Physiological Mechanisms
Respiration
Dr Smita Bhatia
BP-5, II floor,
Shalimar Bagh (West)
Delhi 110088
Contact: 27483738
Email: smitabhatia@edscientia.com
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Respiration
Learning objectives

Structure and organization of the respiratory system

Mechanics of breathing

Exchange of gases

Transport of gases by blood

Control of respiration

Adaptation to high altitude

Diseases and disorders of the respiratory system
In aerobic organisms, energy is derived from fuel molecules in the presence of oxygen
(O2), and carbon dioxide (CO2) and water are formed as by-products. Oxygen is obtained
from the air in the atmosphere by a process called respiration, which has the following
four components:
1. Breathing or pulmonary ventilation: The lungs take in the O2-rich atmospheric air
(inhalation) and exhale CO2-rich air (exhalation).
2. External respiration: It is the exchange of gases at the lung surface between the air
present in the lungs and the blood present in the pulmonary capillaries.
3. Transport of gases: The transport of O2 from the lungs to the cells and the transport
of carbon dioxide from the cells to the lungs in blood.
4. Internal respiration: Exchange of O2 and CO2 between the cells and blood and the
utilization of oxygen by the cells for energy production (also known as cellular
respiration).
The respiratory system consists of the structures responsible for breathing and external
respiration, while the cardiovascular system is responsible for the transport of gases.
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Figure 1: Components of respiration
Structure and Organization of the Respiratory system
The nose, pharynx, larynx, the lungs, the various tubes leading to the lungs, and the
structures that assist in breathing constitute the respiratory system.
Figure 2: Anterior view of the respiratory system
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Air that is breathed in takes the following route.
Air in the atmosphere
Nose
Pharynx
Larynx
Conducting
zone
Trachea
Bronchi (primary / secondary / tertiary)
Bronchioles
Terminal bronchioles
Respiratory bronchioles
Respiratory
zone
Alveolar ducts
[
Alveolar sacs
Alveoli
Figure 3: Structural organization of the respiratory tree
Up to the level of the terminal bronchi is the conducting zone as the tubes till here serve
to conduct the air from the outside to the lungs and there is no exchange of gas up to this
level. This space where air is held without any gas exchange is known as the dead space
(anatomic dead space, physiological dead space refers to the total dead space which
includes the non-functional or partially functional areas of the respiratory zone, especially
alveoli, where due to some abnormality gas exchange is completely or partially absent.)
From the level of respiratory bronchioles onwards the tubes not only serve to conduct air
but there is gas exchange also and this zone is known as the respiratory zone.
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The trachea (or the windpipe) is a tube extending from the larynx up to the lungs where it
divides into the left and right primary bronchi that divide into bronchi. Inside the lung,
primary bronchi divides in (primary, secondary, tertiary) ending in terminal bronchioles.
These lead to respiratory bronchioles which form the alveolar ducts that are connected to
the alveolar sacs, which are groups of alveoli with a common opening. Each alveolus is a
cup shaped thin walled structure where most of the gas exchange takes place.
Histology of the airways and alveoli
The tracheal wall consists of four layers (from the lumen onwards):
1. mucosa
2. submucosa
3. cartilage
4. adventitia
Mucosa consists of peudostratified columnar epithelium made up of ciliated cells and
goblet (mucous) cells that reach the surface and basal cells that are present at the base.
The lamina propria containing elastic and reticular fibres is present beneath the
epithelium. Dust particles are trapped by the mucus and carried towards the pharynx by
the beating cilia where it is swallowed and digested in the stomach.
Submucosa consists of areolar connective tissue with mucous and serous glands.
Cartilage consists of incomplete rings of hyaline cartilage in the trachea (and other
airways) which appear like the letter “c”. The open portion of the cartilage is towards the
oesophagus (dorsal). Transverse smooth muscle and elastic connective tissue hold the
open ends of the cartilage together. The cartilaginous rings prevent the trachea from
collapsing.
Adventitia consists of areolar connective tissue with numerous blood vessels and nerves.
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Adventitia
Cartilage
Submucosa
Lamina propria
Pseudostratified
epithelium
Smooth muscle
Mucosa
Figure 4: Section through trachea
The following histological modifications occur along the airways, as the trachea divides
to form the bronchi which then give rise to other branches, to suit the functional aspect of
the regions:

Bronchi: pseudostratified columnar epithelium in the bronchi changes to non-ciliated
cuboidal epithelium in the terminal bronchioles (here the inhaled particles are
removed by macrophages).

Respiratory bronchioles: cuboidal epithelium changes into simple squamous
epithelium facilitating gas exchange between the lungs and the blood capillaries.

