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Respiratory Physiology
Respiration is the process of gas exchange and occurs on two levels:
Internal Respiration
The use of oxygen by the mitochondria to produce ATP by oxidative phosphorylation with
production of carbon dioxide as a waste product.
External Respiration
Exchange of oxygen and carbon dioxide between the atmosphere and body tissues.
External Respiration Involves:
1. Pulmonary ventilation - movement of air in and out of the lungs.
2. Exchange of gases by diffusion between air and blood.
3. Transportation of gases by blood.
4.Exchange of gases by diffusion between blood and tissues.
Forces for Pulmonary Ventilation
Ventilation results from bulk flow of air as the
result of pressure gradients created
between alveoli and atmospheric
pressure.

Pulmonary Pressures
There are four primary pressures associated
with ventilation:
Atmospheric Pressure (Patm)
The pressure of the outside air at sea level
is 760 mm Hg.The remaining lung
pressures are expressed relative to this
pressure.
Intra-Alveolar Pressure (Palv)
) it is less than atmospheric pressure.
During inspiration (
) it is greater than atmospheric pressure.
During expiration (
At
rest
it
is
equal
to
atmospheric
pressure, which is considered to be at 0 mm Hg.

Intrapleural Pressure (Pip)

At rest it is - 4 mm Hg.
It varies during ventilation but it is always less than intra-alveolar pressure and is always
negative (that is, less than atmospheric pressure) during normal breathing.
This negative pressure results from elastic forces exerted on the intrapleural space by the
chest wall and the lungs.
I. The chest wall is compressed and the elastic forces are pulling it outward.
II. The lung walls are stretched and the elastic forces are pulling them inward.
III. Hence, the elastic forces are trying to open the intrapleural space. The tension resisting
these elastic forces is surface tension of pleural fluid.
To
maintain this negative intrapleural pressure the pleurae need to be sealed. If it is

damaged by trauma (gunshot or knife wound) or disease (pneumonia or emphysema


), air enters and it is called pneumothorax.(lung collapses and the thoracic wall expands)
Transpulmonary Pressure (Palv - Pip)
Transpulmonary pressure is the difference between the intrapleural pressure and the intra-alveolar
pressure. This force operates across the walls of the lungs and causes the lungs to expand.

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Mechanics of Breathing
When lungs are at rest, the volume of air in lungs is called the functional residual capacity
(FRC). No air is moving into or out of the lungs during this time.
Air flow results from the muscles of respiration creating pressure gradients by changing the
volume of the lungs.
The relationship between pressure and volume is
expressed by Boyle's law (P1V1 = P2V2). When volume
increases, pressure decreases and when volume
decreases, pressure increases.

Determinants of Intra-alveolar Pressure


The changes in intra-alveolar pressure creates the
pressure gradient that causes air to flow into and out of
the lungs. Two factors determine intra-alveolar pressure:
1. the quantity (moles) of air molecules in the alveoli;
2. the volume of the alveoli.
The movement of air into and out of the alveoli is due to the
changes in the volume of the thoracic cavity produced
by the muscles of ventilation.
The diaphragm and the external intercostal muscles
are the primary inspiratory muscles
The internal intercostal and abdominal muscles are
the primary expiratory muscles.

Inspiration(

)
The
expansion
of
the thoracic cavity during respiration

causes intrapleural pressure to decrease. This


increases transpulmonary pressure (Palv - Pip)
causes lungs to expand.
The increase in volume of alveoli that accompanies
this expansion decreases intra-alveolar pressure.
The pressure gradient between atmospheric pressure
and intra-alveolar pressure (Patm - Palv) causes air to
flow into the lungs until it equals atmospheric
pressure.

Expiration (

During normal breathing expiration is a passive


process in which muscles of inspiration relax and
elastic properties of chest wall and lungs cause
lung volume to decrease.
This decrease in lung volume causes an increase
in intra-alveolar pressure and pressure gradient
that causes an outflow of air.
A more forceful expiration results from contraction
of the muscles of expiration in a process called
active expiration.

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Lung Volume
1. Tidal volume (VT) (500ml)
Volume inspired or expired with each normal breath(unforced breath).
2. Inspiratory reserve volume (IRV) (3000ml)

Maximum volume that can be inspired after inspiration of tidal


volume.
is used during exercise.
3. Expiratory reserve volume (ERV) (1000ml)
Maximum volume that can be expired after expiration of tidal
volume.
4. Residual volume (RV) (1200ml)
Volume that remains in the lungs after maximal expiration.
can not be measured by spirometry.

Pulmonary Ventilation rate


Total rate of air flow in and out of the lung during normal tidal breathing.

