Respiratory Physiology - Costanzo

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Respiratory Physiology - Costanzo
Respiratory Physiology - Costanzo
Thursday, May 28, 2015
9:41 AM
• Structure of the Respiratory System
○ Airways
 Conducting Zone: Brings air into and out of the lungs
□ Nose, nasopharynx, trachea, bronchi, bronchioles, & terminal bronchioles
□ Transport and warm, humidify, & filter the air
□ Trachea is the main conducting airway
 Divides into 2 bronchi, 23 divisions into increasingly smaller airways
□ Conducting airways lined with mucus-secreting and ciliated cells that function to
remove inhaled particles
 Small particles are captured by mucus and swept upward by rhythmic
ciliary motion
□ Walls contain smooth muscle: Sympathetic and parasympathetic innervation
 Sympathetic Beta2: Relaxation and dilation
 Parasympathetic muscarinic: contraction and constriction of airways
□ Change in diameter = change in resistance: Change in airflow
 Beta2 adrenergic agonists (epinephrine, isoproterenol, albuterol) used to
dilate airways in treatment of asthma
 Respiratory Zone: Structures lined with alveoli and participate in gas exchange
□ Transitional structure: Respirator Bronchioles
 Like conducting airways structurally, but have occasional alveolar buds
that participate in gas exchange
□ Alveolar Ducts: completely lined with alveoli; terminate in alveolar sacs
□ Alveoli: Pouchlike invaginations of respiratory zone
 Diameter ~ 200 micrometers
 Alveolar walls are thin and have large surface area for diffusion
 Walls rimmed with elastic fibers and lined with epithelial cells; type I & II
pneumocytes
 Type II Pneumocytes synthesize pulmonary surfactant and have
regenerative capacity for pneumocytes
 Alveoli contain alveolar macrophages, which keep alveoli free of dust and
debris (because alveoli lack cilia). They fill with debris and migrate out to
be expelled.
○ Pulmonary Blood Flow
 Pulmonary artery--> Respiratory zones--> Pulmonary capillaries
 Pulmonary blood flow is not distributed evenly because of gravitational effects
□ Flow is lowest at top when standing; effects vanish when supine.
 Regulation of Pulmonary Blood Flow is controlled by local factors (primarily O2)
 Bronchial Circulation is very small
• Lung Volumes and Capacities
○ Lung Volumes
 Many measured with a spirometer
 Tidal Volume: Normal quiet in and out respiratory amount (~500 mL)
□ Volume that fills alveoli plus volume that fills airway
 Inspiratory Reserve Volume: Amount that can be brought in on top of Tidal Volume (~
3000mL)
□ Additional amount that can be expired below Tidal Volume = Expiratory Reserve
Volume (~1200 mL)
 Residual Volume: Amount remaining in lungs after maximal expiration (~1200 mL)
Lung Capacities
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○ Lung Capacities
 Inspiratory Capacity: Tidal Volume plus Inspiratory Reserve Volume (~3500 mL)
 Functional Residual Capacity: Expiratory Reserve Volume plus Residual Volume (~2400
mL)
□ Amount remaining in the lungs after a Tidal Expiration: the equilibrium volume
of the lung
 Vital Capacity: Inspiratory Capacity plus Expiratory Reserve Volume (~4700 mL)
 Total Lung Capacity: All lung capacities (~5900 mL)
○ Dead Space: Volume that doesn't participate in gas exchange
 Anatomic Dead Space: Volume of the conducting airways
□ ~150 mL
□ When tidal volume of 500 mL is inspired, 350 mL goes to the alveoli, while 150
mL stays in the conducting airways
□ Related: The first air expired is dead space air; must sample end-expiratory air
to get alveolar gas levels
 Physiologic Dead Space: Total volume of the lungs that doesn't participate in gas
exchange
□ Includes functional dead space: Ventilated alveoli that don't participate in gas
exchange (because of abnormal pathology)
□ In normal persons, Physiologic Dead Space and Anatomic are nearly the same
○ Ventilation Rates: Volume of air moved in and out per unit time
 Minute Ventilation: Tidal Volume x breaths/minute
 Alveolar Ventilation: Minute Ventilation corrected for physiologic dead space
□ (Tidal Volume - Physiologic Dead Space) x Breaths/Minute
○ Alveolar Ventilation Equation: Inverse relationship between alveolar ventilation and alveolar
PCO2
VA=Alveolar Ventilation, VCO2=Rate of CO2 Production, PACO2=Alveolar CO2

Pressure, K=Constant (863)
 If CO2 production is constant, PACO2 is determined by alveolar ventilation
 PACO2 and PaCO2 are the same because CO2 always equilibrates between alveoli and
blood
 Why does PCO2 vary inversely with alveolar ventilation?