As the cartilage reduces, smooth muscle appears which is arranged spirally in the wall
of these airways serving to control the opening of
the lumen.
During exercise, sympathetic stimulation of these
muscles causes them to dilate facilitating ventilation. In
an allergic reaction, as in asthma, these muscles
contract to cause constriction of the airways.
Figure 5: Section through trachea
showing constricted bronchioles
in asthma
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Terminal bronchioles. This is the last component of the conducting zone of the
respiratory tract before the respiratory zone begins. The most numerous type of cells in
the epithelium are the ciliated cells and specialized type of cells called the clara cells,
These are dome shaped, non-mucous, non-ciliated secretary cells with short microvilli.
Their functions include:
1. Protecting the bronchiolar epithelium by secreting a protein and the surfactant (which
is also secreted by the type II alveolar cells)
2. Detoxification of harmful substances inhaled by the lungs.
3. Repairing the bronchiolar epithelium by giving rise to new cells (they act as stem
cells).
4. Counter regulating inflammation.
Respiratory bronchioles. The walls of the respiratory bronchioles contains alveoli where
gas exchange occurs. Between the alveoli the wall consists of cuboidal or columnar
epithelium made up of ciliated cells and clara cells in the initial portions while the distal
parts have only clara cells. Beneath the epithelium is a layer of connective tissue and
smooth muscle consisting of interlacing bundles of smooth muscle and elastic tissue
fibres.
Alveolar sacs. These are groups of alveoli with a common opening (Figure 6).
Alveolar walls. The partition between two alveoli is known as the alveolar wall or
alveolar septum and is made up of type I cells and type II cells (Figure 6 and 7).
Alveolar sacs
Alveolar walls
Alveolar duct
Figure 6: Section through lung showing alveolar duct, alveolar sacs and alveolar wall.
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Alveoli. The ultimate respiratory surface consists of the sac-like alveoli where the
squamous epithelium facilitates exchange between the air in the alveoli and blood in the
capillaries.
Connective tissue
Alveolar type II cell
Alveoli
Alveolar walls
Alveolar type I cell
Alveolar macrophage
Figure 7: Components of the respiratory epithelium
The layer separating the air and the
blood constitute the respiratory
membrane which has the following
components.
1. alveolar epithelium
2. epithelial basement membrane
3. capillary basement membrane
4. capillary endothelium.
Respiratory Distress Syndrome (RDS) in the
newborn
In a prematurely born baby especially
through a caesarean section, there is a
possibility of lack of surfactant causing
respiratory distress that might result even in
death
The deficiency of the surfactant is due to
incomplete maturation of type II cells that
At some places the epithelial
basement membrane and the
capillary basement membranes are
require cortisol for their maturation. Cortisol,
a stress hormone released during vaginal
birth, is absent during caesarean birth.
fused to further reduce the barrier to
only 3 components.
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Alveolar epithelium has
1. Squamous type I cells that are most abundant. These are the site of gas exchange.
2. Cuboidal type II cells or septal cells responsible for the secretion of the fluid that
keeps the alveoli moist and also contains the surfactant.
Surfactant is a mixture of phospholipids and lipoproteins secreted by the type II cells
which act like a detergent serving to reduce the surface tension of the fluid lining the
alveoli. This facilitates the distension of alveoli during inspiration and prevents their
collapse. See RDS
Also present in the alveolar epithelium are macrophages (dust cells) or wandering cells
that phagocytose foreign particles reaching the lungs; and fibroblasts which give rise to
elastic and reticular fibres.
Lungs
These are paired conical structures in the thoracic cavity. The thoracic cavity is bound by
the ribs anteriorly, laterally and posteriorly with the diaphragm at its base into which fit
the concave margins of the lungs. The two lungs
Functions of the pleural membrane
are separated from one another to form an
1. Causes the adherence of the lungs to
individual anatomical unit (in case of injury to
the thoracic wall.
one lung the other one can still function
2. Reduces friction between the lungs
normally). Surface of the lung is lined by a
and the thoracic cavity during
double serous membrane called the pleural
breathing.
membrane. One side faces the thoracic wall (the
parietal pleura) and the other the lungs (visceral pleura). The space between these two
membranes contains intrapleural fluid secreted by the cells of the pleural membrane.
Each lung is divided into lobes by fissures. (See Figure 2) The right lung has three lobes
formed by the oblique and the horizontal fissures and the left lung has 2 lobes formed by
an oblique fissure. The right bronchus divides into three branches (secondary or lobar
bronchi) to supply each lobe while the left primary bronchus divides into two. Each lobe
further has functionally independent segments — the bronchopulmonary segment —
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receiving its own tertiary bronchus. These segments are further divided into lobules each
receiving branches of an arteriole, a venule, a lymph vessel and the tertiary bronchus.
Blood supply to the lungs. Two types of arteries supply blood to the lungs.
1. Pulmonary arteries that carry deoxygenated blood from the right ventricles to the
lungs where it gets oxygenated. Blood returns to left atrium via the pulmonary veins.
2. Bronchial arteries arising from the aorta supply oxygenated blood to the lung tissue.
Deoxygenated blood is returned to the heart via the pulmonary veins while some of it
is returned by bronchial veins emptying into the superior vena cava.
Mechanics of Breathing
Air moves from a region of high pressure to a region of low pressure. For inspiration
(inhalation) to take place the pressure of air inside the lungs must be less than the
pressure of air outside (the atmospheric pressure = 760 mmHg), i.e., it should be negative
with respect to the atmospheric pressure. This is achieved by increasing the size of the
thoracic cavity by causing the lungs to expand. According to Boyle’s law the pressure
exerted by a gas is inversely proportional to the volume occupied by it under conditions
of constant temperature. So when the lungs expand (i.e. their volume increases) the
pressure of air inside the lungs (some air is always present in the lungs, they are never
empty <Click here to know why>) decreases which causes air to rush from outside, into
the lungs. When the lungs return to their original position the volume of air inside the
lungs reduces causing an increased pressure, resulting in the movement of air from the
lungs to the outside (exhalation).
Diaphragm contracted
Inspiration
Diaphragm expanded
Expiration
Figure 8: Position of the diaphragm during expiration and inspiration
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What causes the lungs to expand and contract?
Expansion
Neural signals from the respiratory centre in the medulla [see also control of respiration]
Stimulate the phrenic nerve (innervating the diaphragm) and the external intercostal muscles