6000ml / min = 500ml x 12/min = VE

Lung Capacity
1. Inspiratory Capacity (IC) (3500ml)

Maximum volume of air that can be inspired at the end of a resting expiration.
It is sum of tidal volume and inspiratory reserve volume.
2. Vital Capacity(VC) of Forced Vital Capacity (FVC) (4500ml)

Maximum amount of air that can be expired following a maximum


inspiration.
It is sum of tidal volume, inspiratory reserve volume and expiratory
reserve volume.
3. Functional Residual Capacity(FRC) (2200ml)
Volume of air remaining in the lungs at the end of a tidal expiration.
It is sum of expiratory reserve volume and residual volume.
It can not be measured by spirometry.
4. Total Lung Capacity
Volume of air in the lungs at the end of a maximum inspiration.
It is sum of all the lung volumes including tidal volume, inspiratory
reserve volume, expiratory reserve volume and residual volume.

Factors Affecting Pulmonary Ventilation


Lung Compliance
Compliance is a measure of the ease with which the lungs can be stretched.
Pressure refers to transpulmonary pressure (Palv - Pip)

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At rest, lung volume is at FRC and the pressure in the airways and lungs is
equal to atmospheric pressure. Under these equilibrium conditions, there is
a collapsing force on the lungs and an expanding force on the chest wall.
As a result of these two opposing forces, intra-pleural pressure is negative

Changes in lung compliance

In a patient with emphysema, lung compliance is increased and the


tendency of the lungs to collapse is decreased.

Therefore, at the original FRC, the tendency of the lungs to collapse is less
than the tendency of the chest wall to expand.

The patients chest becomes barrel-shaped, reflecting this higher


volume.

In a patient with fibrosis, lung compliance is decreased and the


tendency of the lungs to collapse is increased.

Therefore, at the original FRC, the tendency of the lungs to collapse is


greater than the tendency of the chest wall to expand.
Surface tension of the alveoli (Laplaces law)
Large alveoli have low collapsing pressures and are easy to keep
open.
Small alveoli have high collapsing pressures and are more
difficult to keep open.
In the absence of surfactant, small alveoli have a tendency to
collapse (atelectasis).
Surfactant
lines the alveoli.
reduces surface tension by disrupting the intermolecular forces between liquid molecules. This
prevents small alveoli from collapsing and increases compliance.
is synthesized by type II alveolar cells and consists primarily of the phospholipid dipalmitoyl
phosphatidylcholine (DPPC).
Neonatal respiratory distress syndrome can occur in premature infants because of the lack
of surfactant. The infant exhibits atelectasis (lungs collapse),
difficulty reinflating the lungs (decreased compliance), and
hypoxemia (decreased V/Q).

Airflow
Is driven by the pressure difference between the mouth (or nose) and
the alveoli.

Airway Resistance
Is described by Poiseuilles law
If airway radius decreases by a factor of 4, then resistance will increase
by factor of 256 (4^4), and airflow will decrease by a factor of 256.

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If the tubes are in series, the total resistance (Rtot) is the sum of the individual resistances:

If the tubes are in parallel (as they are in small airways), the total resistance is the sum of the
inverse of the individual resistances:

Factors that change airway resistance


1. Passive forces exerted on the airways.

Passive forces are due to changes in the transpulmonary pressure during inspiration
and expiration and tractive forces (
) exerted on the airways by the surrounding
tissue.
During inspiration both forces act to decrease resistance while during expiration
increases resistance.
2. Smooth muscles in bronchioles

Sympathetic stimulation (epinephrine) and sympathetic agonists (isoproterenol) via a2


receptors causes smooth muscle relaxation (bronchodilation), radius increases and
resistance decreases.

Parasympathetic stimulation, irritants

, and substance of anaphylaxis


(asthma) causes smooth muscle contraction (bronchoconstriction), radius of the
bronchioles decreases and resistance increases.

Carbon dioxide (CO2) affects the radius of bronchioles by causing bronchodilation when
its concentration increases and bronchoconstriction when its concentration
decreases.
3. Secretion of mucous into airways

Histamine which is released during an allergic reaction increases resistance by


bronchoconstriction and increasing the secretion of mucus.
4. Lung Volume

High lung volumes are associated with greater traction and decreased airway
resistance. Patients with increased airway resistance (e.g., asthma) learn to breathe
at higher lung volumes to offset the high airway resistance associated with their disease.

Low lung volumes are associated with less traction and increased airway resistance,
even to the point of airway collapse.

Pulmonary Function Tests


Spirometry is used to test for respiratory disorders. The diseases that can be
diagnosed fall into two categories:
I.

Obstructive Pulmonary Diseases

Involve abnormal increases in airway resistance.


) and functional
In these diseases lungs become over inflated (
residual capacity and lung volume often increase.