□ Alveolar ventilation is pulling CO2 out of capillary blood
□ The higher the ventilation, the more CO 2 pulled out of the blood and the lower
PACO2
○ Alveolar Gas Equation: Predicts alveolar PO2 based on alveolar PCO2

○ Forced Expiratory Volumes
 Forced Vital Capacity: Total volume of air that can be forcibly expelled after maximal
expiration
□ Measured second by second: FEV 1, FEV2, FEV3
□ The fraction that can be expelled in the first second (FEV 1/FVC) can be used to
differentiate among diseases
 Normal: 0.8 (80% of FVC expelled in 1st second)
 Asthma: Both decreased, but FEV1 is decreased more, so FEV1/FVC is
decreased
 Fibrosis: Both decreased, but FVC is decreased more, so FEV1/FVC is
increased
• Mechanics of Breathing
○ Muscles Used in Breathing
 Inspiration: Contraction of the diaphragm drives most of inspiration
□ When breathing frequency or tidal volume increase (exercise), external
intercostals & accessory muscles are used for more vigorous inspiration
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○
○
○
○
intercostals & accessory muscles are used for more vigorous inspiration
 Expiration: Normally a passive process
□ During exercise, or where airway resistance is increased (Asthma), the
abdominal muscles and internal intercostals assist breathing
Compliance: Describes the distensibility of the system
 Describes the change in lung volume for a given change in pressure
 The compliance of the lungs and chest wall is inversely correlated with their elastance
□ The greater the amount of elastic tissue, the greater the tendency to "snap
back," and the greater the elastic recoil force: lower compliance.
 Measure lung compliance by simultaneously measuring pressure and volume
□ Transmural pressure is the pressure across a structure
□ Lung pressures are always compared to atmospheric pressure, which is
assigned the value zero
 Pressures equal to atmospheric pressure are zero, those higher are
positive, those lower are negative
Compliance of the Lungs
 The sequence of inflating & deflating produces a Pressure-Volume Loop
□ The slope of each limb of the p/v loop is the compliance of the lung
 Negative outside (vacuum) pressure causes the lungs to fill with air during the
inspiration phase of the p/v loop
□ At the highest pressures, when alveoli are filled to the limit, they become stiffer
and less compliant: the curve flattens
 Once the lungs fill maximally, the pressure is gradually made less negative, causing
volume to decrease along the expiration limb of the p/v loop
 The slopes of the relationships for inspiration and expiration are different (hysteresis)
□ Thus, lung compliance must be different for inspiration and expiration
□ Usually, compliance is measured on the expiration curve
Why are the inspiration and expiration limbs of the lung compliance curve so different?
 Surface Tension at the liquid-air interface of the air filled lung:
□ On the inspiration limb, liquid molecules are closest together at low lung
volume, and intermolecular forces are highest. To inflate the lung, these forces
must be broken.
 The lungs produce surfactant to aid in that process
 In the initial part of the inspiration curve, at lowest lung volumes, the lung
surface area is increased faster than surfactant can be added: Surfactant
density is low, surface tension is high, Compliance is low, and the curve
is flat
□ On the expiration limb, one begins at high lung volume, where intermolecular
forces between liquid molecules are low; they don’t need to be broken up to
deflate the lung
 As expiration continues, surfactant is removed from the liquid lining and
the density of surfactant remains relatively constant, as does the
compliance of the lung.
□ Repeating this in a liquid filled lung demonstrates the role of surface tension:
when the liquid air interface, and thus surface tension, is eliminated, the
inspiration and expiration limbs have the same shape.
