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CHAPTER 25
Organization of the
Respiratory System
Walter F. Boron
COMPARATIVE PHYSIOLOGY OF RESPIRATION
EXTERNAL RESPIRATION IS THE EXCHANGE OF O2 AND CO2
BETWEEN THE ATMOSPHERE AND THE MITOCHONDRIA
For millennia, people have regarded life as being synonymous with
breathing. Life begins and ends with breathing. The Bible states that God
“breathed into [Adam’s] nostrils the breath of life,” and then later used part
of Adam’s ventilatory apparatus — a rib — to give life to Eve. In the fourth
and fifth centuries BC, writings attributed to Hippocrates suggested that the
primary purpose of breathing is to cool the heart.
It was not until the 18th century that the true role of breathing began to
emerge as several distinguished investigators studied the chemistry of gases.
At the time, chemists recognized similarities between combustion and
breathing, but thought that both involved the production of a “fire-essence”
principle called “phlogiston.” According to their theory, neither combustion
nor life could be supported once air became saturated with phlogiston.
In the 1750s, the Scottish scientist Joseph Black found that heating
calcium carbonate produces a gas he called “fixed air,” now known to be
carbon dioxide (CO2). This work revolutionized chemistry. It showed that
a chemical reaction can involve a gas, and it further demonstrated that
other gases exist besides ordinary “air.” Shortly thereafter, Cavendish, working in England, showed that fermentation and putrefaction produce “fixed
air.” His countryman Priestley discovered several new gases between the
late 1760s and mid-1770s, including “dephlogistonated air,” co-discovered
by the Swedish chemist Scheele. Priestley found that combustion, putrefaction, and breathing all consume “dephlogistonated air,” and all reduce the
volume of room air by approximately 20%. Conversely, he found that
green plants produce “dephlogistonated air,” which he could quantitate by
reacting it with nitric oxide (a colorless gas) to produce nitrogen dioxide (a
red gas).
In the mid-1770s, Priestley toured the Continent and presented his
findings to the Frenchman Lavoisier, who is often regarded as the father of
modern chemistry. Lavoisier quickly put Priestley’s empirical observations
into a theoretical framework that he used to demolish the phlogiston
theory, which Priestley held to his death. Lavoisier recognized that dephlogistonated air, which he named oxygen (O2), represents the 20% of room
air consumed by combustion in Priestley’s experiments, leaving behind
“non-vital” air, or nitrogen. Furthermore, he proposed that O2 is consumed
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because it reacts with one substance to produce another
substance. Spallanzani, working in Italy during the late
1790s, confirmed Lavoisier’s prediction that O2 consumption and CO2 production occur not in the lungs, but in
isolated tissues.
Therefore, by the end of the 18th century, chemists/
physiologists appreciated that combustion, putrefaction,
and respiration all involve chemical reactions that consume O2 and produce CO2. Subsequent advances in the
chemistry of gases by Boyle, Henry, Avogadro, and others
laid the theoretical foundation for dealing with the physiology of O2 and CO2. Thus, respiration was a unifying
theme in the early histories of physiology, chemistry, and
biochemistry.
It is recognized that mitochondrial respiration (i.e., the
oxidation of carbon-containing compounds to form CO2)
is responsible for the O2 consumption and CO2 production observed by Spallanzani. This aspect of respiration is
often called internal respiration or oxidative phosphorylation, which is summarized in Chapter 57.
In the chapters on respiratory physiology, we focus on
external respiration, the dual processes of (1) transporting O2 from the atmosphere to the mitochondria and (2)
A
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UNICELLULAR ORGANISM, NO CONVECTION
Net movement in
direction from high
concentration to low
concentration.
Net
flow
transporting CO2 from the mitochondria to the atmosphere. CO2 transport as it is intimately related to acidbase homeostasis is discussed.
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DIFFUSION IS THE MAJOR MECHANISM
OF EXTERNAL RESPIRATION FOR SMALL
AQUATIC ORGANISMS
The most important and the most fundamental mechanism of O2 and CO2 transport is diffusion (see Chapter
3). The random movements of molecules such as O2 and
CO2, whether in a gaseous phase or dissolved in water,
result in a net movement of the substance from regions of
high concentration to regions of low concentration (Fig.
25 – 1A, inset). No expenditure of energy is involved. The
driving force for diffusion is the concentration gradient.
Imagine a unicellular organism, suspended in a beaker
of water at 37oC. We will equilibrate the water with an
atmosphere that has the usual composition of O2 and
CO2 (Table 25 – 1). The partial pressures of O2 (Po2) and
of CO2 (Pco2) in the dry air are slightly higher than their
corresponding values in the wet air immediately above
the surface of the water (see the box on Wet Gases). It is
C
MULTICELLULAR ORGANISM, WITH CONVECTION INSIDE
O2
Gas-exchange
barrier
Extracellular fluid
O2
…and
larger
O2
O2
CO2
Flow across barrier
is proportional to ∆P.
CO2
CO2
D
CO2
Bulk
fluid
B
Extracellular
unstirred layer
Intracellular
unstirred layer
UNICELLULAR ORGANISM, WITH CONVECTION OUTSIDE
MULTICELLULAR ORGANISM WITH 4-CHAMBERED HEART
Air pump delivers
inspired air by
convection.
Circulatory system
moves gases by
convection.
O2
Arterial
O2
Mixed-venous
As ∆P increases, the flow
of gas becomes larger…
O2 and CO2 cross
alveolar wall by
diffusion.
O2
Mixed-venous
Arterial
CO2
CO2
O2 and CO2 cross
ECF and cytoplasm
by diffusion.
CO2
Inspired air
(“outside” organism)
Alveoli
Pulmonary Arteries
capillary
and veins
Alveolar wall
Interstitial
space
Systemic capillary
FIGURE 25– 1. Diffusion of O2 and CO2 for a single-celled organism. In A through D, the y axis of grids shows the dissolved concentration (or partial
pressure) of O2 and CO2. The x axis represents distance (not to scale). In D, the broken lines in the pulmonary capillary and systemic interstitial space
represent the magnitude of the gradients driving O2 and CO2 diffusion. The red (O2) and blue (CO2) pathways represent the circuit of blood from the
pulmonary capillaries to the systemic capillaries, and back again.