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II. Restrictive Pulmonary Diseases
Reduce the capacity of lung expansion.
There is a decrease in vital capacity and total lung capacity.
A spirogram displays the volume of gas exhaled against time and provides four major test results:
1. forced vital capacity (FVC)
2. forced expiratory volume in 1 second (FEV1)
3. ratio of FEV1 to FVC (FEV1/FVC)

FEV1 is the volume of air that can be expired in the first second of a forced maximal
expiration.
FEV1 is normally 80% of forced vital capacity, which is expressed as: FEV1 / FVC = 0.8
In obstructive pulmonary disease, such as asthma, FEV1 is reduced more than FVC so that
FEV1/FVC is decreased. (FEV1/FVC < 0.8)
In restrictive pulmonary disease, such as fibrosis, both FEV1 and FVC are reduced and
FEV1/FVC is either normal or is increased. (FEV1/FVC > 0.8)

4. MMEF (midmaximal expiratory flow) or (FEF25-75)


Measure the forced expiratory flow from 25% to 75% of Vital Capacity
MMEF = FVC/t

Lung diseases
1. Asthma
is an obstructive disease in which expiration is impaired.
is characterized by decreased FVC, decreased FEV1 and decreased FEV1/FVC.
Air is not completely expired, leading to air trapping and increased FRC.
increases airway resistance by causing spastic contraction of smooth muscles,
increased mucus secretion and inflammation of bronchioles.
2. COPD
) and emphysema (
).
is a combination of chronic bronchitis (
is an obstructive disease with increased lung compliance in which expiration is impaired.
is characterized by decreased FVC, decreased FEV1, and decreased FEV1/FVC.
Air is not completely expired, leading to air trapping, increased FRC,and barrel-shaped
chest.
increase airway resistance.
3. Fibrosis
is a restrictive disease with decreased lung compliance in which inspiration is impaired.
is characterized by decrease in all lung volumes. Because FEV1 is decreased less than
FVC, FEV1/FVC is increased (or may be normal).

Ventilation

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The process by which air (volume/min) moves in and out of the lung.

Composition of Air
Daltons law of partial pressures

In dry inspired air

PN2 = 0.79 x 760 mm Hg = 600 mm Hg


PO2 = 0.21 x 760 mm Hg = 160 mm Hg
PCO2 = 0.0003 x 760 mm Hg = 0.23 mm Hg
In humidified tracheal air at 37C

PTotal = (760 - 47) mm Hg = 713 mm Hg


PN2 = 0.79 x 713 mm Hg = 563 mm Hg
PO2 = 0.21 x 713 mm Hg = 150 mm Hg
PCO2 = 0.0003 x 713 mm Hg = 0.21 mm Hg
Respiratory quotient is the

ratio of CO2 excreted (VCO2 = 200ml/min) to O2 taken up (VO2 = 250ml/min) by lungs

(VCO2 / VO2 )
ratio of 80 CO2 produced (molecules) to 100 O2 consumed (molecules) in tissue. (CO2 / O2 )
the average respiratory quotient is 0.8
Partial pressure of O2 in the alveolus (PAO2) alveolar oxygen equation

PAO2

= [0.21 x 713 mm Hg] - [41.1mm Hg / 0.8] = 98.4 mm Hg

Partial pressure of CO2 in the alveolus (PACO2)alveolar carbon dioxide equation


VA = (500ml - 150ml) x 12/min = 4200ml/min

VCO2 = 200ml / min


PACO2 = [200 x 863mm Hg] / 4200 = 41.1mm Hg

Alveolar Ventilation rate (VA)


Measured in ml/min, is the rate of air flow in gas exchange areas of the lung encounter during
normal breathing.

Dead space
Anatomical dead space

Volume of conducting airways because conducting airways do not possess (

) alveoli.

Physiological dead space

Refer to those areas of the lung which do not participate in gas exchange.
Includes the conducting airways (anatomical dead space) and any non-perfused alveoli.
Perfusion (Blood flow)
the process by which deoxygenated blood passes through
lung and becomes reoxygenated.

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The Pulmonary Circulation
The driving force of systematic circulation is Pao - Pra = 100-2 = 98
The driving force of pulmonary circulation is Ppa - Pla = 15 - 5 = 10
Pulmonary Vascular Resistance
PVR = 10/6 = 1.67mmHg/L/min
cardiac output flow (QT) = 6L/min
is pulmonary blood flow.
is equal to cardiac output of left
ventricle.
Distribution of pulmonary blood flow
), blood flow is nearly uniform(
When a person is supine(
) through out lung.
When
a person is standing, blood flow is unevenly distributed because of gravity. Blood

flow is lowest at the apex of the lung (zone 1) and highest at the base of the lung (zone 3).
1. Zone 1blood flow is lowest.
Alveolar pressure > arterial pressure > venous pressure. PA > Pa > Pv
Zone 1 likely does not exist in a healthy individual's lungs as pulmonary arterial pressures
exceed alveolar pressure even at the top of the lung apex.
The high alveolar pressure may compress the capillaries
and reduce blood flow in zone 1 and thus creating a zone of
dead space. This situation can occur if arterial blood pressure
is decreased as a result of hemorrhage or if alveolar
pressure is increased because of positive pressure
ventilation.
2. Zone 2blood flow is medium.
arterial pressure > Alveolar pressure > venous pressure. Pa >
PA > Pv
Moving down the lung, arterial pressure progressively
increases because of gravitational effects on hydrostatic
pressure.
Arterial pressure is greater than alveolar pressure in zone 2, and
blood flow is driven by the difference between arterial pressure and alveolar pressure.
3. Zone 3blood flow is highest.
arterial pressure > venous pressure > Alveolar pressure. Pa > Pv > PA
Moving down toward base of the lung, arterial pressure is highest because of gravitational
effects, and venous pressure finally increases to the point where it exceeds alveolar pressure.
In zone 3, blood flow is driven by the difference between arterial and venous pressures, as
in most vascular beds.
Regulation of pulmonary blood flowhypoxic vasoconstriction
(decreased alveolar PO2 < 70 mmHg ) causes vasoconstriction.
In the lungs, hypoxia
This
response
is
the
opposite
in other organs, where hypoxia causes vasodilation.