Diaphragm and intercostal muscles contract
Size of the thoracic cavity increased due to flattening of the diaphragm, rising of the rib
cage outwards and upwards.
Pressure reduces in the lung
Air from outside rushes into the lungs (inspiration)
Contraction
Contraction of the diaphragm and the external intercostal muscle stops without neural
signals from the respiratory centre
Diaphragm and intercostal muscles relax and return to original position due to elastic
recoil
The greater volume of air present in the lungs after inspiration than before it causes
increase in pressure of air inside the lungs when they return to their original position
causing movement of air towards the outside (exhalation)
At rest, i.e. in normal, quiet breathing, no effort is required for exhalation, i.e., exhalation is a
passive process. But during exercise when extra air is taken in and breathed out, exhalation is
not a passive process. During such an activity another set of intercostal muscles, the internal
intercostal muscles, contract during exhalation further reducing the size of the thoracic cavity
(and the lungs) to push the extra air out (which is taken in during inspiration which also needs
more effort here).
Why do the lungs move with the thoracic wall?
The outer surface of the lungs is lined by a double serous membrane, the pleurae. The outer
membrane (which lines the thoracic cavity on the inner side) is called the parietal pleura and the
inner membrane (which lines the outer surface of the lungs) is called the visceral pleura. In
between these two membranes is a very small intrapleural space, filled with intra pleural fluid
secreted by the cells of the membranes. Due to the surface tension of this fluid, the thoracic
wall and the lungs adhere to one another and the lungs move with the thoracic wall.
Why do the lungs not collapse between breaths?
Due to the elastic recoil of the thoracic wall on one side and the lungs on the other both pleurae
tend to move away from one another but, since the intra pleural fluid does not expand, there is a
sort of vacuum created due to the elastic recoil (that is the tendency of the thoracic wall to move
outward and the lungs to curve inward). This causes a small negative pressure (756 mmHg, i-e.
– 4 mmHg relative to atmospheric pressure) acting on the walls of the lungs and the thoracic
wall. That is why the lungs are always distended to a certain degree containing some air even at
rest and do not collapse between breaths.
Lung
Pip 756 mmHg,
(– 4 mmHg)
Palv
Thoracic wall
Visceral pleura
Parietal pleura
Tends to move inward
Tends to move outward
Intrapleural fluid
Figure 9: Pleural membranes
Mechanisms of inspiration and expiration show that it is the difference in pressure across the
lung walls that cause them to increase or decrease in size. This difference is known as the
transpulmonary pressure and is the difference between the pressure on the lung walls on the
inner side — the alveolar pressure (Palv) – and the pressure on the lung walls on the outside —
the intra pleural pressure (Pip).
Transpulmonary pressure = Palv – Pip
Other physical factors that influence the degree of inflation and deflation of lungs are: lung
compliance, airway resistance.
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Lung compliance is a measure of the stretchability of the lung walls and is calculated by the
change in volume of the lungs caused by a particular change in pressure across their walls
(transpulmonary pressure)
Lung compliance = V/P, where V is the volume of lung and P is the transpulmonary
pressure.
Compliance is said to be high when a small change in the transpulmonary pressure causes a
large change in lung volume and is said to be low when a change in the transpulmonary
pressure causes only a small change in the lung volume. So if the lung compliance in a person
is low, a greater change in the transpulmonary pressure is required to achieve the required
change in lung volume. To create this increase in the transpulmonary pressure a greater effort
(for enlarging the thoracic cavity by the contraction of the exterior inter costal muscles and the
diaphragm) is required which needs greater energy. Lung compliance is dependent on two
factors.
1. Elasticity of the lung tissue: Normally, the lung tissue made up of elastic connective tissue
is quite stretchable but under diseased conditions it may become thickened and may lose its
elasticity thus reducing lung compliance.
2. Presence of surfactant: The inner surface of lung on the inside is not dry but lined by a layer
of fluid. If this fluid were only water it would prevent an increase in the volume of the
alveoli because of its high surface tension. To prevent this, the fluid contains a mixture of
phospholipids and proteins called surfactant, which reduces the surface tension and
facilitates the expansion of the alveoli.
Airway resistance: Normally the airways of the respiratory system do not offer any significant
resistance to the flow of air (that is why a small decrease in the alveolar pressure causes air to
rush into the lungs and a small increase causes air to rush out). Airway resistance is also kept
low because during inspiration when the alveoli expand, they pull at the elastic connective
tissue fibres of the airways causing the airways to also expand (lateral traction). During a forced
expiration the airways become narrow offering resistance to airflow which limits the amount of
air that can be expelled forcibly in a given time. In diseases, such as asthma, (where there is a
contraction of smooth muscle fibres lining the airways) and chronic pulmonary obstructive
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disease cause the airways to become narrow increasing the airway resistance making expiration
difficult.
Exchange of gases
Exchange of gases occurs at the lung surface during lung ventilation. When fresh air is taken in
O2 diffuses across the respiratory surfaces (alveoli, alveolar ducts and respiratory bronchioles)
into the blood from where it is transported to the tissues. Oxygen reaching the tissues is utilized
by the cells for their metabolic activities and CO2 is produced. This CO2 is transported from the
tissues by blood to the lungs where it is expelled with the expired air. [see figure]
At the lung surface and tissue, O2 and CO2 enter the blood stream by diffusion while their
transport by blood is by bulk flow. Diffusion of a gas into a liquid medium is directly
proportional to the pressure (or partial pressure in a mixture of gases) of the gas (Henry's law).
Oxygen diffuses from the lungs into blood because the partial pressure of O2 (pO2) in the
inspired air is more than the partial pressure of O2 in the blood entering the lungs. Similarly,
CO2 diffuses in the opposite direction (from blood into the lungs) because the partial pressure
of CO2 (pCO2) in blood is higher than that in the inspired air in the lungs. The partial pressures
of O2 and CO2 in the atmospheric air and in the alveoli are:
pO2 = 160 mmHg
pCO2 = 0–3 mm Hg
Alveolar pO2 = I05 mmHg
Alveolar pCO2 = 40 mmHg
Dalton’s law: Total pressure of a mixture of gases is equal to the sum of the partial pressures of
its constituent gases. Since the total atmospheric pressure of air is 760 mm Hg at sea level and
the amount of O2 is 21%, the partial pressure of O2 would be 21/100 × 760 mm Hg ~ I60
mmHg
Factors affecting alveolar pO2 and pCO2 are:

