CPR 50-51 - Pulmonary Circulation and Hemoglobin Structure/Function

Question 1

When a person has pulmonary edema why does sitting up make breathing easier?

Answer 1

The total blood volume in the pulmonary vasculature falls by 20% when a supine person sits up.

Question 2

Why are pulmonary pressures so much lower than systemic pressures?

Answer 2

• Systemic circulation has to deliver blood to areas much higher than the pulmonary circulation. This requires more pressure.
• The pulmonary vessels have little smooth muscle, thin walls, high compliance, and a lot of unused cross sectional area. All of this means there is a lot less resistance which means less pressure is required to accomodate all of CO
• Pressure has to be low to prevent edema

Question 3

Describe the concepts of pulmonary circulation recruitment and distension.

Answer 3

CO can increase 4 fold and only a 33% increase in pulmonary arterial pressure will be seen. This is because the pulmonary circulation has a lot of unused cross sectional area that can be recruited and the vessels are very compliant so they distend easily to create more cross sectional area.

Question 4

What is an extra alveolar vessel? Why are they important?

Answer 4

It is similar to an arteriole in the systemic circulation. It is the smallest vessel besides the capillary. It does not come into contact with the alveolus, hence the name. They have a web of interlinking alveolar vessels between them in parallel. They are important because their dilation/constriction directly controls blood flow to the alveoli.

Question 5

How does lung volume affect blood flow through alveolar and extra alveolar vessels?

Answer 5

Since alveolar vessels are in the walls of the alveoli they lose cross sectional area upon inspiration. Extra alveolar vessels on the other hand are pulled open by radial traction and so their cross sectional area increases upon inspiration.

Question 6

What forces increase and decrease fluid filtration and absorption at the capillary-alveoli interface?

Answer 6

Question 7

Describe how hypoxia affects the pulmonary circulation?

Answer 7

If an alveolus is not properly ventilated and becomes hypoxic then blood flow to that alveolus is restricted via vasoconstriction.

Question 8

Describe how alveoli surface tension affects the pulmonary capillary filtration and absorption.

Answer 8

An increase in alveoli surface tension means that the alveolus is being inflated. This will push on the interstitial fluid compartment and increase its pressure which will decrease fluid filtration. However, when the alveoli collapses again it will increase a stronger than usual negative pressure in the interstitial space which promotes fluid filtration. The net effect is fluid filtration.

Question 9

Describe the concept of lung zones.

Answer 9

The lung is separated into 4 zones based upon the pressure present in the alveoli, arteries, veins, and interstitium.

1. Zone 1 (apex)-P_A>P_a>P_V, this limits blood flow throughout capillary
2. Zone 2 - P_a>P_A>P_V, this limits blood flow along venous capillary
3. Zone 3 - P_a>P_V>P_A, normal flow across capillary
4. Zone 4 (base) - due to little P_TM changes there is very little radial traction and the extra alveolar vessels have increased resistance. This causes there to be less blood flow than Zone 3 but still more than 1 and 2.

Question 10

What is a “shunt” in the pulmonary circulation? When does a shunt most commonly occur?

Answer 10

Any route in the lungs that allows venous blood to get back to the left atrium without coming undergoing gas exchange. This most commonly occurs when an alveolus is not properly ventilated.

Question 11

What is hypoxemia?

Answer 11

An abnormally low level of oxygen in the blood.

Question 12

How is pulmonary capillary wedge pressure (PCWP) measured? What is it indicative of? Why is it typically done?

Answer 12

A balloon catheter with a barometer on the end is advanced into a pulmonary artery. The balloon is then inflated to stop blood flow into that artery. The barometer then reads the PCWP on the venous end of the artery. This pressure is indicative of left atrial pressure and it is used to determine the degree of contestion present in the pulmonary circulation. Both left heart failure and pulmonary congestion will increase PCWP

Question 13

What is the ratio of alpha helices to beta sheets present in the globin protein monomer?