Physiologically,
is
a
protective
response by shifting blood flow from hypoxic areas to well
perfused areas in an effort to enhance gas exchange.
Low inspired O2 levels can constrict pulmonary vessels and increase PVR.
High levels of inspired O2 can dilate pulmonary vessels and decrease PVR.

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Ventilation-Perfusion ratio ( V / Q )
is the ratio of alveolar ventilation (V) to pulmonary blood flow (Q).
If breathing frequency, tidal volume, and cardiac output are normal,
alveolar ventilation is about 4.0 L/min, whereas pulmonary blood flow
is about 5.0 L/min. the V/Q ratio is approximately 0.8.
This V/Q ratio results in arterial PO2 of 100 mm Hg and arterial PCO2 of
40 mm Hg.
V/Q ratios in different parts of the lung
Ventilation is lower at the apex and higher at the base, but the regional
differences are not as great as for perfusion.
Blood flow is lowest at the apex and highest at the base because of gravitational effects.
Therefore, the V/Q ratio is higher at the apex of the lung and lower at the base of the lung.
As a result of the regional differences in V/Q ratio, there are corresponding differences in the
efficiency of gas exchange and in the resulting pulmonary capillary PO2 and PCO2.
At the apex(higherV/Q), PO2 is highest and PCO2 is lower because gas exchange is more
efficient.
At the base (lower V/Q), PO2 is lowest and PCO2 is higher because gas exchange is less
efficient.
Changes V/Q ratio
1. V/Q ratio in airway obstruction
If the airways is blocked, then ventilation is decreased. If blood flow is
normal, V/Q < 0.8
There is less gas exchange in lung that is perfused but not ventilated.The
blood leaving these capillaries will then have lower PO2 and higher
PCO2

2. V/Q ratio in pulmonary embolism

If blood flow is blocked, then blood flow is decreased. If ventilation is


normal, then V/Q is infinite, which is called dead space.
There is greater gas exchange in lung that is ventilated but not perfused.
The blood and air in these alveoli will have higher PO2 and lower PCO2.

Anatomical shunt
Mixed venous blood bypasses the gas exchange unit and goes
directly into arterial blood
Mix deoxygenated blood with oxygenated blood
Right-Left Shunt
Occur when oxygen-poor blood from right heart flows in the
left heart without passing through functional, ventilated
alveoli.(2% of cardiac output by passes the lungs)
Result in decrease in arterial PO2 because of the mixture of
venous blood with arterial blood.
The magnitude of a right-to-left shunt can be estimated by having
the patient breathe
100% O2 and measuring the degree of dilution of oxygenated
arterial blood by non oxygenated shunted (venous) blood.

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Left-Right Shunt
are more common than right-left shunts because pressures are higher on left side of heart.
cardio abnormalities or traumatic injury.
are caused by congenital
1. Patent ductus arteriosus (PDA) : ductus arteriosus fails to close after birth.
2. Atrial septal defect (ASD) : deficiency of interartrial septum between left and right atrium
3. Atrioventricular septal defect (AVSD) : deficiency of atrioventricular septum between left
ventricle and right atrium
4. Ventricular septal defect (VSD) : deficiency of ventricular septum between left and right
ventricle
arterial
PO2 will be elevated on the right side of the heart because there has been

admixture of arterial blood with venous blood.


Physiological Shunt
The gas exchange units without ventilation (no gas is
exchanged) but with perfusion (blood flow) has a V/Q = 0.
Mix deoxygenated blood with oxygenated blood
Atelectasis (obstruction of gas exchanging unit) is caused by
mucous plugs, airway edema, foreign bodies, and tumors in
the airway.

Local Control of Ventilation and Perfusion


In order to maintain V/Q=0.8 , changes in the partial pressure of gases in the alveoli and
tissues affect contractile activity of bronchiolar smooth muscle that adjust the diameter of the
passageway, and also the smooth muscle in the arterioles that affect the blood flow.

Oxygen acts primarily on pulmonary arterioles with a


low PO2 causing vasoconstriction with decreased flow

Carbon dioxide acts primarily on the bronchioles with a


high PCO2 causing bronchodilation and increased
ventilation.
When V/Q is high the increase in PO2 causes
vasodilation and the decrease in PCO2 causes
bronchoconstriction.
When V/Q is low the decrease in PO2 causes
vasoconstriction and the increase in PCO2 causes
bronchodilation.
Note that the effect of oxygen and carbon dioxide on
pulmonary arterioles is the opposite of the effects of
these gases on systemic arterioles.