Alveolar ventilation: It is the amount of air entering the alveoli per unit time. Any decrease
in this will cause the pCO2 to rise and pO2 to reduce and vice versa pO2 and PCO2 in the
atmospheric air.
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
pO2 and pCO2 in the atmospheric air: Under conditions when the pO2 of the inspired air
decreases, e.g. at high altitudes where the atmospheric pressure is lower, the alveolar pO2
will decrease. Here the pCO2 of the inspired air will not make much difference because the
pCO2 of the inspired air at a normal atmospheric pressure is also insignificant, but the
alveolar pCO2 may increase due to insufficient O2.

Rate of O2 consumption and CO2 production (metabolic rate).
Lung Surface
pO2
40
mmHg
Venous blood
Tissue Level
pCO2
45
mmHg
O2
pO2
100
mmHg
O2
CO2
pO2
105
mmHg
Arterial blood
pCO2
40
mmHg
pCO2
40
mmHg
CO2
pO2
40
mmHg
Alveoli
pCO2
45
mmHg
Tissue
Figure 10: Partial pressures that facilitate the exchange of gases (CO2 and O2) at different
levels (lungs and tissues)
As seen above the arterial pO2 is 5 mmHg less than the pO2 of the alveoli. This is because of
not so perfect ventilation coordination between alveolar ventilation and blood supply to the
individual alveoli (perfusion) called the ventilation–perfusion inequality. While under normal
conditions there is a difference of 5 mmHg in the arterial and alveolar pO2, under diseased
conditions this might be greater. The most important mechanism working in normal individuals
to minimize this is the local vasoconstriction of the pulmonary capillaries in poorly ventilated
areas of the lungs so that this blood is diverted to the better ventilated regions (though in other
regions of the body where less O2 is available capillaries undergo vasodilation to deliver more
O2 to the tissues).
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Rate of O2 consumption and CO2 production
This is dependent upon the metabolic rate of the body tissues. An increased rate of O2
consumption will reduce the alveolar pO2 and vice versa. An increased rate of CO2 production
will increase the alveolar pCO2 and vice versa.
Hypoventilation and Hyperventilation
Hypoventilation occurs when alveolar
ventilation is not sufficient enough to
Respiratory quotient (RQ)
eliminate the CO2 produced in the body,
This is the ratio of O2 consumption to that of
so the pCO2 in the alveoli increases above
CO2 production. Its value is dependent upon
the normal value (40 mmHg).
the type of molecules used by the cells for
Hyperventilation occurs when alveolar
energy production, e.g. for molecules RQ is
ventilation is much greater than that
1.0 for proteins it is 0.8 and for fats it is 0.7.
required
For a mixed type of molecule the RQ is 0.8.
for
eliminating
CO2 being
produced in the body, so the pCO2
decreases (below 40 mmHg). Hyperventilation does not refer to just an increased ventilation,
but is in relation to the rate of CO2 production in the body. During exercise, for example, there
is an increase in the rate of ventilation to keep pace with the increased CO2 production, so the
alveolar pCO2 remains normal (and does not reduce as would in the case of hyperventilation).
Lung Volumes and Capacities
The amount of air that can be breathed in and expelled can be measured by using an instrument
called the spirometer or the respirometer. It consists of a pipe-like device connected to the gas
cylinders that supply air. The subject puts this in the mouth and breathes in from and out into
this. The volumes taken in and breathed out are recorded on a graph paper by a recording
device connected to it. The upward strokes indicate inspiration and the downward stroke shows
expiration. The volumes and rate of inspiration and expiration can be calculated from the
recording. Lung capacities are derived by adding up more than one lung volume.
<<External link: http://www.njc.org/patient-info/progs/pps/tests/pulmonary-test.aspx#2>>
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Figure 11: Spirogram showing lung volumes and capacities

Tidal volume: The amount of air breathed in or expelled at rest, which is much less than the
potential of the lungs for inspiration and expiration; about 500 ml in a normal individual.

Inspiratory reserve volume: The extra volume of air that can be taken in over and above the
tidal volume; 3 L.

Expiratory reserve volume: The extra air that can be expelled after expiring the tidal
volume; I.5 L. (The lungs can expel a large volume of air by a forced expiration when the
expiratory muscles come into play.)

Residual volume: The air left in the lungs that cannot be expelled, even after expelling the
maximum amount of air by a forced expiration; I L.