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TABLE 25– 1
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COMPOSITION OF AIR
WET AIR
Trachea
DRY AIR
Atmosphere
Fraction In
Air (%)
Gas
Partial Pressure
At Sea Level
(mm Hg)
Fraction In
Air (%)
Partial Pressure
At Sea Level
(mm Hg)
Nitrogen
78.09
593.48
73.26
556.78
Oxygen
20.95
159.22
19.65
149.37
Carbon dioxide
0.03
0.23
0.03
0.21
Argon
0.93
7.07
0.87
6.63
Water
0
0
6.18
47
760
100.00
760
Total
100.00
these partial pressures in wet air that determine the concentrations of dissolved O2 ([O2]Dis) and dissolved CO2
([CO2]Dis) in the water (see the box on Henry’s Law).
Thus, the Po2 in the wet air — as well as the water beneath it — will be approximately 149 mm Hg (or torr),
and the Pco2 will be an almost negligible 0.2 mm Hg.
These numbers describe the composition of the water in
the bulk phase, at some distance from the organism.
However, because the mitochondria within the organism
continuously consume O2 and produce CO2, the Po2 at
the surface of the mitochondria will be lower than the
bulk-phase Po2, whereas the Pco2 at the mitochondrial
surface will be higher than the bulk-phase Pco2. These
differences in partial pressure cause O2 to diffuse from
the bulk fluid toward the mitochondria, and the CO2 to
diffuse in the opposite direction.
The diffusion of O2 follows a gradient of decreasing Po2
(see Fig. 25 – 1A). The region over which Po2 falls gradually from the bulk fluid toward the organism’s outer surface is the extracellular unstirred layer, so named because no convective mixing occurs in this zone. A similar
gradual decline in Po2 drives O2 diffusion through the
“WET GASES”: PARTIAL PRESSURES OF O2 AND CO2 IN SOLUTIONS THAT ARE EQUILIBRATED WITH WET AIR
Imagine that a beaker of water is equilibrated with a
normal atmosphere, both at a temperature of 37oC. For
dry air (i.e., air containing no water vapor), O2 makes
up ⬃21% of the total gas by volume (see Table 25–1).
Thus, if the barometric pressure (PB) is 760 mm Hg, the
partial pressure of O2 (PO2) is 21% of 760 mm Hg, or
159 mm Hg (Fig. 25– 2A). However, if the air-water interface is reasonably stationary, then water vapor will saturate the air immediately adjacent to the liquid. What is
the PO2 in this wet air? At 37oC, the partial pressure of
water (PH2O) is 47 mm Hg. Thus, of the total pressure of
the wet air, PH2O makes up 47 mm Hg, and the components of the dry air make up the remaining 760 ⫺ 47 or
713 mm Hg. The partial pressure of O2 in this wet air is
therefore:
The CO2 composition of dry air is ⬃0.03% (see Table
25–1). Thus, the partial pressure of CO2 in wet air is:
PCO2 ⫽ FCO2 ⫻ (PB ⫺ PH2O)
⫽ (0.03%) ⫻ (760 mm Hg ⫺ 47 mm Hg)
⫽ 0.21 mm Hg
Box Equation 25–2
These examples are realistic for respiratory physiology:
As we inhale relatively cool and dry air, the nose and
other upper respiratory passages rapidly warm and moisturize the passing air so that it assumes the composition
of wet air given in Table 25–1.
Fraction of dry
air that is O2
p
PO2 ⫽ FO2 ⫻ (PB ⫺ PH2O)
⫽ (21%) ⫻ (760 mm Hg ⫺ 47 mm Hg)
⫽ 149 mm Hg
Box Equation 25–1
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B
PARTIAL PRESSURE OF O2 IN WET AIR
HENRY'S LAW
Atmospheric pressure
760 mm Hg
PO
2
100 mm Hg
P O2
159 mm Hg
(21% of
760 mm Hg)
Dry air
(bulk phase)
PO
2
149 mm Hg
P H2 O
(21% of
47 mm Hg 713 mm Hg)
Wet air
(unstirred layer
above water)
[O2]Dis
0.13 mMol
[O2]Dis
0.05 mMol
Solution #1
Solution #2
37°
C
PO
2
40 mm Hg
37°
DIFFUSION OF DISSOLVED GAS
37°
37°
[O2]Dis
0.13 mMol
[O2]Dis
0.05 mMol
Solution #1
Solution #2
Semipermeable
membrane
FIGURE 25– 2. Partial pressures.
intracellular unstirred layer, from the organism’s inner
surface to the mitochondria. The final remarkable feature
of the Po2 profile is the abrupt fall in Po2 at the organism’s surface. The profile for Pco2 is similar, but has the
opposite orientation.
The rate at which O2 or CO2 moves across the surface
of the organism is the flow (units: moles/s). According to
a simplified version of Fick’s Law (see Chapter 3), the
flow is proportional to the concentration difference across
this barrier. Because we know from Henry’s Law that the
concentration of a dissolved gas is proportional to its
partial pressure in the gas phase, the flow is also proportional to the partial-pressure difference (⌬P):
Flow ⬀ ⌬P
Equation 25 – 1
Simple diffusion (see Chapter 26) is the mechanism by
which O2 and CO2 move short distances in the respiratory
system: between the air and the blood in the alveoli, and
between the mitochondria and the blood of the peripheral
circulation.
CONVECTION ENHANCES DIFFUSION BY
PRODUCING STEEPER GRADIENTS ACROSS THE
DIFFUSION BARRIER
A purely diffusive system can establish only a relatively
small ⌬P across the gas exchange barrier of the organism
(see Fig. 25 – 1A). Yet, for small organisms, even this
relatively small ⌬P is adequate to meet the demands for
O2 uptake and CO2 removal. However, when the organism’s diameter exceeds approximately 1 mm, simple diffusion becomes inadequate for gas exchange. One way of
ameliorating this problem is to introduce a mechanism for
local convection on the outside surface of the organism.
For a paramecium, the beating cilia bring bulk-phase water — having a Po2 of approximately 154 mm Hg at 25⬚C
and a Pco2 of approximately 0.2 mm Hg — very near to
the cell’s surface. This mixing reduces the size of the
extracellular unstirred layer, thereby increasing the Po2
and decreasing the Pco2 on the outer surface of the organism. The net effect is that the partial-pressure gradients for both O2 and CO2 increase across the gas-exchange barrier (see Fig. 25 – 1B), leading to a
proportionate increase in the flow of both substances.
A filter feeder, such as an oyster or a clam, pumps
bulk-phase water past its organ of gas exchange. Because
of the relatively low solubility of O2 in water, such an
organism may need to pump 16,000 ml of water to extract a mere 1 ml of O2 gas. In fish, which are far more
efficient, the ratio is considerably lower, approximately
400:1.