Gas Exchanges
Dissolved gases
The amount of gas dissolved in a solution (such as blood) is proportional to its partial pressure.
The units of concentration for a dissolved gas are mL gas/100 mL blood.
Henrys Law

Cgas in blood = k x Pgas in blood


[O2] = 0.003ml / 100ml / mmHg x 100mmHg = 0.3ml / 100ml / mmHg
[CO2] = 0.067ml / 100ml / mmHg x 40mmHg = 2.68ml / 100ml / mmHg
Diffusion of gases
The diffusion rates of O2 and CO2 depend on the partial pressure differences across the
membrane and the area available for diffusion.

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Ficks Law
Rate of diffusion of a gas across a permeable membrane
V'gas = D x A x P/T

V'gas = Rate of gas diffusion across permeable membrane


D = Diffusion coefficient of that particular gas for that membrane
A = Surface Area of the membrane
P = Difference in partial pressure of the gas across the membrane (Palveolar - Pcapillary)
T = Thickness of the membrane

Diffusing Capacity
Because these variables are impossible to measure directly (surface area, thickness, and
cofficient), the concept of "Diffusing Capacity" has been developed as measurable factor that
combines the contribution of these variables.
DL = D x A/T
V'gas = DL x P
DL = Vgas / P (Palveolar - Pcapillary)

In order to determine

the DL for any particular gas, partial pressure gradient must be


determined (P) as well as its rate of transport (V'gas).
Sadly, this is experimentally challenging for oxygen and carbon dioxide because their
partial pressure gradients changes as blood is transported through pulmonary
capillaries.
However, because Carbon Monoxide is rapidly bound by hemoglobin through pulmonary
capillary, its partial pressure gradient in pulmonary blood can be ignored.
Consequently, diffusing capacity for CO can be determined simply by (V'CO) as well as
its partial pressure in alveoli PACO.
Perfusion-limited exchange
is illustrated by N2O (nitrous oxide) and by O2 under
normal conditions.

In perfusion-limited exchange, the partial pressure of


the gas in blood becomes equal to the partial pressure
in alveolar air.

Thus, for a perfusion-limited process, diffusion of the gas


can be increased only if blood flow increases.
Diffusion-limited exchange
is illustrated by CO and by O2 during strenuous exercise.

is also illustrated in disease states.


In fibrosis, diffusion of O2 is restricted because
thickening of alveolar membrane increases diffusion
distance.
II. In emphysema, diffusion of O2 is decreased
because surface area for diffusion is decreased.
CO are chemically bound to hemoglobin (in high
affinity) cannot contribute to blood partial pressure of
CO. (large partial pressure gradient remains).
I.

Rate of CO diffusion across alveolar membrane is the


principal factor limiting further blood transport of carbon
monoxide away.

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Gas Exchange in the Lungs
Partial pressures of O2 and CO2 in the atmosphere are 160 mm
Hg and 0.23 mm Hg.
In the alveoli the pressures of O2 and CO2 are 100 mm Hg and
40 mm Hg.
Deoxygenated blood entering the pulmonary capillaries has a
PO2 of 40 mm Hg and PCO2 of 46 mm Hg. The gases diffuse
down their concentration gradients and leave at the same partial
pressures as the gases in the alveoli (PO2 = 100 mm Hg and
PCO2 = 40 mm Hg).
Oxygen Transport
Hemoglobin
Each subunit contains a heme moiety, which is iron-containing
porphyrin.
The iron is in the ferrous state (Fe2+), which binds O2.
Each subunit has a poly peptide chain. Two of the subunits
have chains and two of the subunits have chains; thus,
normal adult hemoglobin is called 22.
Methemoglobin
Iron is in the Fe3+ state.
Does not bind O2.
Hemoglobin S
causes sickle cell disease.
Two chains are mutated.
In the deoxygenated form, deoxyhemoglobin forms sickle-shaped chain that deform
red blood cells.
O2-binding capacity of blood O2 saturation (SO2)
is the maximum amount of O2 that can be bound to hemoglobin in blood.
is dependent on the hemoglobin concentration in blood.
limits the amount of O2 that can be carried in blood.
is measured at 100% saturation.
O2 content of blood
is the total amount of O2 carried in blood, including bound and dissolved O2.
depends on the hemoglobin concentration, the PO2, and the P50 of hemoglobin.

HemoglobinO2 dissociation curve


Hemoglobin combines rapidly and reversibly with O2 to form oxyhemoglobin. The higher the
PO2 the greater the binding.

The curve is a plot of percent saturation of hemoglobin as function of PO2.


At a PO2 of 100 mm Hg (e.g., arterial blood)
hemoglobin is 98.5% saturated;1.5% of the oxygen transported in the
blood is dissolved in plasma or the cytosol of red blood cells

O2 is bound to all four heme groups on all hemoglobin molecules.

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At a PO2 of 40 mm Hg (e.g., mixed venous blood)

hemoglobin is 75% saturated, which means that, on average, three of


the four heme groups on each hemoglobin molecule have O2 bound.