Compliance of the Chest Wall
 Normally, the intrapleural space has a negative pressure. This negative intrapleural
pressure is created by two opposing elastic forces:
□ The lungs, which tend to collapse
□ The chest wall, which tends to spring out
 This negative intrapleural pressure prevents the lungs from collapsing and the chest
wall from springing out.
 When air is introduced into the intrapleural space, intrapleural pressure suddenly
becomes equal to atmospheric pressure, with two important consequences:
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becomes equal to atmospheric pressure, with two important consequences:
□ Without negative pressure to hold the lungs open, they collapse;
□ Without negative pressure to keep the chest wall from expanding, the chest
wall springs out
○ P/V curves for the Lungs, Chest Wall, and Combined Lung/Chest Wall System
 The slopes of each of the curves is compliance. However, the slope of the combined
lung and chest wall system is less than that of either structure alone.
 Interpret by beginning at FRC, the resting/equilibrium volume of the combined
lung/chest wall system. FRC is the amount remaining in the lungs after a normal
person has expired a normal tidal breath.
 Compare:
□ Volume is FRC: The combined lung and chest wall system is at equilibrium.
Airway pressure is equal to atmospheric pressure.
 The lungs "want" to collapse, and the chest-wall "wants" to expand, but
the forces on these structures (Shared by the negative pressure of the
intrapleural space) are exactly equal: The combined system neither has a
tendency to collapse nor expand
□ Volume < FRC: There is less volume in the lungs and the collapsing force of the
lungs is decreased. The expanding force on the chest wall is greater, and the
combined systemic force "wants" to expand.
□ Volume > FRC: There is more volume in the lungs, and the collapsing force of
the lungs is greater. The expanding force on the chest wall is also lower, and the
combined systemic force "wants" to collapse.
 At highest lung volumes, both lung and chest wall "want" to collapse, and
there is a large collapsing force on the system.
○ Diseases of Lung Compliance: If the compliance of the lungs changes because of disease, the
slopes of the relationships change, and as a result the volume of the combined lung and
chest wall system also changes.
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 Emphysema (increased lung compliance): Associated with loss of elastic fibers in the
lungs, leading to increased compliance.
□ An increase in compliance is associated with increased slope. At a given volume,
the collapsing force of the lungs is decreased.
□ The original FRC will no longer be equilibrium; Volume must be added to the
lungs to increase their collapsing force (Increased FRC)
□ Patients with emphysema "breathe at higher lung volumes" and will have a
barrel shaped chest
Fibrosis
(decreased lung compliance): Stiffening of lung tissues and decreased

compliance (decreased slope of P/V curve)
□ The lung-chest wall system will seek out a new, lower FRC
○ Surface Tension of Alveoli: Alveoli are lined with a film of fluid. The attractive force between
the molecules creates surface tension.
 As the molecules are drawn together by these forces, they form a sphere: forms a
pressure that tends to collapse the sphere.
 Pressure generated is governed by the Law of Laplace:
□
□ The pressure tending to collapse an alveolus is directly proportional to the
surface tension, and indirectly proportional to alveolar radius.
 Thus, a large alveolus will have low collapsing pressure, and a small alveolus will
require higher pressure to keep open (but smaller is more desirable for gas exchange:
higher surface area compared to volume)
 Conflict is resolved by Surfactant
○ Surfactant: A mixture of phospholipids that line the alveoli and reduce their surface tension,
reducing collapsing pressure for a given radius.
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reducing collapsing pressure for a given radius.
 Synthesized from FAs by type II alveolar cells.
 Amphipathic components in surfactant counter the collapsing forces of surface
tension.
 Surfactant also increases lung compliance, which decreases the work of expanding
the lungs during inspiration
 Surfactant is lacking in neonatal respiratory distress syndrome: lung compliance will
be decreased and the work of inflating the lungs during breathing will be increased.
• Airflow, Pressure, and Resistance Relationships
○
○ Airflow is directly proportional to the pressure difference between the mouth/nose and the
alveoli, and inversely proportional to the resistance of the airways
○ Pressure difference is the driving force of respiration
○ The medium sized bronchi are the sites of the highest airway resistance
 Because of their parallel arrangement, the smallest airways do not have the highest
collective resistance.