In mammals, the bulk phase is the atmosphere and the
external convective system is an air pump consisting of
the lungs, the airways, and the respiratory muscles. Ventilation is the process of moving air into and out of the
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PARTIAL PRESSURES AND HENRY’S LAW
Respiratory physiologists generally express the concentration of a gas, whether mixed with another gas (e.g., O2
and N2, as is the case for air) or dissolved in an aqueous
solution (e.g., O2 dissolved in water), in terms of partial
pressure. Dalton’s Law states that the total pressure
(PTotal) of a mixture of gases is the sum of their individual
partial pressures. Imagine that we are dealing with an
ideal gas (Z) mixed with other gases. The ratio of the
partial pressure of Z (PZ) to the total pressure (PTotal) is its
mole fraction (XZ):
PZ ⫽ XZ · PTotal
⫽ 0.13 mMol
Box Equation 25–5
Now imagine that we have a second beaker equilibrated with an atmosphere having a PO2 of 40 mm Hg,
the partial pressure of O2 in mixed-venous blood (see Fig.
25–3B, solution #2). For this solution,
[O2]Dis ⫽ 0.0013 mMol/mm Hg ⫻ 40 mm Hg
⫽ 0.05 mMol
⫽ 0.05 mM
Box Equation 25–3
Thus, if PZ were twice as high in one sample of gas
than in another, XZ (i.e., concentration of Z) would also
be twice as high.
It may not be immediately obvious why partial pressures are also useful for expressing concentrations when
dealing with situations in which Z is dissolved in aqueous
solutions. According to Henry’s Law, the concentration
of O2 dissolved in water ([O2]Dis) is proportional to the
PO2 in the gas phase:
[O2]Dis ⫽ s ⫻ PO2
[O2]Dis ⫽ 0.0013 mMol/mm Hg ⫻ 100 mm Hg
Box Equation 25–4
The proportionality constant s is known as the solubility; for O2, this value is ⬃0.0013 mMol/mm Hg at
37ⴗC for a solution mimicking arterial blood plasma. The
solubility of CO2 is ???-fold higher. Consider a beaker of
water at 37oC equilibrated with an atmosphere having a
PO2 of 100 mm Hg, the partial pressure in mammalian
arterial blood plasma (see Fig. 25– 3B, solution #1). Thus,
Box Equation 25–6
If we were to place samples of each of these two
solutions on opposite sides of a semipermeable barrier in
a closed container (see Fig. 25–3C), the O2 gradient
across this barrier expressed in terms of concentrations
(⌬[O2]) would be 0.13 ⫺ 0.05 or 0.08 mMol. Expressed
in terms of partial pressures (⌬PO2), this same gradient
would be 100 ⫺ 40 ⫽ 60 mm Hg.
Imagine now that we take a 5-ml sample of each of
the solutions in the beakers in Figure 25–3B, drawing the
fluid up into syringes, sealing the syringes, putting them
on ice, and sending them to a clinical laboratory for
analysis—as is routinely done with samples of arterial
blood. Even though there is no gas phase in equilibrium
with either of the solutions in the syringes, the laboratory
will report the O2 levels in “mm Hg.” These are the
partial pressures of inspired O2 with which the solutions
were or would have to be equilibrated to achieve the
[O2]Dis in the samples.
CONVENTIONS FOR MEASURING VOLUMES OF GASES
Gases within the lung are saturated with water vapor at
37ⴗC (310 ⴗK). At this temperature, the partial pressure of
water is 47 mm Hg. The total pressure of the air in the
lungs is equal to barometric pressure, which we will assume to be 760 mm Hg. We can be certain that alveolar
pressure equals barometric pressure if the glottis is open
and no air is flowing. Thus, the partial pressure of the dry
gases in the lungs is (760 ⫺ 47) ⫽ 713 mm Hg. Whereas
the air in the lungs is at “Body Temperature and Pressure, Saturated with Water” (BTPS), this same air, when
expelled from the lungs into the spirometer, is at “Ambient Temperature and Pressure, Saturated” (ATPS). Thus,
we must correct the volume change (⌬VATPS) registered
by the spirometer (at ATPS) to have an accurate measure
of the volume (⌬VBTPS) that this same gas had previously
occupied in the lungs (at BTPS). According to the ideal
gas law:
PBTPS · ⌬VBTPS PATPS · ⌬VATPS
⫽
TBTPS
TATPS
Box Equation 25–7
or
⌬VBTPS ⫽
PATPS TBTPS
·
· ⌬VATPS
PBTPS TATPS
Box Equation 25–8
We will assume that the ambient temperature is 25ⴗC
(or 298ⴗK). The partial pressure of the dry gases at 25ⴗC
is simply the total barometric pressure minus the vapor
pressure of water at 25ⴗC, 24 mm Hg. Thus, substituting
real numbers into Box Equation 25–8:
⌬VBTPS ⫽
(760 ⫺ 24) 310ⴗK
·
· ⌬VATPS ⫽ 1.074 · ⌬VATPS
(760 ⫺ 47) 298ⴗK
Box Equation 25–9
Thus, the same gas that occupies 1000 ml in the
spirometer at ATPS, occupies 1074 ml in the body at
BTPS.
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lungs. Amphibians move air into their lungs by swallowing it. Reptiles, birds, and mammals expand their lungs
by developing a negative pressure inside the thorax. Because of the much higher content of O2 of air (⬃210 ml
O2/L of air at standard temperature and pressure/dry or
STPD), as opposed to water (⬃35 ml O2/L of water),
humans need to move far less air than oysters need to
move water. For example, a human may ventilate his/her
alveoli with 4000 ml of fresh air every minute, and extract from this air 250 ml of O2 gas, a ratio of 16:1.
Although we are 1000-fold more efficient than oysters,
the principle of external convective systems is the same:
ensure that the external surface of the gas-exchange barrier is in close contact with a fluid whose composition
matches — as closely as is practical — that of the bulk
phase. How “closely” is “practical”? The composition of
alveolar air approaches that of wet inspired air as alveolar
ventilation approaches infinity (see Chapter 30). Because
high ventilatory rates have a significant metabolic cost,
the body must trade off optimizing alveolar Po2 and Pco2
on the one hand, against minimizing the work of ventilation on the other. In the average adult human, the compromise that has evolved is an alveolar ventilation of
approximately 4000 ml/min, an alveolar Po2 of approximately 100 mm Hg (versus 149 mm Hg in a wet atmosphere at 37⬚C) and an alveolar Pco2 of approximately 40
mm Hg (versus 0.2 mm Hg).