Functional residual capacity: The volume of air remaining in the lungs (some of which can
be expelled by a forced expiration (ERV) and some which cannot be expelled — residual
volume (RV)); is the sum of ERV and RV = 1.5 L + 1 L = 2.5 L. (When a person is
breathing at rest only the inspired tidal volume is inspired and expelled.)

Vital capacity: The total volume of air that can be taken in by a forced inspiration and
expelled by forced expiration. It is the sum of TV, ERV and IRV = 0.5 L + 1.5 L + 3 L = 5
L.

Total lung capacity: The theoretical value of the total amount of air that can be held by the
lungs (including the residual volume that can never be expelled). This is given by the sum
of TV, ERV, IRV and RV = 0.5 L + 1.5 L + 3 L + 1 L = 6 L.
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All volumes and capacities are measured during lung function tests to test abnormalities in lung
function. Another important measurement is the FEV1, which is the forced expiratory volume in
1 second. For measuring this the subject is made to breathe in the maximum amount of air and
then made to expel as fast as possible. If the airways and the lungs are normal FEV is 80% of
the vital capacity. Any reduction in this indicates an obstructive pulmonary disease.
Transport of Gases in Blood
Once O2 diffuses into the blood at the lung surface it has to be transported to the tissues and
CO2 from the tissues transported to the lungs by the blood. The efficiency of this transport of
gases in blood is increased by the presence of haemoglobin <link to circulation>(Hb) in the red
blood cells which can specifically bind to O2, CO2 and H+ ions.
Transport of oxygen
Oxygen is relatively less soluble in water. So, in
Only 0.33 ml of O2 can be
addition to the small amount of O2 that gets dissolved in
dissolved in 100 ml of plasma
plasma and the water present in erythrocytes, a large
while 19.7 ml is carried by Hb
proportion of it is carried by Hb.
present in the erythrocytes (1 ml
of Hb can carry 1.34 ml of O2).
Haemoglobin can reversibly bind O2 when it is
abundant (in the lungs) and can release it where O2
levels are low (in tissues) making it a perfect
molecule for the transport of O2. Each Hb molecule
has 4 heme groups each containing one Fe2+ in the
centre. Each Fe2+ can bind with one molecule of
oxygen so a single Hb molecule can carry 4
molecules of O2. Binding of one O2 molecule to Hb
increases its affinity for binding subsequent molecules
Figure 12: Heme group containing a
central Fe2+
of O2 (cooperativity). This is caused by steric conformational changes in the protein part of the
haemoglobin molecule when it binds to one oxygen molecule increasing its affinity for binding
subsequent oxygen molecules. This O2 does not react with Fe2+ but just binds with it by a loose
reversible coordination bond. The form of Hb when combined with O2 is called
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oxyhaemoglobin (Hb.O2) and when devoid of O2 it is called deoxyhaemoglobin (Hb). The
amount of Hb saturated with O2 gives the percent saturation of Hb (if Hb is carrying 60% of the
total O2 that it can bind it is said to be 60% saturated). The maximum amount of O2 that can be
carried by Hb is known as the oxygen carrying capacity.
The graphic representation of the relationship between Hb and O2 at different partial pressures
of O2 is known as the oxygen dissociation curve for haemoglobin, though it also shows the
association of Hb with O2. This curve (shown below) has some characteristic features that have
specific physiological significance.
Figure 13: Oxygen dissociation curve of haemoglobin

This is an s-shaped curve with a plateau showing almost 100% saturation.

Hb is almost fully saturated at a pO2 of 70 mmHg though the alveolar pO2 is 100 mmHg.
This is a safety feature for conditions, such as high altitude or some diseases, wherein even
when O2 levels go down to 60 mmHg, Hb can carry enough oxygen.

Between the arterial pO2 of 100 mmHg and venous pO2 (at rest) of 40 mmHg, only a small
amount of oxygen is unloaded by Hb.