○ Changes in Airway Resistance: Changes in airway diameter provide the major mechanism for
altering resistance and airflow
 Autonomic Nervous System:
1) Parasympathetic Stimulations produce constriction of bronchial smooth
muscle, decreasing diameter and increasing resistance. Stimulated by
muscarinic agonists (eg muscarine and carbachol) and can be blocked by
muscarinic antagonists (eg atropine)
2) Sympathetic Stimulation produces relaxation of bronchial smooth muscle, via
stimulation of β2 receptors.
 Lung Volume: High lung volumes are associated with greater traction, which
decreases airway resistance. Low lung volumes are associated with less traction,
which increases airway resistance, even to the point of airway collapse.
 Viscosity of Inspired Air: Not common, seen in deep sea diving (increased viscosity
increases resistance)
• Breathing Cycle
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○ Normal breathing cycle is divided into phases:
i. Rest: the period between breaths when the diaphragm is at equilibrium
□ No air is moving into or out of the lungs: Alveolar pressure equals atmospheric
pressure
 Alveolar pressure is zero; no pressure difference means there is no
airflow.
□ Intrapleural pressure is negative: Opposing forces create negative pressure
 Transmural pressure across lungs at rest is +5cm H2O, which means the
alveoli stay open
□ The volume in the lungs at this point is, by definition, equilibrium volume or
FRC: the normal amount remaining in the lungs after a normal expiration
ii. Inspiration: The diaphragm contracts, causing the volume of the thorax to increase
□ Halfway through inspiration alveolar pressure falls below atmospheric pressure;
this pressure gradient drives airflow into the lungs
□ At the end of inspiration the pressure gradient has dissipated and airflow ceases
□ The volume inspired in one breath is called the tidal volume (~0.5 L)
□ During inspiration, intrapleural pressure becomes even more negative. Why?
 As lung volume increases, the elastic recoil also increases and pulls more
forcefully against the intrapleural space.
 Airway and alveolar pressures become more negative
□ The extent to which intrapleural pressure changes during inspiration can be
used to estimate the dynamic compliance of the lungs
iii. Expiration: A passive process. Alveolar pressure becomes positive because elastic
forces of the lungs compress the greater volume of air in the alveoli.
□ The volume expelled is the tidal volume.
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Direction and magnitude of transmural pressure during the breathing cycle.
 Transmural pressure is calculated as alveolar pressure minus intrapleural pressure
 Forced Expiration: A person deliberately and forcefully breathes out.
□ Normal Lungs: Pressures on lungs and airways become very positive.
 Contraction of the expiratory muscles also raises intrapleural pressure.
 As long as the transmural pressure is positive in the lungs and airways
they will remain open.
□ In Emphysema, forced expiration may cause the airways to collapse
 Intrapleural pressure increases just like regular lungs
 Because the structures have decreased elastic recoil, alveolar and airway
pressure are lower than in a normal person
 The large airways collapse because the transmural pressure gradient
across them reverses, becoming negative.
 Persons with emphysema learn to expire slowly with pursed lips, which
raises airway pressure, prevents the reversal of the transmural pressure
gradient and prevents collapse.
• Gas Exchange
O2 transferred from alveolar gas--> capillary blood--> tissues
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○ O2 transferred from alveolar gas--> capillary blood--> tissues
○ CO2 tissue--> venous blood--> capillary blood
○ Gas Laws: Gas exchange is governed by fundamental properties of gases and their behavior
in solution
 General Gas Law: PV=nRT
□ In the gas phase, body temperature (37C), ambient pressure, and gas saturated
with water vapor (BTPS) is used; in the liquid phase (dissolved in blood),
standard temperature (0C), standard pressure (760 mmHg), and dry gas ( STPD)
is used.
 Boyle's Law: Pressure times volume is constant at constant temperature (P1V1=P2V2)
□ To maintain this relationship, gas pressure in the lungs must decrease as lung
volume increases
 Dalton's Law of Partial Pressures: The partial pressure of a gas in a mixture of gases is
the pressure it would exert if it were the total volume of the mixture.