Answer 13

The globin protein monomer is devoid of beta sheets and is composed almost entirely of alpha helices and a few bends and turns.

Question 14

Describe the kind of iron that is found in globin monomers and why only that type is found in globin proteins.

Answer 14

Ferrous iron (Fe²⁺) is what is found in globin proteins. This is because it can form 6 coordinate bonds which allows it to be bonded to 4 nitrogen atoms in the porphyrin ring, 1 nitrogen atom in a histidine of the globin protein, and to reversibly bind O₂

Question 15

Why is it important that the ferrous iron in hemoglobin is buried deep into the protein?

Answer 15

• This helps to ensure that O₂ is released as O₂ and is not radicalized
• O₂ entrance and exit has to occur along a defined path which is easily controlled.

Question 16

Describe the subunit composition of hemoglobin A (HbA) and how these subunits are associated with one another.

Answer 16

• HbA consists of four subunits: two α and two β
• one α and one β will form a dimer that is held together primarily by strong hydrophobic interactions.
• Two of these dimers will then associate with each other to form the mature α₂β₂ tetramer that is hemoglobing. The two dimers are held together by relatively weak ionic and hydrogen bonds.

Question 17

How many O2 molecules can one hemoglobin hold?

Answer 17

4

Question 18

What is metHemoglobin (metHb) and how does it form?

Answer 18

metHb is hemoglobin that contains ferric iron (Fe³⁺) in the porphyrin ring. This occurs when O2 bound to hemoglobin gets radicalized to superoxide which then oxidizes ferrous iron to ferric iron. Ferric iron cannot bind O2 and it prevents the 3 remaining ferrous irons from binding O2. Therefore metHb does not function as an O2 carrier.

Question 19

Why does the presence of one ferric iron in hemoglobin affect the whole hemoglobin binding curve?

Answer 19

That one ferric iron will stay in the plane of the porphyrin ring which will lock the Hb in the T-state and make it unresponsive to low pH, 2,3-BPG, and ppCO2 increases.

Question 20

How often is metHb formed? Why? What happens to metHb and what develops if this doesn’t happen?

Answer 20

metHb is formed at a very low rate due to the shape of Hb. When it is formed it get enzymatically reduced back to the ferrous form. If there is a deficiecy in this reduction process then metHb can accumulate which creates a characteristic blue appearance.

Question 21

Draw out the oxygen dissociation graphs for hemoglobin and myoglobin. Indicate the zones that represent the peripheral tissues and lungs. The graph doesn’t have to be exact.

Answer 21

Make sure the axes, shapes of curves, and tissue regions are correct

Question 22

Describe the conformational changes that occur when O2 binds to Hb. What is the significance of this change?

Answer 22

The iron in hemoglobin is usually a little below the plane of the porphyrin ring. When it binds to O2 it gets pulled into the plane of the porphyrin ring. This also pulls on the histidine it is attached to which pulls on the whole protein, causing a conformational change. This change weakens some of the ionic/H-bonding interactions that were holding the αβ dimers to each other. This causes the hemoglobin to develop a relaxed conformation that can bind oxygen more easily.

Question 23

Are the terms oxyHb and R-state synonymous? Are the terms deoxyHb and T-state synonymous?

Answer 23

No

Question 24

What is the glycolytic intermediate that interacts with hemoglobin? Describe what it does and how?

Answer 24

2,3-bisphosphoglycerate (2,3-BPG) is a negatively charged glycolytic intermediate consisting of several carboxylate and phosphate groups. There is a positively charged cavity that exists between the β subunits of hemoglobin. 2,3-BPG binds to this cavity which allows for additional salt bridges to form between the αβ dimers. This causes Hb to form a more tense state and let go its O2s more readily.

Question 25

Does 2,3-BPG shift the Hb binding curve to the left or right?

Answer 25

Right

Question 26

List the two glycolytic pathway deficiencies that affect the Hb binding curve and how they do this.