Between the normal venous pO2 at rest (40 mmHg) and the venous pO2 under conditions of
strenuous exercise, a lot of O2 can be made available to the exercising muscle and the body
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tissues. Since this portion of the curve has a steep slope, a small reduction in pO2 causes a
release of large amounts of O2 i.e., with an increase in the demand of O2, a lot of oxygen is
given to the tissues.
Bohr effect
The relationship between O2 and Hb does not
remain constant, it changes with change in the
levels of certain factors, e.g. when the blood pCO2
becomes higher (e.g. at the tissue level) the entire
curve shifts to the right, i.e., the affinity of Hb for
O2 decreases so that more O2 is released at the
tissue level than the amount released. If the O2 and
Hb followed the initial curve, which means that Hb
has a higher affinity for O2 at high pO2, e.g., at the
lung surface when it is supposed to pick up as
much O2 as it can, and its affinity for O2 decreases
under conditions of high pCO2 (e.g. at the tissue
level) so that it can release as much O2 as is needed
in the tissues; such a shift of the oxygen
dissociation curve toward the right also occurs
under other conditions related to a low pO2, i.e.,
Carbon monoxide poisoning
Hb can bind to carbon monoxide
(CO) with 200 times greater affinity
than O2. CO is formed on combustion
of coal gas, wood, etc. Since it has a
greater affinity for CO it binds to CO
in preference to O2 thus hampering
its oxygen carrying capacity. This
results in CO poisoning. Hb bound to
CO is called carboxy haemoglobin
and its formation does not alter the
pO2 of oxygen dissolved in plasma.
Chemoreceptors sensitive to changes
in O2, CO2 and H+ ion levels are not
stimulated to alter the respiratory
rate.
high H+ ion concentration (also associated with a
high pCO2 (Transport of CO2) and higher concentration of 2, 3, BPG (2,3 bisphosphoglycerate;
a metabolite produced by the erythrocytes during glycolysis. Its concentration increases under
conditions of low pO2). High temperature also causes the curve to shift to the right because
when temperature is high, the metabolic rate of the cells is high and oxygen demand is greater.
This phenomenon of shifting of the O2 dissociation curve to the right under these conditions
(high blood pCO2, higher H+ ion concentration, temperature and 2, 3 BPG concentration) is
known as Bohr Effect.
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Under conditions of high
concentrations of H+ ions, 2,3 BPG,
High temperature and high pCO2
Figure 14: Oxygen dissociation curve of Hb showing Bohr effect
Alveolar level
The partial pressures of O2 in the blood is the pressure caused by the O2 dissolved in plasma
and not by the O2 combined with Hb in the erythrocytes. This facilitates the diffusion of O2
from the alveoli into the blood at the lung surface and from the blood to the cells at the tissue
level. At the lung surface, as O2 keeps diffusing from a higher alveolar pO2 to a lower pO2 in
the blood in alveolar capillaries it keeps combining with the Hb molecules in the erythrocytes
so a low pO2 is maintained in the blood as there is almost no O2 dissolved in plasma. This
facilitates the diffusion of large amounts of O2 from the alveoli into the blood by maintaining a
large pressure gradient. Only after the Hb is saturated with O2 that the rest of the O2 gets
dissolved in plasma and there is an equilibration of O2 between the alveoli and blood.
Alveoli
O2
Plasma
O2
Hb in
RBCs
Tissue level
Similarly at this level when blood has to release O2, the first one to be released is the O2
dissolved in plasma, so pO2 in the plasma remains low, which facilitates the release of greater
quantities of O2 from the Hb into the plasma from where it is taken up by the interstitial fluid
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and finally by the cells as the metabolically active cells have the lowest pO2. As the metabolic
rate of a cell increases, as in an exercising muscle, the amount of O2 used by the cells increases
creating a lower pO2 in the cell facilitating the release of larger amounts of O2 by creating a
greater pressure gradient.
Hb in
RBCs
O2
Interstitial
fluid
O2
Plasma
O2
Body cells
Transport of carbon dioxide
CO2 is carried by the blood in three forms:
1. Dissolved in plasma. Carbon dioxide is more soluble in water than O2, so a larger volume of
CO2 (10% of total CO2) is transported in dissolved from in plasma than O2.
2. As carbamino haemoglobin. CO2 can combine with the amino groups of the globin part of
Hb to form carbamino Hb. 30% CO2 is carried in this form.
R – NH2
+
CO2
R–N
H
COO-
Hb
3. As HCO3– ions. Maximum amount (60%) of CO2 is transported in this form. These ions are
generated by the following reactions catalysed by the enzyme carbonic anhydrase (CA)
present in the RBCs.
Carbonic
anhydrase
CO2
+
H2O
H2CO3
H+ + HCO3–
H+ and HCO3– ions are formed in the RBCs, but, the HCO3– ions diffuse out into the plasma in
exchange of a Cl– ion that moves into the RBC. This exchange is facilitated by a transporter
and is known as “chloride shift” or “Hamburger phenomenon”.
RBC
Plasma
CO2 + H2O
HHb
CA
Cl–
H2CO3
Transporter
protein in RBC
membrane
HCO3–
H+ + HCO3–
Hb
(deoxy)
Figure 15: Chloride shift or Hamburger phenomenon
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The H+ ions generated in the RBCs by this reaction combine with Hb which has already
released its O2 (deoxyHb). Blood picks up CO2 when it unloads O2 at the tissue level; the
deoxyHb thus formed has a high affinity for H+ ions. Thus, Hb molecules act as buffers to keep
these H+ ions away from the plasma and prevent the pH from decreasing (or acidity from
increasing). That is why venous blood is only slightly acidic (pH 7.36) than arterial blood (pH
7.4). At the lung surface all these reactions are reversed, because the pCO2 in the alveoli is
lower, CO2 from the plasma diffuses out reducing the blood pCO2. This results in the shifting of
equilibrium towards the dissociation of H2CO3 into H2O and CO2; CO2 is released at the lung
surface but if there is hypoventilation resulting in increased pCO2, the concentration of H+ ions
increases beyond what can be buffered by Hb resulting in increased acidity (lowered pH) of
blood. This condition is known as respiratory acidosis. On the contrary, under conditions of
hyperventilation pCO2 is reduced resulting in a reduced H+ ion concentration (reduced acidity
or increased alkalinity). This is known as respiratory alkalosis. Just as the affinity of Hb for O2
changes under different conditions of pO2, pCO2, H+ ions, temperature and 2, 3 BPG, its
affinity changes for CO2 under different conditions of pO2. At a higher pO2, as in the lungs, Hb
binds less CO2 (so it gives off CO2 at the lung surface) and at a low pO2, as in the tissues, Hb
binds more CO2 (and less O2). This change in the affinity for CO2 is known as the Haldane
effect and can be understood by examining the CO2 dissociation curves of Hb.
Figure 16: Carbon dioxide dissociation curve of Hb showing Haldane effect
Consider curve A which shows the percent saturation of Hb with CO2 at different values of
pCO2. Point “a” shows the pCO2 in tissues (45 mmHg) where Hb is 52% saturated. If the
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affinity of Hb for CO2 did not change at a pCO2 of 40 mmHg (as found in the lungs) the %
saturation would have been ~ 50% (point “b”) (not much change from the original value of
52%). But the curve shifts to the right when the pO2 increases (as in the lungs) so at the pCO2 of
40 mmHg the percent saturation of Hb with CO2 reduces to 48% (point “c”). This facilitates the
release of CO2 from Hb at the lung surface.
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Control of Respiration
Four specialized regions of neurons in the medulla oblongata and Pons play a major role in
controlling respiration.
1. Inspiratory area in the medulla
2. Expiratory area in the medulla
Pneumotaxic area
3. Pneumotaxic area in the Pons
4. Apneustic area in the Pons
Pons
Apneustic area
Inspiratory area
Medulla
Expiratory area
Figure 17: Neurons in the medulla and pons responsible for controlling respiration
The inspiratory area in the medulla is responsible for setting up the rhythm of normal breathing
at rest. It generates pace maker potentials periodically (autorhythmic) to give rise to action
potentials which stimulate the phrenic nerve and intercostal nerves resulting in the contraction
of the diaphragm and the respiratory inter costal muscles, respectively. This causes the thoracic
cavity to enlarge and inspiration occurs, such signals are sent to these structures for about 2
seconds. When these signals stop, the diaphragm and intercostal muscles return to their original
position causing the thoracic cavity also to go return to its original position by elastic recoil.
Expiration follows as it is a passive process (at rest).
The expiratory area does not have any role to play in normal quiet breathing but when a person
is exercising and breathing heavily, the expiratory area is stimulated by the inspiratory area
resulting in the contraction of expiratory intercostal muscles which causes expiration to become
an active process (i.e. to force the extra volume of air out).
The pneumotaxic area and the apneustic area help in setting up the breathing rate by
influencing the depth of breathing. Pneumotaxic area inhibits the inspiratory area so it helps to
stop inspiration. Apneustic area stimulates the inspiratory area, prolonging inspiration. But the
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pneumotaxic area is dominant over the apneustic area so when the pneumotaxic area is active
the apneustic area is overridden by it.
Some receptors in the body also influence the respiratory rate. These include:
I. Chemoreceptors, and 2. Stretch receptors
Chemoreceptors are sensitive to the concentration of substances such as O2, CO2, H+ ions.
These receptors sense the level of these substances and accordingly send signals to the
respiratory area to alter the rate and depth of breathing.
Based on their location in the body there are two types of chemoreceptors:
1. Central, and 2. Peripheral
Central chemoreceptors