□ Dry Gas: Partial pressure = Barometric Pressure x Fractional Concentration of
the gas
□ Humidified: Partial Pressure = (Barometric-Water Vapor Pressure) x F
□ Barometric pressure = the combined partial pressures of O 2, CO2, N2, and H2O.
 Henry's Law for Concentrations of Dissolved Gases: To calculate a gas concentration in
the liquid phase, the partial pressure in the gas phase is converted to a liquid partial
pressure, then to concentration in a liquid.
□ Partial pressure in liquid phase = Partial pressure in Gas phase.
□ Concentration = Partial pressure of gas x Solubility
□ The concentration of a gas in a solution applies only to dissolved gas that is free
in solution, not gas that is in bound form (like O 2 to Hb)
○ Diffusion: Fick's Law: All simple diffusion, Directly proportional to driving force and available
surface area, inversely proportional to the thickness of the membrane

 Special points:
1) The driving force for diffusion is partial pressure difference, not the
concentration difference;
2) Diffusion coefficient: the usual diffusion coefficient (based on molecular
weight) and the solubility of the gas.
 Lung Diffusion Capacity: Takes into account the diffusion coefficient, surface area,
thickness of membrane, and time required for the gas to combine with proteins in
pulmonary capillaries.
 Lung diffusion capacity changes predictably in disease states:
□ Emphysema: DL decreases because alveolar destruction decreases surface area
□ Fibrosis/Pulmonary Edema: DL decreases because membrane
thickness/interstitial volume are increased.
□ Anemia: DL decreases because the amount of hemoglobin in the blood is
decreased
□ Exercise: DL increases because additional capillaries are perfused, increasing the
surface area for gas exchange.
• Forms of Gas in Solution
○ Dissolved gas: All gases in solution are carried, to some extent, in dissolved form.
 Henry's Law: At a given partial pressure, the higher the solubility of a gas, the higher
the concentration in solution
 Only nitrogen is carried exclusively in dissolved form.
○ Bound Gas: O2, CO2, and CO are bound to proteins in blood.
 All bind to hemoglobin, and CO2 also binds to plasma proteins.
○ Chemically modified gas: CO2 is converted to HCO3- by RBCs
 Most CO2 in circulation is carried this way.
• Overview: Gas Transport in Lungs
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• Overview: Gas Transport in Lungs
○ Values for PO2 and PCO2 at various sites:
 Dry inspired air: PO2 = 160. no CO2 in dry inspired air so PCO2 = 0.
 Humidified Tracheal Air: PO2 is reduced because it is "diluted" by water vapor.
 Alveolar air: PAO2 < inspired air; PACO2 > inspired air.
□ Because O2 leaves the alveolar air and is added to pulmonary capillary blood,
and CO2 enters alveolar air from pulmonary blood.
□ On a daily basis, O2 from alveolar air = O2 consumption; CO2 to alveolar air = CO2
production.
 Mixed Venous blood: PO2 is relatively low because tissues have taken up O2; PCO2 is
relatively high because tissues have added CO2 to venous blood.
 Systemic Arterial Blood: Blood leaving pulmonary arteries normally has the same PO2
and PCO2 as alveolar air.
○ Physiologic Shunt: Systemic arterial blood has a slightly lower PO2 than alveolar air.
 WHY? A small fraction of pulmonary flow bypasses the alveoli and is not arterialized.
There are two sources for this bypassing blood:
□ Bronchial blood flow; and
□ A small portion of coronary venous blood that drains directly into the left
ventricle
 An increase in the physiologic shunt is a ventilation/perfusion defect: equilibration
between alveolar gas and pulmonary blood cannot adequately occur, and blood is not
fully arterialized.
• Diffusion Limited and Perfusion Limited Gas Exchange
○ Diffusion Limited: the total amount of gas transported across the alveolar-capillary barrier is
limited by the diffusion process; as long as partial pressure is maintained, diffusion will
continue along the length of the capillary.
 Illustrated by CO transport (and O2 during strenuous exercise, emphysema, fibrosis)
□ PACO rises only slightly along the capillary length because it is avidly bound to
hemoglobin (only free, dissolved gas causes a partial pressure).