At a PO2 of 25mmHg
hemoglobin is 50% saturated.
At 100% saturation 1 gram of hemoglobin carries 1.34 ml of oxygen.
Hemoglobin in blood 12-17gm/dL or an average of 150 gm/L
Oxygen carrying capacity
1.34 ml/gram x 154 grams/liter ~ 200 ml/L
The s-shape of the curve is the result of a change in the affinity of hemoglobin as
each successive O2 molecule binds to a heme site (called positive cooperativity).
Binding of first O2 molecule increases the affinity for the second O2
molecule,and so forth.
The affinity for the fourth O2 molecule is the highest.
This change in affinity facilitates the loading of O2 in the lungs (flat
portion of the curve) and the unloading of O2 at the tissues (steep
portion of the curve).
In the lungs
Alveolar gas has a PO2 of 100mmHg.
Pulmonary capillary blood is oxygenated by the diffusion of O2 from
alveolar gas into blood, so that the PO2 of pulmonary capillary
blood also becomes 100 mm Hg.
The very high affinity of hemoglobin for O2 at a PO2 of 100mm Hg
facilitates the diffusion process. By tightly binding O2, the free O2
concentration and O2 partial pressure are kept low, thus
maintaining partial pressure gradient (that drives the diffusion
of O2).
The curve is almost flat when the PO2 is between 60 and
100mmHg.
In the peripheral tissues
O2 diffuses from arterial blood to the cells.
The gradient for O2 diffusion is maintained because the cells
consume O2 for aerobic metabolism, keeping the tissue PO2 low.
The lower affinity of hemoglobin for O2 in this steep portion of the
curve facilitates the unloading of O2 to the tissues.
The hemoglobin oxygen disassociation curve can shift either to the left or to the right.
When the curve shifts to the right, the affinity of oxygen for hemoglobin decreases and
oxygen can be more easily unloaded.
When the curve shifts to the left, the affinity of oxygen for
hemoglobin increases and oxygen can be more easily loaded.
Factors Affecting Affinity of Hemoglobin for O2
1. Temperature
A higher temperature cause a decrease in affinity of hemoglobin. In
more active tissue with a higher temperature O2 unloads more
easily.

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2. pH (Bohr effect)
[H+] increases (pH decreases) in more active tissue. This decreases
the affinity of hemoglobin : Hb + O2 Hb-O2 + H+
3. PCO2 (carbamino effect)
CO2 binds reversibly with Hb to form carbaminohemoglobin, which has
a lesser affinity for O2 . The increase of CO2 cause decrease in the
affinity of hemoglobin
4. 2,3 - Diphosphoglycerate
2,3 -DPG is produced from glycolysis and decrease affinity of
hemoglobin.
At low [O2], enzyme catalyzes synthesis of 2,3-DPG, decrease in affinity of hemoglobin.
This is helpful during anemia and at high altitudes (chronic hypoxemia) by enhancing
unloading of oxygen by hemoglobin thus results in enhanced oxygen transport to tissues
At high [O2], oxyhemoglobin inhibits enzyme that synthesizes 2,3-DPG and 2,3-DPG levels
decrease.
5. Carbonmonoxide (CO) poisoning

CO competes for O2-binding sites on hemoglobin. The affinity of hemoglobin for CO is 200
times its affinity for O2.
In addition, binding of CO to hemoglobin increases the affinity of remaining sites for O2, causing
a shift of the curve to the left.
Hypoxemia
is decrease in arterial PO2.
The normal Aa gradient is (< 10mmHg). Since O2 normally
equilibrates between alveolar gas and arterial blood, PAO2 is
approximately equal to PaO2.
The Aa gradient is increased (>10mmHg) if O2 does not
equilibrate between alveolar gas and arterial blood (e.g., diffusion
defect, V/Q defect, and right-to-left shunt).
Hypoxia

is decreased O2 delivery to tissues


insufficient O2 unable to maintain aerobic metabolism. The net result can lead to a significant
decrease in blood pH.
May appear blue-gray (cyanotic) because of lack of O2 and increased deoxyhemoglobin.
There are four major types of tissue hypoxia
1. Hypoxic hypoxia is caused by a variety of lung diseases (e.g., chronic obstructive pulmonary
disease, pulmonary fibrosis, neuromuscular diseases) that result in decreased PaO2
2. Circulatory (stagnate) hypoxia is caused by reduced blood flow to organ and is usually
due to vascular disease or arteriovenous shunt.
3. Anemic hypoxia is caused by an inability of blood to carry sufficient O2 because of either
low Hgb (anemia) or an inability of Hgb to carry O2 (CO poisoning).
4. Histotoxic hypoxia is often caused by poisons that block the electron transport system in
mitochondria and prevent the utilization of O2 by the cell.