Answer 26

Hexokinase Deficiency - leads to a reduction in 2,3-BPG and a left shift on the Hb binding curve

Pyruvate Kinase Deficiency - leads to an elevation in 2,3-BPG levels and a right shift of the Hb binding curve.

Question 27

Describe the Bohr effect.

Answer 27

A decrease in blood pH causes a right shift on the Hb binding curve. The increase in H+ ions leads to protonation of Hb residues which allows for more salt bridges to form between the αβ dimers. This causes Hb to form a more tense state and to let go of its O2 more readily.

Question 28

How does an increase in ppCO2 in the blood affect the Hb binding curve? Explain

Answer 28

It shifts it to the right by two different mechanisms

1. An increase in CO2 means a decrease in pH
2. CO2 may react with the N-terminus of the Hb α chains, forming carbamamino Hb. This allows for the formation of more salt bridges between the αβ dimers, stabilizing the tense state.

Question 29

Which way does the Hb binding curve shift in the lungs? Why does this happen?

Answer 29

To the left

In the lungs, CO2 is removed from the blood which shifts the carbonic anhydrase reaction towards making more CO2 which raises blood pH. Both of these things shift the binding curve to the left.

The high ppO2 is also enough to bind O2, even in the T-state. This forces Hb into the R-state and causes it to release 2,3-BPG. This also shifts the curve to the left

Question 30

Why does the binding of one CO molecule to one globin subunit of Hb reduce the ability of the other globin subunits?

Answer 30

The binding of CO to one iron pulls that iron into the plane of the porphyrin ring which locks the whole Hb into the T-state. This makes it immune to the effects of low pH, 2,3-BPG, and high ppCO2 levels.

Question 31

What do you call a Hb that is bound to CO?

Answer 31

Carboxyhemoglobin

Question 32

How is CO poisoning treated?

Answer 32

With a hyperbaric chamber at 100% oxygen and high pressure. The objective is to displace the CO with O2

Question 33

When do the various Hb chains appear and disappear before and after birth?

Answer 33

The α chain appears in early pregnancy and remains high in concentration throughout life

The γ chain appears during fetal developmen and remains high in concentration until birth, it quickly disappears after that

The β chain appears during fetal development and very slowly rises in concentration until birth, when it quickly rises to a high concentration that is maintained throughout life.

The δ and ε chains are found in embryonic hemoglobin. α₂δ₂ is found in small amounts in adults

Question 34

What is the predominant from of Hb in a fetus? Why does it bind O2 more tightly than HbA?

Answer 34

Fetal Hb is HbF (α₂γ₂) and it has a slightly higher affinity for O2 because it binds less tightly to 2,3-BPG.

Question 35

What is the difference between glycation and glycosylation and why is this concept relevant to Hb?

Answer 35

Both reactions involve the covalent addition of glucose to a molecule. However, glycation happens spontaneously and glycosylation is enzymatic and regulated by the body. Hb can be glycated to HbA_1c. HbA_1c​ levels can be used to monitor blood glucose levels from the past three months.

Question 36

Describe the causes and consequences of Sickle Cell Anemia?

Answer 36

A mutation in the Hb β chain gene causes the 6th residue, Glutamate, to become Valine. This creates a hydrophobic interaction to occur between Hb molecules, leading to aggregation. Deoxygenated HbS (mutated Hb) polymerizes into filaments which alters RBC shape. Sickled erythrocytes are more rigid which may block blood flow in the capillaries, causing microinfarcts.

Question 37

Does the sickly cell mutation alter the ability of Hb to carry oxygen?

Answer 37

No

Question 38

What is thought to be a possible cure for β-thalassemia and sickle cell anemia? Why?

Answer 38

Since both diseases affect the β chain only it is thought that if fetal hemoglobin (HbF-α₂γ₂) could be induced it could eliminate the symptoms of these diseases.