A clinical example in which the external convective
system fails is barbiturate poisoning. Here, drug intoxication inhibits the respiratory-control centers in the medulla
(see Chapter 31), so that ventilation slows or even stops.
From a theoretical perspective, the consequence is that
the unstirred layer between the bulk-phase atmosphere
and the alveolar blood-gas barrier becomes extremely
large (i.e., the distance between the nose and the alveoli).
As a result, alveolar Po2 falls to such low levels that the
⌬Po2 across the alveolar wall cannot support an O2 flow
and an arterial [O2] that is compatible with life. Cessation
of ventilation also causes the alveolar Pco2 to rise to such
high levels that the CO2 flow from blood to alveolar air is
unacceptably low and arterial [CO2] rises to lethal levels.
An external convective system maximizes gas exchange
by continuously supplying bulk-phase water or air to the
external surface of the gas-exchange barrier, thereby
maintaining a high external Po2 and a low external Pco2.
A circulatory system is an internal convective system that
maximizes the flow of O2 and CO2 across the gas-exchange barrier by delivering, to the inner surface of this
barrier, blood that has as low a Po2 and as high a Pco2 as
practical. Perfusion is the process of delivering blood to
the lungs. Figure 1C shows a very primitive- and hypothetical-internal convective system, one that essentially
stirs the entire internal contents of the organism, so that
the PO2 of the bulk internal fluids is uniform, right up to
the surface of the mitochondria. The result is that the
⌬Po2 across the gas-exchange barrier is rather large, but
the ⌬Po2 between the bulk internal fluid and the mitochondria is rather small.
Figure 1D summarizes the Po2 and Pco2 profiles for a
sophisticated circulatory system built around a four-chambered heart and separate pulmonary and systemic circulations. The circulatory system carries (by convection) low-
Po2 blood from a systemic capillary near the mitochondria
to the alveolar wall. At the beginning of a pulmonary
capillary, a high alveolar-to-blood Po2 gradient insures a
high O2 inflow (by diffusion), and blood Po2 rises to
match the alveolar (i.e., external) Po2 by the time the
blood leaves the pulmonary capillary. Finally, the systemic arterial blood carries (by convection) this high-Po2
blood to the systemic capillaries, where a high blood-tomitochondria Po2 gradient maximizes the O2 flux into the
mitochondria (by diffusion). The opposite happens with
CO2. Thus, separate pulmonary and systemic circulations
ensure maximal gradients for gas diffusion at the level of
both the alveoli and the peripheral mitochondria.
The scenario outlined in Figure 1D requires the fourchambered heart characteristic of mammals as well as
advanced reptiles and birds. The right ventricle pumps
low-Po2/high-Pco2 blood received from the peripheral
veins to the lungs, whereas the left ventricle pumps highPo2/low-Pco2 blood received from pulmonary veins to the
periphery (i.e., mitochondria). Maintaining maximal gradients for O2 and CO2 diffusion at both the gas-exchange
barrier and at the mitochondria requires that right- and
left-ventricular blood not mix. However, this sort of mixing is exactly what occurs in fish and amphibians, whose
hearts have a common ventricle. In these animals, the
aortic blood has Po2 and Pco2 values that are intermediate
between the extreme values of venous blood returning
from the systemic circulation and the blood returning
from the gas-exchange-barrier circulation. The result is
less-than-optimal Po2 and Pco2 gradients at both the gasexchange barrier and the mitochondria.
In humans, the internal convective system may fail
when diseased heart valves cause a decrease in cardiac
output. Another example is the shunting of blood between the pulmonary and the systemic circulations, as
may occur in newborns with congenital anomalies (e.g.,
atrial or ventricular septal defects). The result is the same
sort of mixing of systemic venous and gas-exchange-barrier blood that occurs in amphibians and fish. Thus, patients with shunts cannot establish maximal Po2 and Pco2
gradients in the pulmonary and peripheral capillaries, and
thus cannot generate maximal fluxes of O2 and CO2.
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SURFACE-AREA AMPLIFICATION ENHANCES
DIFFUSION
The passive flow of O2 or CO2 across a barrier is proportional not only to the concentration gradient, but also to
the area of the barrier:
Flow ⬀ ⌬P ⫻ Area
Equation 25 – 2
Indeed, higher animals have increased their ability to
exchange O2 and CO2 with their environment by increasing the surface area across which gas exchange takes
place. For example, molluscs (e.g., squid) and fish have
gills, which they form by evaginating the gas-exchange
barrier, and thus greatly amplifying its surface area.
Higher land animals amplify their gas-exchange barriers
by invaginating them, forming lungs. In an amphibian
such as the adult frog, the lungs are simple air sacs with
a relatively small surface area. Not surprisingly, a large
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portion of their gas exchange must occur across the skin.
The gas-exchange barrier is considerably more sophisticated in reptiles, which line their lungs with alveoli, or
even subdivide them with alveoli-lined barriers. The net
effect is that the surface-to-volume ratio of the lungs is
greatly increased. Mammals increase the area available for
diffusion even more, by developing highly complex lungs
with bronchi and a large number of alveoli.
In humans, the lung surface is so large and so thin that
O2 and CO2 transport across the alveolar wall is approximately three-fold faster than necessary when cardiac output is normal. Nevertheless, this redundancy is extremely
important during exercise (when cardiac output can increase markedly), life at high altitude (where the Po2 is
low), and in old age (when lung function diminishes). A
substantial decrease in surface area, or thickening of the
barrier, can be deleterious. Examples are the surgical removal of a lung (which reduces the total surface for gas
exchange by about half) and pulmonary edema (which
increases the effective thickness of the barrier). Thus, if
an individual with a thickened barrier looses a lung, the
remaining surface area may not be large enough to sustain normal rates of gas exchange and normal blood levels
of O2 and CO2.
RESPIRATORY PIGMENTS SUCH AS HEMOGLOBIN
INCREASE THE CARRYING CAPACITY OF THE BLOOD
FOR BOTH O2 AND CO2
In mammals, the external convective system (i.e., ventilatory apparatus), the internal convective system (i.e., circulatory system), and the barrier itself (i.e., alveolar wall)
are so efficient that the diffusion of O2 and CO2 is not
what limits the exchange of gases, at least not in healthy
subjects at sea level.