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Erythropoiesis
Red blood cell production (erythropoiesis) in the bone marrow is controlled by the hormone
erythropoietin, which is synthesized in the kidney by cortical interstitial cells.
Decreased O2 delivery, low Hgb concentration, and low PaO2 stimulate secretion of
erythropoietin. This increases the production of red blood cells.
Chronic renal disease damages the cortical interstitial cells and thereby suppresses their
ability to synthesize erythropoietin. This causes anemia, along with decreased Hgb because
of the lack of erythropoietin. Erythropoietin replacement therapy effectively increases red blood
cell production.
Carbon Dioxide Transport
The carbon dioxide in the blood exists as
Dissolved as CO2: 5-6%
Carbaminohemoglobin : 5-8%
Dissolved as HCO3 - : 86-90%
Role of Carbonic Anhydrase in Carbon Dioxide Transport
Carbonic anhydrase catalyzes the reaction that converts CO2 and H2O to carbonic acid.
Carbonic acid (H2CO3) reversibly disassociates to H+ + bicarbonate.
CO2 + H2O H2CO3 H+ (H+ is buffered by hemoglobin HbH) + HCO3Increase in PCO2 makes the blood more acidic while a decrease in PCO2 does the opposite.
CO2 Exchange and Transport in Systemic Capillaries and Veins
In the tissue
Cell produce CO2 at the rate of 200 ml/minute. As CO2 increases in the
tissues it goes down its concentration gradient from the plasma and into
the erythrocyte.

Most of the CO2 is converted to bicarbonate and H+ by carbonic


anhydrase in the erythrocytes.

As [HCO3-] in the erythrocyte increase, bicarbonate ions are


transported out of the erythrocyte in exchange for Cl- , which is referred
to as the chloride shift.

The H+ left behind in the erythrocyte is buffered by binding to hemoglobin.


In the lungs

The pressure gradient favors the diffusion of CO2 from the blood into the
alveoli.

The decrease in CO2 causes the reaction tend to converted into CO2 and
H2O by carbonic anhydrase.

While [HCO3-] in the erythrocyte decreases, more bicarbonate is


brought into the erythrocyte in exchange for Cl- .

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Effect of Oxygen on Carbon Dioxide Transport(Haldane Effect)
The PO2 affects the ability of the blood to carry CO2.

The increase of PO2 (increase binding of O2 to hemoglobin) decreases binding of CO2 to


hemoglobin.

The decrease of PO2 (decrease binding of O2 to hemoglobin) increases binding of CO2 to


hemoglobin.

Central Regulation of Ventilation


The pattern of ventilation is initiated and modified within the central nervous
system.
Neural Control of Breathing by Motor Neurons

During quiet breathing the breathing cycle consists in the contraction of


the inspiratory muscles followed by relaxation of the same muscle
during expiration.

During more active breathing the expiratory muscles contract during


the expiration phase. This is reflected by the activity of motor
neurons innervating the respective muscles.
Generation of Breathing Rhythm in the Brainstem
Respiratory control regions are present in the medulla and pons of the brainstem. There are
two general classes of neurons located here:
Inspiratory neurons which generate action potentials during inspiration.
Expiratory neurons which generate action potentials during expiration.
Respiratory Centers of the Medulla
1. Dorsal Respiratory Group (nucleus tractus solitarius)
contains primarily inspiratory neurons. The inspiratory neurons show
ramp increase in activity during inspiration followed by an abrupt
termination.

Input to the dorsal respiratory group comes from vagus and


glossopharyngeal nerves. The vagus nerve relays information from
peripheral chemoreceptors and mechanoreceptors in the lung. The
glossopharyngeal nerve relays information from peripheral
chemoreceptors.

Output from the dorsal respiratory group travels, via the phrenic
nerve, to the diaphragm and external intercostal muscles

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2. Ventral Respiratory Group
contains two regions of expiratory neurons (nucleus
retrofacialis and the nucleus retroambiguus) and one region
of inspiratory neurons (nucleus paraambiguus)

During exercise, inspiratory neurons contribute to


enhanced inspiration and expiratory neurons stimulate
the muscles that increase the force of expiration.
Respiratory Centers of Pons
This center contains both inspiratory and expiratory
neurons and mixed neurons that control both inspiratory
and expiratory neurons. This center may facilitate the
transition between inspiration and expiration.

1. Apneustic center
is located in the lower pons.
Stimulate inspiration by sending stimulatory impulses to
Dorsal Respiratory Group (delay 'switch off' signal from
pneumotaxic center ) activates and prolongs inspiration
(long deep breaths).
2. Pneumotaxic center (a.k.a pontine respiratory group)

is located in the upper pons.


Inhibits inspiration by inhibiting Apneustic center and
sending inhibitory impulses ('switch off' signal) to Dorsal
Respiratory Group (inhibition DRG ramping time).Therefore, raising respiratory rate but
reducing inspiratory volume.
Central Pattern Generator(Pre-Btzinger complex)
The central pattern generator is a network of neurons in medulla that generates a regular,
repeating pattern of neural activity called the respiratory rhythm.
Peripheral Input to Respiratory Centers
The central pattern generator (Pre-Btzinger complex) is reflexively controlled by
various types of receptors that include:
1. Chemoreceptors
monitor conditions in arterial blood and in cerebrospinal fluid
Peripheral chemoreceptors
are
located in the carotid bodies near the carotid sinus (connect to

glossopharyngeal nerves). These cells respond to changes in arterial


PO2, PCO2 or pH.
I.