□ CO does not equilibrate by the end of the capillary; diffusion would continue
indefinitely along a longer capillary.
○ Perfusion Limited: Total gas transported is limited by blood flow; Partial pressure gradient
is not maintained: can only increase the gas transported by increased blood flow.
 Illustrated by N2O
□ N2O is not bound in blood; it is entirely free in solution.
□ Initially there is a large partial pressure gradient and N 2O diffuses rapidly
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•
•
•
•
□ Initially there is a large partial pressure gradient and N 2O diffuses rapidly
□ All N2O creates partial pressure, which increases rapidly and is quickly fully
equibrilated.
□ Once equilibrium is reached, the only way to get more N 2O into blood is to
provide "new" blood with lower partial pressure.
○ O2 Transport: Perfusion Limited and Diffusion Limited
 Perfusion limited O2 Transport: Normal Conditions
□ As O2 added to capillary blood, PA O2 increases
□ Diffusion gradient is maintained because O 2 binds to hemoglobin, which
decreases free O2.
□ Equilibration occurs ~1/3 of the distance along the capillary, and now ne O 2 can
be added.
□ Pulmonary blood flow determines net O 2 transfer: increased blood flow =
increased transfer and vice versa.
 Diffusion Limited O2 Transport: Strenuous exercise and fibrosis
□ Fibrosis: Alveolar wall thickens, increases diffusion distance and decreases D L.
 Slows diffusion and prevents equilibration.
 Although partial pressure gradient maintained for longer length, total
transfer is greatly decreased.
□ O2 Transport at High Altitude: Barometric pressure is decreased, so partial
pressures in alveolar gas are decreased.
 Diffusion of O2 will be decreased, equilibration occur more slowly, with
complete equilibrium achieved at later point along the capillary.
Oxygen Transport in Blood
○ Forms of O2 in Blood
 Dissolved: Accounts for ~2% of O2 in blood.
□ Only form that produces partial pressure.
□ Grossly insufficient to meet the demands of the tissue.
 Bound to Hemoglobin: Remaining 98% is reversibly bound to hemoglobin.
□ Globular protein consisting of 4 subunits: α2β2
 Each subunit can bind one molecule of O2: 4 O2 per hemoglobin.
 Iron must be in the ferrous state (Fe2+) to bind O2.
□ Variants:
 Methemoglobin: Iron is in ferric state (Fe3+): does not bind O2
 Fetal: Two β chains are replaced by γ chains, which have a higher affinity
for O2.
 S: Sickle cell (β subunits are abnormal); the deoxygenated form has a
sickle shape, and Hemoglobin S has a lower affinity for O 2 than
Hemoglobin A.
O2 Binding Capacity and O2 Content
○ Binding Capacity: Maximum amount of O2 that can be bound to hemoglobin per volume of
blood.
○ O2 Content: Actual amount of O2 per unit of blood.
 O2 Content = (O2 binding capacity x % saturation) + dissolved O2
O2 Delivery to Tissues: Determined by blood flow and O 2 content of blood.
○ Cardiac output x O2 content of blood.
O2-Hemoglobin Dissociation Curve
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○ Sigmoidal Shape: Shape of the steepest part of the curve is the result of a change of affinity
of the heme groups for O2 as each successive O2 molecule binds.
 Each O2 molecule that binds increases the affinity for additional O2 molecules
(positive cooperativity)
○ P50: The PO2 at which hemoglobin is 50% saturated.
 Increase in P50 represents a decreased affinity for oxygen; decrease in P50 represents
an increased affinity for oxygen.
○ Loading and Unloading of O2
 In the lungs, hemoglobin is nearly 100% saturated, affinity is highest: it is important
to have as much O2 as possible loaded into arterial blood in the lungs.
□ Humans can tolerate substantial decrease in alveolar P O2 (from 100 mmHg to 60
mmHg) without significantly compromising the amount of O 2 carried by
hemoglobin (represented by the flat slope at lung pressures).
 In the tissues, PO2 is much lower than in the lungs. Decreasing hemoglobin saturation
decreases hemoglobin O2 affinity: O2 is not as tightly bound, which facilitates
unloading of O2 in tissues.