Imagine what would happen if the mixed-venous blood
flowing down a pulmonary capillary contained only water
and salts. The diffusion of O2 from the alveolar air space
into the “blood” would be so fast — and the solubility of
O2 in saline is so low (see the box on Henry’s Law) —
that, before the blood could move approximately 1% of
the way down the capillary, the Po2 of the blood would
match the Po2 of the alveolar air (i.e., all of the O2 that
could move would have moved). For the remaining approximately 99% of the capillary, the Po2 gradient across
the barrier would be nil, and no more O2 would flow
into the blood. As a result, at a normal cardiac output,
the “blood” could never carry away enough O2 from the
lungs to the tissues to sustain life. The same is true in
reverse for the elimination of CO2.
Animals solve this problem with respiratory pigments,
specialized metalloproteins that greatly increase the carrying capacity of blood for O2 and CO2. In some arthropods and molluscs, the pigment is hemocyanin, a protein
containing copper. Polychaete worms and brachiopods
use hemerythrins. However, the most common respiratory pigments are the hemoglobins, which contain iron.
All vertebrates as well as numerous unrelated groups of
animals use hemoglobin (Hb), which is the chief component of red blood cells (erythrocytes).
The presence of Hb markedly improves the dynamics
of O2 uptake by blood passing through the lungs. The Hb
9
reversibly binds approximately 96% of the O2 that diffuses from the alveolar air spaces to the pulmonary capillary blood, greatly increasing the carrying capacity of
blood for O2. Hemoglobin also plays a key role in the
transport or carriage of CO2 by reversibly binding CO2
and by acting as a powerful pH buffer. In anemia, the
Hb content of blood is reduced, thus lowering the carrying capacity of blood for O2 and CO2. The most common
cause of anemia in industrialized societies is a shortage in
the diet of the iron necessary to synthesize Hb. An individual with anemia can compensate only if the systemic
tissues extract more O2 from each liter of blood and/or if
cardiac output increases. However, there are limits to the
amount of O2 tissues can extract, or to the level to which
the heart can increase its output.
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PATHOPHYSIOLOGY RECAPITULATES PHYLOGENY —
IN REVERSE
It should be clear from the pathophysiologic examples
discussed that whenever one of the key components of
the respiratory system fails in a higher organism, external
respiration in that organism becomes more like that of an
organism that is lower on the evolutionary ladder. For
example, a failure of a mammal’s air pump makes this
individual behave more like a unicellular aquatic organism without cilia. A reduction in the surface area of the
alveoli in a mammal creates the same problems faced by
an amphibian with simple sack-like lungs. A major shunt
in the circulatory system makes a mammal behave more
like a fish. In severe anemia, a mammal faces the same
problems as a lower life form that lacks a respiratory
pigment in the extracellular fluid.
ORGANIZATION OF THE RESPIRATORY
SYSTEM IN HUMANS
HUMANS OPTIMIZE EACH OF THE PROCESSES
INVOLVED IN EXTERNAL RESPIRATIONVENTILATION, CIRCULATION, AREA AMPLIFICATION,
GAS CARRIAGE, LOCAL CONTROL, AND CENTRAL
CONTROL
The human respiratory system (Fig. 25 – 3) has two important characteristics. First, it uses highly efficient convective systems (i.e., ventilatory and circulatory systems)
for long-distance transport of O2 and CO2. Second, it
reserves diffusion exclusively for short-distance movements of O2 and CO2. The key components of this respiratory system are:
1. An air pump: The external convective system in humans consists of the lungs and other airways, the thoracic cavity and its associated skeletal elements, and
the muscles of respiration. These components deliver
air to, and remove air from, the alveolar air spaces —
alveolar ventilation. Inspiration occurs when the
muscles of respiration increase the volume of the thoracic cavity, creating a partial vacuum in the alveolar
air spaces, and causing the alveoli to expand passively.
A quiet expiration occurs when these muscles relax, as
discussed in Chapter 26 (“Mechanics of Respiration”).
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External convection
10
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3. A surface for gas exchange: The gas-exchange barrier
in humans consists of the alveoli, which provide a
huge but extremely thin surface area for passive diffusion of gases between the alveolar air spaces and the
pulmonary capillaries. The anatomy of the alveoli is
discussed later in this chapter, and pulmonary gas
exchange is explored in Chapter 29 (“Gas Exchange in
the Lungs”). A similar process of gas exchange occurs
between the systemic capillaries and (p. [⬃/???]).
Control centers
in medulla
Motor output
to respiratory
muscles
O2
sensor
CO2
Pulmonary
diffusion
Chest wall
CO2
pH
O2
Lung
Hb
•
O2
Right
heart
Left
heart
H+
Internal convection
Hb
HC
– 3
O
Hb
• CO
Tissue diffusion
2
CO2
Hb •
Hb
O2
Cell
CO2
O2
FIGURE 25– 3. The respiratory apparatus in humans.
2. Mechanisms for carrying O2 and CO2 in the blood:
Red blood cells are highly specialized for transporting
O2 from the lungs to the peripheral tissues and for
transporting CO2 in the opposite direction. They have
extremely high levels of hemoglobin and other components (2,3-diphosphoglycerate, carbonic anhydrase;
and Cl-HCO3 exchangers) that help to rapidly load
and unload huge amounts of O2 and CO2. In the
pulmonary capillaries, Hb binds O2, thereby enabling
the blood to carry approximately 65-fold more O2
than ordinary saline. At the same time, Hb chemically
reacts with approximately 20% of the CO2 produced
by the mitochondria and carries this CO2 back to the
lungs. Hemoglobin also plays a key role as it buffers
the H⫹ formed as carbonic anhydrase converts CO2 to
HCO3- and H⫹. Thus, hemoglobin plays a central role
in acid-base chemistry, as discussed in Chapter 27
(“Acid-Base Physiology”) as well as for the carriage of
O2 and CO2, treated in Chapter 28 (“The Transport of
Oxygen and Carbon Dioxide in the Blood”).
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4. A circulatory system: The internal convective system
in humans consists of a four-chambered heart, and
separate systemic and pulmonary circulations. The
flow of blood to the lungs — perfusion — is discussed
in Chapter 30 (“Ventilation, Perfusion and VentilationPerfusion Ratio”).
5. A mechanism for locally regulating the distribution
of ventilation and perfusion: Neither the delivery of
fresh air to the entire population of alveoli nor the
delivery of mixed-venous blood to the entire population of pulmonary capillaries is uniform throughout
the lungs. Nevertheless, efficient gas exchange requires
that, to the extent possible, the ratio of ventilation to
perfusion be uniform for all alveoli. The lungs attempt
to achieve a uniform distribution of ventilation/perfusion ratios by using sophisticated feedback-control
mechanisms to regulate local air flow and blood flow,
as discussed in Chapter 30.