Peripheral chemoreceptors
Found in the central nervous
system in or around the medulla
oblongata.

Are more sensitive to an increase
in H+ ion concentration or pCO2.
CO2 is more lipid soluble and can
diffuse into the cerebrospinal fluid
(CSF) from the capillaries in the
central nervous system (it can
cross the blood–brain barrier

Present in the form of aortic bodies in
readily). In the CSF it forms
the wall of the aortic arch and as carotid
H2CO3 by the action of carbonic
bodies in the wall of the carotid sinus.
anhydrase, which dissociates to
The carotid bodies are supplied by the
form H+ and HCO3- ions.
sensory fibres of the glossopharyngeal
The H+ ions stimulate the
nerve and aortic bodies are supplied by
chemoreceptors which in turn
the sensory fibres of the vagus nerve.
stimulate the inspiratory area to

Are sensitive to the levels of O2, CO2
cause an increase in the rate and
and H+ ions. Whenever there is an
depth of breathing so that the
increase in pCO2 or H+ ions or
increased pCO2 can be brought
reduction in pO2 (only drastic reduction
down to the normal levels.
in case of pO2 because a slight reduction
in pO2 around higher values of pO2
26

Not stimulated by H+ ions
would not affect as the Hb is 90%
generated by other sources, e.g.
saturated even at a pO2 of 60 mmHg)
lactic acid because H+ ions
causes these chemoreceptors to be
themselves cannot cross the blood-
stimulated which in turn stimulates the
brain barrier so readily.
inspiratory area to increase the rate and
depth of breathing (hyperventilation) so
that normal O2, CO2 and H+ ion levels
can be restored.

Respond to pO2 in the plasma and not
oxygen bound to Hb, which is why there
is no change in the respiratory rate in
response to anaemia.
Stretch receptors are present in the walls of bronchi and bronchioles which are supplied by the
sensory fibres of the vagus nerve. When the lungs inflate beyond three times the tidal volume,
these receptors get stimulated sending signals to the inspiratory area and apneustic area to
inhibit them so that inflation stops. This is known as the inflation or Hering-Breuer reflex
which is a protective mechanism for preventing over-stretching of the lungs beyond a limit
(This comes into play only when the lungs overstretch and not during normal quiet breathing).
Myoglobin
It is a red pigment protein found in muscle cells. It is responsible for supplying oxygen to the
muscle tissue for ATP generation during muscle contraction. Affinity of myoglobin for oxygen
is much higher than Hb, so myoglobin picks up O2 from Hb and stores it. This O2 is released
only when the pO2 levels become very low. This is evident from the O2 dissociation curve of
myoglobin which is a rectangular hyperbola.
Figure 18: Oxygen
dissociation curve of
myoglobin
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Fetal haemoglobin
Hb found in fetal blood is different from the adult Hb — it has a higher affinity for O2 than
adult Hb. At the placental level fetal Hb can pick up O2 from the maternal (adult) Hb and
deliver it to fetal tissues. <<link to fetal Hb in Circulation chapter for structure>>
Adaptation to high altitude
As we move up from sea level atmospheric air becomes rarer and thus the atmospheric pressure
reduces. At Mt. Everest (9000 m) atmospheric pressure is reduced to 253 mmHg with pO2 of 53
mmHg only. Under such conditions the body must undergo some changes to supply adequate
amount of O2 to the tissues. These changes are:

Due to a low pCO2 the peripheral receptors get stimulated causing increased rate and depth
of breathing.

