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1. Intermediary Metabolism of the
Lung

2. The structure of the pulmonary
extracellular matrix
• consists mainly of collagen, elastic fibers, and
proteoglycans.
• Proteoglycans are responsible for two important
aspects of microvascular and interstitial fluid
dynamics, namely the sieving properties of the
capillary membrane and of the matrix and the
compliance of the interstitial tissue.

3. • Proteoglycans include families of multidomain core
proteins covalently linked to one or more
glycosaminoglycan chains.
• Versican is a large chondroitin sulfate (CS)
proteoglycan found in the interstitial matrix, where
it forms aggregates with hyaluronic acid.

6. The lung is a metabolically active organ that is engaged in
1. secretion,
2. clearance and
3. other maintenance functions
that require
1. reducing potential,
2. energy and
3. substrates for biosynthesis.
These metabolic requirements are met in part through uptake
and catabolism of glucose which represents the major fuel
utilized by lung tissues.

7. • Glucose is catabolized in the lung by cytoplasmic and
mitochondrial pathways that are responsive to regulatory
mechanisms as in other tissues.

8. • The lung tissue can oxidize to a variable degree glucose, fatty
acids, amino acids, lactate, and glycerol.
• However, the rate of glucose oxidation is greatest
• There is apparently more than one transport system for
hexoses in the lung and both facilitated diffusion and active
transport may occur.

9. Gas Exchange in the Lungs
• Deoxygenated blood enters the capillaries of
the alveoli, where CO2 diffuses out of the
blood and O2 binds to hemoglobin in red
blood cells.

10. Key Points
• Gas exchange is taking in molecular oxigen from the environment and
subsequently releasing carbon dioxide back into the environment.
• In a mixture of ideal gases, each gas has a partial pressure that is the
pressure the gas would have if it alone occupied the volume. The total
pressure of a gas mixture is the sum of the partial pressures of each
individual gas in the mixture.
• Gas diffuses from a higher partial pressure area to a lower partial pressure
area.

12. Terms
• gas exchange
• Gas exchange is a process in biology where gases contained
in an organism and atmosphere transfer or exchange. In
human gas-exchange, gases contained in the blood of human
bodies exchange with gases contained in the atmosphere.
• respiration
• The process by which cells obtain chemical energy by the
consumption (intake) of oxygen and the release of carbon
dioxide.

13. • Gas Exchange occurs across the 300 million alveoli (60-80 m2 total surface area) .
• The alveoli contain some collagen and elastic fibres. The elastic fibers allow the
alveoli to stretch as they are filled with air during inhalation. They then spring
back during exhalation in order to expel the carbon dioxide-rich air.
• Type I alveolar cells- creates the air sac.
• Type II alveolar cells- secretes surfactant and absorbs sodium and water.

14. • Ventilation is the process of air movement into and out of
the lungs.

15. • A diffusion of O2 into and CO2 out of the blood occurs in the alveoli once
air enters the lungs. The oxygenated blood is then perfused throughout the
body where gas exchange occurs in the tissue capillary beds.
Inhaled oxygen required for cellular respiration enters the tissues and
carbon dioxide, a waste product of cellular respiration, diffuses into the
blood stream to the lungs to be exhaled.

17. 3 ways CO2 is carried in blood
• CO2 + H2O carbonic acid bicarbonate + H ion
(H2CO3) (HCO3)
The bicarbonate ions reduce the pH in blood and this is detected by the
medulla.
3 ways CO2 is carried in blood:
1. 70% as a bicarbonate ion in your plasma
2. 20 % as carboxyhemoglobin (HbCO2)
3. 10 % floats in your plasma as CO2
carbonic anhidrase

18. • Oxygen and CO2 are carried between the lungs and the other tissues by
the blood. In the blood some of each gas is present in simple physical
solution, but mostly each is involved in some sort of interaction with
hemoglobin, the major protein of the red blood cell.
• There is a reciprocal relation between haemoglobin's affinity
for O2 and CO2, so that the relatively high level of O2 in the
lungs aids the release of CO2, which is to be expired, and the
high CO2 level in other tissues aids the release of O2 for their
use.