The primary stimulus for chemoreceptors is pH. The main cause of


decreases in pH is an increase in PCO2 and then
increase breathing rate

Peripheral chemoreceptors also respond to arterial PO2


(only when < 60 mm Hg).

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II. Central chemoreceptors


are located in the medulla that respond directly to changes of [H+]
in the cerebrospinal fluid.

CO2 is converted to H+ and HCO3- by carbonic anhydrase in the


CSF.

Chemoreceptor Reflexes
Changes in PCO2 are primary stimuli for changes in ventilation
under normal conditions. Both central and peripheral chemoreceptors
are sensitive to changes in pH .
Activation of chemoreceptors cause an increase in ventilation.
2. Pulmonary stretch receptors
Type of mechanoreceptor present in the bronchial smooth
muscle which sense and respond to physical stretching of
airways.
When these receptors are stimulated by distention of lungs,
produce a reflex decrease the respiratory rate by increasing
the length of expiration(HeringBreuer reflex).
3. Irritant receptors
Sensory cells present within respiratory epithelium which can sense and respond to a
variety of chemical irritants.
Initiate coughing and might induce bronchoconstriction in those with asthma.
4. J (juxtacapillary) receptors
to pulmonary
Sensory cells located within in the alveolar walls and are juxtaposed
capillaries
Activated by engorgement of pulmonary capillaries (blood backs into pulmonary
circulation due to left heart failure) or increased pulmonary interstitial volume (pulmonary
edema), then cause rapid, shallow breathing.
5. Joint and muscle receptors
are activated during movement of the limbs.
are involved in the early stimulation of breathing during exercise.

Respiratory System in Acid-Base Homeostasis


Acid-Base Disturbances in Blood
Changes in the pH of the body has serious consequences because it changes the shape of
protein molecules.

Arterial pH affects the pH of body tissues hence it is necessary to regulate blood pH around
the normal of 7.4.

If the pH < 7.35 it is said to be in a condition of acidosis. causes depression of CNS activity and
leads to coma.

If the pH > 7.45 it is said to be in a condition of alkalosis.causes the nervous system to become
overly excitable and causes uncontrollable muscle seizures and convulsions.

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Role of Respiratory System in Acid-Base Balance
Hemoglobin as a Buffer
Hemoglobin can bind or release H+. Deoxyhemoglobin has a greater affinity for H+ than
oxyhemoglobin as described by the Bohr effect.
In the tissues:
HbO2 O2 + Hb
Hb + H+ Hb-H
This serves as a buffer for the increase in H+ resulting from CO2.
In the lungs:
HbH H+ + Hb
Hb + O2 HbO2
Bicarbonate Ions as a Buffer
When H+ increases in the blood it combines with HCO3- to form CO2.
When CO2 increases this reaction goes in reverse to form HCO3- and H+.
The relationship between CO2 and acidity is described by the Henderson-Hasselbach equation:

To maintain a pH of 7.4, the ratio of [HCO3-] to [CO2] should remain at


20:1.
The lungs can regulate the concentration of CO2.
Respiratory acidosis is increase in blood acidity due to increased CO2. PCO2 > 40 mmHg
Respiratory alkalosis is decrease in blood acidity due to decreased CO2. PCO2 < 40 mmHg

Response of Respiratory System


A. Exercise
During exercise, joint and muscle receptors are activated during movement and cause an
increase in respiratory rate at the beginning of exercise.

The mean values for arterial PO2 and PCO2 do not change during exercise.
Arterial pH does not change during moderate exercise, although it may decrease during
strenuous exercise (lactic acidosis)

Venous PCO2 increases during exercise because the excess CO2 produced by the
exercising muscle is carried to the lungs in venous blood.

Pulmonary blood flow increases because cardiac output increases during exercise. As
a result, more pulmonary capillaries are perfused, and more gas exchange occurs,
resulting decrease the physiologic dead space.

The distribution of V/Q ratios throughout the lung is more during exercise.
B. Adaptation to high altitude
Alveolar PO2 is decreased at high altitude. As a result, arterial PO2 is also decreased
(hypoxemia).

Stimulates peripheral chemoreceptors and increases ventilation rate (hyperventilation)


that produces respiratory alkalosis, which can be treated by administering acetazolamide.

Stimulates renal production of erythropoietin, which increases production of RBCs. As


a result, increased O2- carrying capacity of blood.

2,3-DPG concentration are increased, shifting hemoglobinO2 dissociation curve to right,


resulting decrease in affinity of hemoglobin for O2 that facilitates unloading of O2 in the
tissues.

Pulmonary vasoconstriction cause an increase in pulmonary arterial pressure,


increased work of the right side of the heart against the higher resistance, and
hypertrophy
of the right ventricle.