Large amount of erythropoietin is released from the kidney which stimulates the production
of more RBCs.

2,3 BPG concentration increases reducing the affinity of Hb for O2, thus facilitating greater
unloading of O2 to the tissues. But, beyond a point this increase could be detrimental as it
would then affect the loading of O2 in the lungs.

Density of mitochondria in the cells, capillaries in the tissue and the amount of muscle
myoglobin increases to facilitate increased O2 transfer.

Peripheral receptors also stimulate loss of Na+ and water in the kidney tubules resulting in a
reduced blood volume thereby increasing the concentration of Hb in the blood per unit
volume.
Effects of cigarette smoking on the respiratory system

Smoke immobilizes the cilia in the airways so they do not drain the mucus efficiently.

Smoke injures the macrophages in the lungs so they cannot fight infections.

Nicotine in smoke constricts the terminal bronchioles increasing airway resistance.

Carbon monoxide in cigarette smoke binds to Hb reducing its O2 carrying capacity.

Smoke irritates the lining of the bronchial tree causing swelling and increased mucus
secretion both leading to increased airway resistance.

Smoke causes destruction of the elastic fibres in the alveolar walls reducing their elastic
recoil (emphysema) and reducing the efficiency of gas exchange.
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Some important terms

Tachypnoea. Rapid breathing

Dyspnoea. Difficult or painful breathing

Atelactasis. Incomplete expansion of a part of a lung caused by airway obstruction, lack of
surfactant or lung compression.

Cheyne Stokes Respiration. A typical breathing characterized by irregular deep breaths
followed by a temporary cessation of breathing. It is the normal pattern of breathing in
infants. In adults it occurs just before death due to cardiac, kidney, pulmonary or cerebral
disease.

Hypoxia. Deficiency of O2 at the tissue level. It can be of different types:
Hypoxic hypoxia: low arterial pO2 due to high altitude or some disease.
Ischemic hypoxia: caused by reduced blood flow to the tissue.
Anaemic hypoxia: reduced O2 in arterial blood due to reduced Hb content.
Histotoxic hypoxia: when the tissues cannot use O2 properly due to the toxic effect of some
agent, e.g. cyanide.

Hypercapnia or Hypercarbia. Increase in pCO2.

Minute ventilation. The volume of air inhaled and exhaled in one minute. Minute ventilation
= Tidal volume x Respiratory rate (no. of breaths per minute)
Diseases and Disorders of the Respiratory System
Cystic fibrosis
Pneumonia
Tuberculosis
Asthma
Emphysema
Chronic Obstructive Pulmonary Disease
Severe Acute Respiratory Syndrome
Other disorders and more information:
http://medicalcenter.osu.edu/patientcare/healthinformation/diseasesandconditions/respiratory/lu
ng/
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Cystic fibrosis. It is a genetic disorder that affects the secretory epithelia of all tissues, e.g. in
the airways, pancreas, small intestine, liver. In this a transporter protein responsible for carrying
Cl– ions across the cell membrane is defective. Due to this mucus and other secretions
accumulate in the ducts of various organ systems and do not drain easily. So the ducts of the
digestive system, reproductive system and the airways get blocked.
Pneumonia. It is commonly caused by the bacterium Streptococcus pneumoniae, but may also
be caused by other bacteria, viruses, protozoans, fungi, etc. The infection results in edema due
to inflammation and immune response of the body which causes the alveoli to become filled
with fluid making ventilation and gas exchange difficult.
Tuberculosis. is an infectious disease caused by the bacterium, Mycobacterium tuberculosis
which infects the lungs and other organs of the body. The immune response includes formation
of tubercles in the lungs to ward off the infection. The bacterium may remain dormant in the
body if the person’s immune system is strong enough but in an immunocompromised person
the bacterium may escape into the blood and lymph infecting other organs of the body.
Tuberculosis is curable if persons complete treatment. Non-completion of treatment causes the
bacteria to become resistant to many drugs, making cure difficult.
Asthma. It is an allergic response to substances such as pollen grains, dust mites, molds, some
drugs or certain food items. This response involves the constriction of respiratory airways due
to smooth muscle spasms, increased mucus secretion and swelling of the mucosal lining.
Children are more prone to attacks of asthma than adults. Symptoms of asthma include difficult
breathing, wheezing, coughing fatigue.
Emphysema. It is a disorder characterized by damaged alveolar walls caused by irritants such
as cigarette smoke, pollutants, industrial dust. Alveoli lose their elastic fibres so exhalation is
not complete and stale air remains in the alveoli reducing the efficiency of gas exchange.
Chronic Obstructive Pulmonary Disease (COPD). Any factor causing chronic and recurrent
obstruction to airflow increasing airway resistance results in COPD. These factors include
cigarette smoking, air pollution, pulmonary infection and genetic factors.
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Severe Acute Respiratory Syndrome (SARS). It is a new infective disease of the respiratory
tract caused by a pulmonary coronavirus. The elderly and people with other diseases are more
prone to this. No effective treatment is available. Symptoms include dry cough, difficulty in
breathing, headache, diarrhoea, and chills.
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