6. A mechanism for centrally regulating ventilation:
Unlike the rhythmicity of the heart, that of the respiratory system is not intrinsic to the lungs or the chest
wall. Instead, respiratory control centers in the central
nervous system (CNS) rhythmically stimulate the
muscles of inspiration. Moreover, these respiratory
centers must appropriately modify the pattern of ventilation during exercise or other changes in physical or
mental activity. Sensors for arterial Po2, Pco2, and pH
are part of feedback loops that stabilize these three
“blood-gas” parameters. These subjects are the topic of
Chapter 31 (“Control of Ventilation”).
Respiratory physiologists have agreed on a set of symbols for describing parameters that are important for pulmonary physiology and pulmonary-function tests (Table
25 – 2).
CONDUCTING AIRWAYS DELIVER FRESH AIR TO THE
ALVEOLAR SPACES
Lung development is discussed in Chapter 56. In the
embryo, each lung invaginates into a separate pleural sac,
which reflects over the surface of the lung. The parietal
pleura, the wall of the sac that is farthest from the lung,
contains blood vessels that are believed to produce an
ultrafiltrate of the plasma called pleural fluid. About 10
ml of this fluid normally occupies the virtual space between the parietal and the visceral pleura. The latter lies
directly on the lung and contains lymphatics that drain
the fluid from the pleural space. When the production of
pleural fluid exceeds its removal, the volume of pleural
fluid increases (pleural effusion), limiting the expansion
of the lung. Under normal circumstances, the pleural
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11
TABLE 25– 2
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SYMBOL CONVENTIONS IN RESPIRATORY PHYSIOLOGY
RESPIRATORY MECHANICS
GAS EXCHANGE
Main Symbols
Main Symbols
C
Compliance
C
Concentration (or content) in a liquid
f
Respiratory frequency
D
Diffusion capacity
P
Pressure
f
Respiratory frequency
R
Resistance
F
Fraction
V
ⴢ
V
Volume of gas
P
ⴢ
Q
Pressure
R
Gas-exchange ratio
S
Saturation of hemoglobin
V
ⴢ
V
Volume of gas
Flow
Flow of blood (perfusion)
Ventilation
A
Modifiers
Alveolar
a
Modifiers
Systemic arterial
aw
Airway
A
Alveolar
B
Barometric
B
Barometric
c
Pulmonary capillary
E
Expired
I
Inspired
v
Systemic venous (in any vascular bed)
v
Mixed systemic venous
Macklem PT: Symbols and abbreviations. In The American Physiological Society Staff: Handbook of Physiology. Section 3: The Respiratory
System. Vol 1. Bethesda, MD, American Physiological Society, 1985.
fluid probably lubricates the pleural space, facilitating
physiologic changes in the size and shape of the lung.
The lungs themselves are divided into lobes, three in
the right lung (i.e., upper, middle, and lower lobes) and
two in the left (i.e., upper and lower lobes). The right
lung, which is less encumbered than the left by the presence of the heart, makes up approximately 55% of total
lung mass and function.
We refer to the progressively bifurcating pulmonary
airways by their generation number (Fig. 25 – 4): The
zeroth generation is the trachea, the first generation airways are the right and left mainstem bronchi, and so on.
Inasmuch as the right mainstem bronchus has a greater
diameter than does the left, and is more nearly parallel
with the trachea, inhaled foreign bodies more commonly
lodge in the right lung than in the left. There is a total of
approximately 23 generations of airways. As generation
number increases (i.e., as airways become smaller), the
amount of cilia, the number of mucus-secreting cells, the
presence of submucosal glands, and the amount of cartilage in the airway walls all gradually decrease. The mucus
is important for trapping small foreign particles. The cilia
sweep the carpet of mucus — kept moist by secretions
from the submucosal glands — up toward the pharynx,
where swallowing eventually disposes of the mucus. The
cartilage is important for preventing airway collapse,
which is especially problematic during expiration (see
Chapter 29). Airways maintain some cartilage to about
the 10th generation, up to which point they are referred
to as bronchi.
At about the 11th and succeeding generations, the now
cartilage-free airways are called bronchioles. Because
these bronchioles lack cartilage, they can maintain a patent lumen only because the pressure surrounding them
may be more negative than the pressure inside, and because of the outward pull (radial traction or tethering) of
surrounding tissues. Thus, bronchioles are especially susceptible to collapse during expiration. Up until generation
approximately 16, no alveoli are present, and the air cannot exchange with the pulmonary-capillary blood. These
alveoli-free airways are the conducting airways, which
serve only to move air by convection (i.e., like water
moving through a pipe) to those regions of the lung that
participate in gas exchange. The most distal conducting
airways are the terminal bronchioles (⬃ generation 16).
The total aggregate volume of conducting airways, from
the lips/nose to the generation-16 airways, the anatomic
dead space, amounts to approximately 150 ml in healthy
young males and somewhat over 100 ml in females. The
anatomic dead space is only a small fraction of the total
lung capacity, which averages 5 to 6 L in adults, depending on the size and health of the individual.
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Generation #
Trachea
Cartilage
0
Mainstem
bronchi
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1
2
Bronchi
(cartilage)
10
Conducting
airways
(anatomic
dead space)
11
12
13
14
Terminal
bronchiole
Bronchioles
(no cartilage)
15
Terminal
bronchiole
16
Respiratory
bronchioles
12
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Alveolar
air spaces
Alveolus 17
Smooth
muscle fibers
18
Pulmonary
venule
19
20
Alveolar
ducts
21
22
Alveolar
sacs
Alveolus
Terminal
respiratory
unit
Alveolar
capillaries
Pores of Kohn
23
Type-I pneumocyte
Pulmonary
arteriole
Air in alveolus
Alveolar
acinus
Air in
alveolus
Interstitial
space
Endothelial
cell
Red blood
cells
FIGURE 25– 4. Generations of airways.
600
200%
Conducting airways
Alveolar
airways
400
Velocity
Relative air 100%
velocity
(—)
Crosssectional
area
200
0%
0
2
4
6
8
10
12
14
Airway generation number
16
18
20
Aggregate
cross-sectional
area (cm2)
(—)
0
FIGURE 25– 5. Dependence of aggregate cross-sectional area and of linear velocity on generation number.