19. Need for a Carrier of Oxygen in Blood
• An O2 carrier is needed in blood because O2 is not soluble enough in
blood plasma to meet the body's needs. At 38°C, 1 L of plasma dissolves
only 2.3 mL of O2.
• Whole blood, because of its haemoglobin, has a much greater oxygen
capacity. One liter of blood normally contains about 150 g of haemoglobin
(contained within the erythrocytes), and each gram of haemoglobin can
combine with 1.34 mL of O2.
• Thus the hemoglobin in 1 L of blood can carry 200 mL of O2, 87 times as
much as plasma alone would carry. Without an O2 carrier, the blood would
have to circulate 87 times as fast to provide the same amount of O2.
• The availability of a carrier also gives us a way of controlling oxygen
delivery, since the O2 affinity of the carrier is responsive to changing
physiological conditions.

20. Hemoglobin
• Hemoglobin (heme-containing protein) is a tetramer composed of two different
types of subunits (2α and 2β -polypeptide chains). Each subunit has a strong
sequence homology to myoglobin and contains an O2 binding site. (Myoglobin is
an oxygen-binding single-chain globular protein, containing a heme, found in the
muscle tissue).

21. Heme
The Fe is bound to four
nitrogen atoms in the center
of the heme porphyrin ring.
Heme is a complex of protoporphyrin IX and
ferrous iron (Fe2+). The iron is held in the
center of the heme molecule by bonds to
the four nitrogens of the porphyrin ring.
The heme Fe2+ can form two additional bonds,
one on each side of the planar porphyrin
ring.
In myoglobin and hemoglobin, one of these
positions is coordinated to the side chain of
a histidine residue of the globin molecule,
whereas the other position is available to
bind oxygen.

23. Structure of hemoglobin
• Hemoglobin A, the major hemoglobin in adults, is composed of four
polypeptide chains—two α chains and two β chains—held together by
noncovalent interactions .
• Each subunit has stretches of α-helical structure, and a heme-binding
pocket.
• However, the tetrameric hemoglobin molecule is structurally and
functionally more complex than myoglobin.
• For example, hemoglobin can transport H+ and CO2 from the tissues to
the lungs, and can carry four molecules of O2 from the lungs to the cells
of the body

24. Quaternary structure of
hemoglobin
• The hemoglobin tetramer can be envisioned as being
composed of two identical dimers, (αβ)1 and (αβ)2, in which
the numbers refer to dimers one and two.
• The two polypeptide chains within each dimer are held tightly
together, primarily by hydrophobic interactions , Ionic and
hydrogen bonds also occur between the members of the
dimer.
• The weaker interactions between these mobile dimers result
in the two dimers occupying different relative positions in
deoxyhemoglobin as compared with oxyhemoglobin

26. T and R form of Hemoglobin
• a. T form: The deoxy form of hemoglobin is called the “T,” or
taut (tense) form. In the T form, the two αβ dimers interact
through a network of ionic bonds and hydrogen bonds that
constrain the movement of the polypeptide chains. The T
form is the low oxygen-affinity form of hemoglobin.
• b. R form: The binding of oxygen to hemoglobin causes the
rupture of some of the ionic bonds and hydrogen bonds
between the αβ dimers. This leads to a structure called the
“R,” or relaxed form, in which the polypeptide chains have
more freedom of movement. The R form is the high oxygen-
affinity form of hemoglobin.

28. Myoglobin
• Myoglobin, a hemeprotein present in heart and skeletal
muscle, functions both as a reservoir for oxygen, and as an
oxygen carrier that increases the rate of transport of oxygen
within the muscle cell.
• Myoglobin consists of a single polypeptide chain that is
structurally similar to the individual subunit polypeptide
chains of the hemo -globin molecule.
• α-Helical content: Myoglobin is a compact molecule, with
approximately 80% of its polypeptide chain folded into eight
stretches of α-helix.
• The heme group of myoglobin sits in a crevice in the
molecule, which is lined with nonpolar amino acids

30. Figure compares the structures of myoglobin and haemoglobin.
Each haem molecule can take up one oxygen
molecule.
Myoglobin can thus take up one oxygen molecule and
haemoglobin can take up four oxygen molecules.