□ Pressure gradient is maintained in 2 ways:
a) Tissues consume O2, keeping their PO2 low; and
b) Lower affinity for O2 ensures that O2 is more readily unloaded from
hemoglobin.
• Changes in O2-Hemoglobin Dissociation Curve: Shifts reflect changes in affinity of hemoglobin for
O2, and P50
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○ Shifts to the Right: Decreased affinity of hemoglobin for O2; Unloading of O2 in tissues is
facilitated.
 Factors:
□ Increase in PCO2 and decrease in pH: This mechanism helps ensure O 2 delivery
can meet O2 demand (Bohr Effect).
□ Increase in temperature: Heat produced by working muscle shifts curve to right,
providing more O2 to tissues.
□ Increase in 2,3-DPG concentration: Byproduct of glycolysis in RBC, increases
under hypoxic conditions. Part of the adaptive mechanism facilitating O 2
delivery to tissues at high altitudes.
○ Shifts to the Left: Reflect an increase in affinity of hemoglobin for O2; Unloading of O2 in
tissues is more difficult.
 Factors:
□ Decrease in PCO2 and increase in pH: When demand for O2 decreases, O2 is more
tightly bound to hemoglobin and less O 2 is unloaded to the tissues.
□ Decrease in temperature: Less heat is produced when tissue metabolism
decreases, and less O2 is unloaded.
□ Decrease in 2,3-DPG concentration
□ Hemoglobin F: The β chains of HbA are replaced by γ chains in HbF
○ Carbon Monoxide: Decreases O2 bound to hemoglobin and causes left shift of O2Hemoglobin curve
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 Binds to hemoglobin with an affinity 250 times that of O2 to form
Carboxyhemoglobin.
 O2 can't bind heme groups bound to CO.
 Heme groups not bound to CO have increased affinity for O2, making it more difficult
for O2 to be unloaded in the tissues: Catastrophic!
• Erythropoietin (EPO): Glycoprotein growth factor synthesized in the kidneys; major stimulus of
erythropoiesis.
○ Synthesis in kidneys in response to hypoxia in these steps:
i. Decreased O2 delivery to the kidneys leads to increased production of HypoxiaInducible Factor I-α.
ii. That factor acts on fibroblasts in the renal cortex/medulla to cause synthesis of mRNA
for EPO.
iii. mRNA directs increased synthesis of EPO.
iv. EPO causes differentiation of proerythroblasts.
v. Proerythroblasts undergo further steps in development to form mature RBCs.
○ The kidneys can distinguish between decreased blood flow as a cause of decreased O2
delivery and decreased O2 content of blood as a cause of decreased O2 delivery.
○ Anemia is a common finding in chronic renal failure because the decrease in functional
renal mass leads to decreased synthesis of EPO, and thus decreased RBC production. Treat
this with recombinant human EPO.
• Carbon Dioxide Transport in Blood
○ Forms of CO2 in Blood
 Dissolved: approximately 5% of total CO2 in blood
 Carbaminohemoglobin: About 3% of total CO2 in blood
□ CO2 binds to a different site on Hemoglobin than O 2, decreases its affinity for O 2.
□ When less O2 is bound to hemoglobin it increases hemoglobin's affinity for CO 2
(Haldane Effect); O2 release increases affinity for CO 2 that is being produced by
the tissues.
 HCO3-: 90% of CO2 carried in blood is in this form; the reaction is catabolized by
carbonic anhydrase.
□
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1) In tissues, CO2 produced by aerobic metabolism diffuses across cell membranes
and capillary walls (driven by partial pressure differential).
2) Carbonic anhydrase in RBC catabolizes hydration of CO 2 to H2CO3. The reaction
is driven to the right by mass action (CO 2 being produced by tissue).
3) H2CO3 dissociates into H+ and HCO3- in RBC.
4) H+ is buffered in RBC by deoxyhemoglobin to maintain normal pH. This causes
hemoglobin to release more O 2, which in turn makes hemoglobin a better buffer
for H+.
5) HCO3- exchanged across membrane for Cl - by anion exchange protein called
Band Three Protein.
□ The entire process occurs in the reverse in the lungs.
