissues: the Fick Principle
Let:
CaO2 = arterial O2 content (O2/ml blood)
CvO2 = venous O2 content (O2/ml blood)
F = blood flow (ml/min)
Then:
Rate of O2 delivery = F * CaO2 (O2/min)
Rate of O2 removal = F * CvO2 (O2/min)
QO2 (oxygen delivery) = F * CaO2 — F * CvO2 OR
QO2 (oxygen delivery) = F * (CaO2 — CvO2)
Applying algebra:
F = QO2/(CaO2 — CvO2)

72. Measurement of Oxygen Delivery to Tissues: the Fick Principle
The Fick Principle is applied in clinical medicine to determine pulmonary blood flow (hence cardiac output) . One can calculate CaO2 and CvO2 from samples of arterial and venous blood, and QO2 can also be calculated.
However, QO2 is normally assumed to be:
125 ml O2 per minute per square meter of body surface area.