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ALVEOLAR AIR SPACES ARE THE SITE OF
GAS EXCHANGE
Alveoli first appear budding off bronchioles at approximately generation 17. These respiratory bronchioles participate in gas exchange over at least part of their surface.
Respiratory bronchioles extend from approximately generation 17 to generation 19, the density of alveoli gradually
increasing with generation number (see Fig. 25 – 4). Eventually, alveoli completely line the airways. These alveolar
ducts (generations 20 – 22) finally terminate blindly as
alveolar sacs (generation 23). The aggregation of all airways arising from a single terminal bronchiole (i.e., the
respiratory bronchioles, alveolar ducts, and alveolar sacs),
along with their associated blood and lymphatic vessels, is
a terminal respiratory unit or primary lobule.
The cross-sectional area of the trachea is approximately
2.5 cm2. Unlike the situation in systemic arteries (see
Chapter 18), wherein the aggregate cross-sectional area of
the branches always exceeds the cross-sectional area of
the parent vessel, an aggregate cross-sectional area falls
from the trachea through the first four generations of
airways (Fig. 25 – 5). Because all of the air that passes
through the trachea also passes through each generation
of conducting airways, the product of aggregate crosssectional area and linear velocity is a constant. Thus, the
linear velocity of air in the first four generations is higher
than that in the trachea, which may be important during
coughing (see later). In succeeding generations, however,
the aggregate cross-sectional area rises, at first slowly, and
then very steeply. As a result, the linear velocity falls to
very low values. For example, at the level of the terminal
bronchioles (generation 16), the aggregate cross-sectional
area is approximately 180 cm2. Thus, the average linear
velocity of the air at generation 16 is only (2.5 cm2)/
(180 cm2) ⫽ 1.4% of the value in the trachea. As air
moves into the respiratory bronchioles and further into
the terminal respiratory unit, where the linear velocity is
minuscule, convection gradually becomes even less and
less important for the movement of gas molecules, and
diffusion dominates. Notice that the long-distance movement of gases from lips/nose to the end of the generation16 airways occurs by convection. However, the short-distance movement of gases from generation-17 airways to
the farthest reaches of the alveolar ducts occurs by diffusion. The movement of gases across the gas-exchange barrier (⬍0.5 ␮m) also occurs by diffusion. Thus, the distances over which convection occurs are long, whereas
the distances over which diffusion takes place are short.
The alveolus is the fundamental unit of gas exchange.
Alveoli are hemispheric structures with diameters that
range from 75 to 300 ␮m. The approximately 300 million alveoli have a combined surface area of 50 to 100 m2
and an aggregate maximal volume of 5 to 6 L in the two
lungs. Both the diameter and the surface area depend on
the degree of lung inflation. The lungs have a relatively
modest total volume (i.e., ⬃5.5 L), very little of which is
invested in conducting airways (i.e., ⬃0.15 L). However,
the alveolar area is tremendously amplified. For example,
a sphere with a volume of 5.5 L would have a surface
area of only 0.16 m2, which is far less than 1% of the
alveolar surface area.
13
The alveolar lining consists of two distinct types of
epithelial cells, called type-I and type-II alveolar pneumocytes. The cuboidal type-II cells exist in clusters and are
responsible for elaborating pulmonary surfactant, which
substantially eases the expansion of the lungs (see Chapter 29). The type-I cells are much thinner than the type-II
cells. Thus, even though the two cell types are present in
approximately equal numbers, the type-I cells cover 90%
to 95% of the alveolar surface, and represent the shortest
route for gas diffusion. After an injury, type-I cells slough
and degenerate, whereas type-II cells proliferate and line
the alveolar space, re-establishing a continuous epithelial
layer. Thus, the type-II cells appear to serve as repair
cells.
The pulmonary capillaries are usually sandwiched between two alveolar air spaces. In fact, the flowing blood
almost forms an uninterrupted sheet that flows like a
twisted ribbon between abutting alveoli. At the type-I
cells, the alveolar wall (i.e., pneumocyte plus endothelial
cell) is typically 0.15 – 0.30 ␮m thick. Small holes (pores
of Kohn) perforate the septum separating two abutting
alveoli. The function of these pores, which are surrounded by capillaries, is unknown.
The lung receives two blood supplies: (1) the pulmonary arteries and (2) the bronchial arteries (Fig. 25 – 6).
The pulmonary arteries, by far the major blood supply
to the lung, carry the relatively deoxygenated mixed-venous blood. After arising from the right ventricle, they
bifurcate as they follow the bronchial tree, and their divisions ultimately form a dense, richly anastomosing, hexagonal array of capillary segments that supply the alveoli
of the terminal respiratory unit. The pulmonary capillaries
have an average internal diameter of approximately 8 ␮m,
and each segment of the capillary network is approximately 10 ␮m in length. The average erythrocyte spends
approximately 0.75 sec in the pulmonary capillaries as it
traverses up to three alveoli. After gas exchange in the
alveoli, the blood eventually collects in the pulmonary
veins.
The bronchial arteries are branches of the aorta and
thus carry freshly oxygenated blood. They supply the
conducting airways. At the level of the respiratory bronchioles, capillaries derived from bronchial arteries anastomose with those derived from pulmonary arteries. Because capillaries of the bronchial circulation drain
primarily into pulmonary veins, there is some venous
admixture of the partially deoxygenated blood from the
bronchial circulation and the newly oxygenated blood.
This mixing represents part of a small physiologic shunt.
A small amount of the bronchial blood drains into the
azygos and accessory hemiazygos veins.
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THE LUNGS PLAY IMPORTANT NONRESPIRATORY
ROLES, INCLUDING FILTERING THE BLOOD,
SERVING AS A RESERVOIR FOR THE LEFT
VENTRICLE, AND PERFORMING SEVERAL
BIOCHEMICAL CONVERSIONS
Although the main function of the lungs is to exchange
O2 and CO2 between the atmosphere and the blood, the
lungs also play important roles that are not directly related to external respiration.
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Deoxygenated
blood from
right heart goes
to alveoli…
Pulmonary
artery
…whereas
oxygenated blood
from left heart goes to
conducting airways.
Bronchial
artery
Bronchiole
All blood returns
to left heart via
pulmonary veins.
Pulmonary
vein
Shunt
FIGURE 25– 6. The blood supply to the airways.
OLFACTION. Ventilation is essential for delivering odorants to the olfactory epithelium (see Chapter 13). Sniffing
behavior, especially important for some animals, allows
one to sample the chemicals in the air without the risk of
bringing potential noxious agents deep into the lungs.