• Ventilation/Perfusion Relationships
• Pulmonary Blood Flow
○ Pulmonary Blood Flow, Pressure, and Resistance Relationships
 Pulmonary Blood Flow is directly proportional to pressure gradient between
pulmonary artery and left atrium, and inversely proportional to pulmonary vascular
resistance (
).
 Pulmonary circulation has much lower pressures and resistances than systemic
circulation.
○ Regulation of Pulmonary Blood Flow
 Hypoxic Vasoconstriction: Decrease in partial pressure of O2 in alveolar gas produce
vasoconstriction
□ Occurs as an adaptive mechanism, decreases blood flow to poorly ventilated
areas where it would be "wasted." Blood flow is directed away from poorly
ventilated areas where gas exchange would be inadequate, toward wellventilated regions, where gas exchange will be better.
□ Mechanism: Direct action of alveolar P O2 on vascular smooth muscle of
pulmonary arterioles.
 When PAO2 is normal, O2 diffuses from alveoli into nearby smooth muscle
cells, keeping arterioles relatively relaxed and dilated.
 Tone is unaffected until PAO2 falls below 70 mmHg, at which point hypoxia
causes vasoconstriction, restricting pulmonary blood flow in that region
(mechanism not understood).
○ Distribution of Pulmonary Blood Flow: Uneven, can be explained by effects of gravity.
 Supine: no effects (entire lung at same gravitational level).
 Upright: Blood flow is lowest at apex and highest at the base.
 Zone 1 (apex): Arterial pressure may be lower than alveolar pressure.
□ Normally, arterial pressure is just high enough to prevent capillary closure, and
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□ Normally, arterial pressure is just high enough to prevent capillary closure, and
zone 1 is perfused.
□ If arterial pressure is decreased (hemorrhage) or if alveolar pressure is
increased (positive pressure breathing), the blood vessels will close. No gas
exchange without perfusion: becomes part of physiologic dead space.
 Zone 2 (middle): Compression of the capillaries is not a problem, but blood flow is
driven by the difference between arterial and alveolar pressure, not the difference
between arterial and venous pressure.
 Zone 3 (base): Blood flow is driven by the difference between arterial and venous
pressure.
□ The greatest number of capillaries is open and blood flow is highest.
○ Shunts: Normally a small fraction of pulmonary blood flow bypasses the alveoli.
 Physiological shunt: Small physiologic shunts are always present, and PaO2 will always
be slightly less than PAO2.
 Right-to-left Shunts: Hypoxemia always occurs because a significant fraction of
cardiac output is not delivered to the lungs for oxygenation.
□ A defining characteristic is that the hypoxemia cannot be corrected by having
the person breathe high O 2 because the shunted blood never goes to the lungs.
 Left-to-Right Shunts: More common; do not cause hypoxemia (PDA, trauma).
□ Pulmonary blood flow becomes higher than systemic blood flow.
□ PO2 in blood on the right side of the heart will be elevated.
• Ventilation/Perfusion Ratios
• It is useless for alveoli to be ventilated but not perfused or vice versa.
• Normal Value for V/Q is 0.8
• Distribution of V/Q in the lungs: 0.8 is the average for the lung. It is uneven, like blood flow.
○ V/Q is highest in zone 1 and lowest in zone 3.
• Ventilation/Perfusion Defects: A mismatch in ventilation and perfusion results in abnormal gas
exchange.
• Dead Space (V/Q=∞): Ventilation of lung spaces that are not perfused.
○ Pulmonary Embolism: Blood flow to a portion of the lung is occluded.
○ Because no gas exchange occurs in regions of dead space, alveolar gas has the same
composition as humidified inspired air.
• High V/Q: Usually occurs because blood flow is decreased.
○ Because ventilation is high relative to perfusion, capillary blood from these regions has a
high PO2 and low PCO2
• Low V/Q: Low ventilation relative to perfusion.
○ Pulmonary capillary blood from these regions has low PO2 and high PCO2.
• Shunt (V/Q=0): Perfusion of lung regions that are not ventilated.
○ Airway Obstruction/Right-to-Left cardiac shunts: no gas exchange can occur with a shunt,
so pulmonary capillary blood from these regions has the same composition as mixed venous
blood.
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