31. Cooperativity of Oxygen Binding in Hemoglobin
The cooperativity in oxygen binding in hemoglobin comes from
conformational changes in tertiary structure that take place when O2
binds. The conformational change of hemoglobin is usually described as
changing from a T (tense or taut) state with low affinity for O2 to an R
(relaxed) state with a high affinity for O2.
Breaking the salt bridges in the contacts between subunits is an energy-
requiring process, and consequently, the binding rate for the first O2 is
very low. When the next O2 binds, many of the hemoglobin molecules
containing one O2 will already have all four subunits in the R state, and
therefore the rate of binding is much higher. With two O2 molecules
bound, an even higher percentage of the hemoglobin molecules will have
all four subunits in the R state. This phenomenon, known as positive
cooperativity, is responsible for the sigmoidal O2 saturation curve of
hemoglobin

32. These curves show that when the
pO2 is high, as in the lungs, both
myoglobin and hemoglobin are
saturated with O2.
Myoglobin takes up oxygen at
low oxygen presures and is
rapidly saturated.
Haemoglobin takes up
oxygen quite differently -
slowly to start with, then
more readily.
Adding some oxygen to
haemoglobin increases its
affinity for more oxygen
molecules. This is known as
a cooperative effect.

33. • In the context of the affinity of hemoglobin for
oxygen there are four primary regulators, each
of which has a negative impact. These are
CO2, hydrogen ion (H+), chloride ion (Cl–), and
2,3-bisphosphoglycerate (2,3BPG, or also just
BPG). Although they can influence O2 binding
independent of each other.

34. Effect of 2,3-bisphosphoglycerate
on oxygen affinity
• 2,3-Bis - phospho glycerate (2,3-BPG) is an important
regulator of the binding of oxygen to hemoglobin. It
is the most abundant organic phosphate in the RBC,
where its concentration is approximately that of
hemoglobin.
• 2,3-BPG is synthesized from an intermediate of the
glycolytic pathway

35. Binding of 2,3-BPG to
deoxyhemoglobin
• 2,3-BPG decreases the oxygen affinity of hemoglobin
by binding to deoxy-hemoglobin but not to
oxyhemoglobin. This preferential binding stabilizes
the taut conformation of deoxyhemoglobin.
• The effect of binding 2,3-BPG can be represented
schematically as:
HbO2 + 2,3-BPG -----→ Hb–2,3-BPG + O2

37. Agents That Affect Oxygen
Binding
• Agents that affect
oxygen binding by
hemoglobin. Binding of
hydrogen ions, 2,3-
bisphosphoglycerate,
and CO2 to hemoglobin
decrease its affinity for
oxygen.

38. Proton Binding (Bohr Effect)
• The binding of protons by hemoglobin lowers its affinity for O2,
contributing to a phenomenon known as the Bohr effect .
• The pH of the blood decreases as it enters the tissues (and the proton
concentration rises) because the CO2 produced by metabolism is
converted to carbonic acid by the reaction catalyzed by carbonic
anhydrase in red blood cells. Dissociation of carbonic acid produces
protons that react with several amino acid residues in hemoglobin,
causing conformational changes that promote the release of O2.
• In the lungs, this process is reversed. O2 binds to hemoglobin (due to the
high O2 concentration in the lung), causing a release of protons, which
combine with bicarbonate to form carbonic acid. This decrease of protons
causes the pH of the blood to rise. Carbonic anhydrase cleaves the
carbonic acid to H2O and CO2, and the CO2 is exhaled. Thus, in tissues
where the pH of the blood is low because of the CO2 produced by
metabolism, O2 is released from hemoglobin. In the lungs, where the pH
of the blood is higher because CO2 is being exhaled, O2 binds to
hemoglobin.

39. Effect of H+ on oxygen binding by
hemoglobin (Hb).
A. In the tissues, CO2 is released. In
the red blood cell, this CO2 forms
carbonic acid, which releases
protons. The protons bind to Hb,
causing it to release oxygen to
the tissues.
B. In the lungs, the reactions are
reversed. O2 binds to protonated
Hb, causing the release of
protons. The protons bind to
bicarbonate (HCO3
2), forming
carbonic acid, which is cleaved to
water and CO2, which is exhaled.