PROCESSING OF INHALED AIR BEFORE IT REACHES THE
ALVEOLI. Strictly speaking, warming, moisturizing, and
filtering the inhaled air in the conducting airways is a
respiratory function. It is part of the cost of doing the
business of ventilation. Warming cool, inhaled air is important so that gas exchange in the alveoli takes place at
body temperature. If the alveoli and the associated blood
were substantially cooler than body temperature, then the
solubility of these alveolar gases in the cool pulmonary
capillary blood would be relatively high. As the blood
later warmed, the solubility of these gases would decrease, resulting in air bubbles (i.e., emboli) that could
lodge in small systemic vessels, and cause infarction.
Moisturizing is important to prevent the alveoli from
becoming desiccated. Finally, filtering large particles is
important to prevent small airways from being clogged
with debris that may also be toxic.
Warming, moisturizing, and filtering are all more efficient with nose breathing, rather than mouth breathing.
The nose, including the nasal turbinates, has a huge surface area and a rich blood supply. Nasal hairs tend to
filter out large particles (greater than ⬃15 ␮m in diameter). The turbulence set up by these hairs — as well as the
highly irregular surface topography of the nasal passages — increases the likelihood that particles larger than
approximately 10 ␮m in diameter will impact and embed
themselves in the mucus that coats the nasal mucosa.
Moreover, air inspired through the nose must make a
right-angle turn as it heads toward the trachea. The inertia of larger particles causes them to strike the posterior
wall of the nasopharynx, which coincidentally is endowed
with large amounts of lymphatic tissue that can mount an
immunologic attack on inspired microbes. Of the larger
particles that manage to escape filtration in the upper
airways, almost all will impact on the mucus of the trachea and the bronchi.
Smaller particles (2 – 10 ␮m in diameter) also may impact a mucus layer. In addition, gravity may cause them
to sediment from the slowly moving air in small airways
and embed themselves in mucus. Particles with diameters
below approximately 0.5 ␮m tend to reach the alveoli
suspended in the air as aerosols. The airways do not trap
most (⬃80%) of these aerosols, but expel them in the
exhaled air.
The lung has a variety of strategies for dealing with
particles that remain on the surface of the alveoli or
penetrate into the interstitial space. Alveolar macrophages
(on the surface) or interstitial macrophages may phagocytize these particles, enzymes may degrade them, or lymphatics may carry them away. In addition, particles suspended in the fluid covering the alveolar surface may
flow with this fluid up to terminal bronchioles, where
they meet a layer of mucus that the cilia propel up to
progressively larger airways. There, they join larger particles — which entered the mucus by impacting or sedimenting — on their journey to the oropharynx. Coughing
and sneezing (see Chapter 31), reflexes triggered by airway irritation, accelerate the movement of particulates up
the conducting airways and out of the body.
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LEFT-VENTRICULAR RESERVOIR. The highly compliant
pulmonary vessels of the typical 70-kg human contain
approximately 500 ml of blood (see Chapter 18), which
is an important buffer for filling the left ventricle. For
example, even if — under experimental conditions — one
clamps the pulmonary artery, so that no blood may enter
the lungs, the left heart can suck enough blood from the
pulmonary circulation to sustain cardiac output for about
two beats.
FILTERING SMALL EMBOLI FROM THE BLOOD. The
mixed-venous blood contains microscopic emboli, small
particles (e.g., blood clots, fat, air bubbles) capable of
occluding a blood vessel. If these emboli were to reach
the systemic circulation and lodge in small vessels that
feed tissues with no collateral circulation, the consequences — over time — could be catastrophic. Fortunately,
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TABLE 25– 3
HANDLING OF AGENTS BY THE PULMONARY
CIRCULATION
UNAFFECTED
LARGELY REMOVED
PGA1 , PGA2 , PGI2
PGE1 , PGE2 , PGF2␣ , leukotrienes
Histamine, epinephrine,
dopamine
Serotonin
Bradykinin
Angiotensin II, arginine
vasopressin, gastrin,
oxytocin
Angiotensin I (converted to
angiotensin II)
From Levitzky MG: Pulmonary Physiology, 4th ed. New York,
McGraw-Hill, 1999.
the pulmonary vasculature can trap these emboli before
they have a chance to reach the left heart. If the emboli
are sufficiently few and small, the affected alveoli can
recover their function. Keep in mind that alveolar cells do
not need the circulation to provide them with O2 or
remove their CO2. In addition, after a small pulmonary
embolism, alveolar cells may obtain nutrients from anastomoses with the bronchial circulation. However, if pulmonary emboli are sufficiently large or frequent, they can
cause serious symptoms or even death. A liability of the
blood-filtration function is that emboli made up of cancer
cells may find the perfect breeding ground for supporting
metastatic disease.
15
BIOCHEMICAL REACTIONS. The entire cardiac output
passes through the lungs, exposing the blood to the tremendous surface area of the pulmonary capillary endothelium. It is apparently these cells that are responsible for
executing biochemical reactions that selectively remove
many agents from the circulation, while leaving others
unaffected (Table 25 – 3). Thus, the lung can be instrumental in determining which signalling molecules in the
mixed-venous blood reach the systemic arterial blood.
The pulmonary endothelium also plays an important role
in converting angiotensin I (a decapeptide) to angiotensin
II (an octapeptide), a reaction that is catalyzed by angiotensin converting enzyme (ACE) (see Chapter ??).
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Bouhuys A: The Physiology of Breathing. New York, Grune & Stratton,
1977.
Kellog RH: Laws of physics pertaining to gas exchange. In The American
Physiological Society Staff: Handbook of Physiology, Section 3: The
Respiratory System, Vol IV. Bethesda, MD, American Physiological
Society, 1985.
Macklem PT: Symbols and abbreviations. In The American Physiological
Society Staff: Handbook of Physiology, Section 3: The Respiratory
System, Vol I. Bethesda, MD, American Physiological Society, 1985.
Mason RJ, Williams MC: Alveolar type II cells. In Crystal RG, West JB:
The Lung. New York, Raven, 1991.
Satir P, Sleigh MA: The physiology of cilia and mucociliary interactions.
Annu Rev Physiol 52:137, 1990.
Schneeberger EE: Alveolar type I cells. In Crystal RG, West JB: The
Lung. New York, Raven, 1991.
Weibel ER: Lung cell biology. In The American Physiological Society
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I. Bethesda, MD, American Physiological Society, 1985.
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