add much oxygen to hemoglobin that is almost 100 percent satu-
rated. If poorly ventilated, diseased alveoli are perfused, they con-
tribute blood with low oxygen to the pulmonary vein and thus to
the general circulation. If increases in ventilation ensue in order
to compensate for this, the increase in
in the healthy part of
the lung does not add much oxygen to the blood from that region
because of the minimal increase in oxygen saturation. As blood
from these different areas of the lung mix in the pulmonary vein,
the net result is still deoxygenated blood (hypoxemia).
The situation for CO
, however, is very different. The
content curve is relatively linear because CO
ported in the blood mainly as highly soluble bicarbonate,
which does not reach saturating levels at physiological concentra-
tions. Therefore, although poorly ventilated areas of the lungs do
cause increases in the CO
content of the blood entering the pul-
monary vein, a compensatory increase in ventilation
content below normal in the blood from the well-ventilated
areas of the lung. The net result, as blood mixes in the pulmo-
nary vein in this case, is essentially normal arterial CO
. Thus, clinically signiﬁ cant ventilation-perfusion mis-
matching can lead to low arterial
The pathophysiology of emphysema, a major cause of hypoxia,
offers an excellent review of many basic principles of respira-
is characterized by the destruc-
tion of the alveolar walls leading to an increase in compliance.
Furthermore, there is atrophy and collapse of the lower air-
ways—those from the terminal bronchioles on down. The lungs
actually self-destruct, attacked by proteolytic enzymes secreted
by leukocytes in response to a variety of factors. Cigarette
smoking is by far the most important of these factors; it stimu-
lates the release of the proteolytic enzymes and destroys other
enzymes that normally protect the lung against them.
As a result of alveolar-wall loss, adjacent alveoli fuse to
form fewer but larger alveoli, and there is a loss of the pulmonary
capillaries that were originally in the walls. The merging of alve-
oli, often into huge balloon-like structures, reduces the
face area available for diffusion, and this impairs gas exchange.
Moreover, because the destructive changes are not uniform
throughout the lungs, some areas may receive large amounts of
air and little blood, while others show just the opposite pattern.
The result is marked ventilation-perfusion inequality.
In addition to problems in gas exchange, emphysema is
associated with a marked increase in airway resistance, which
greatly increases the work of breathing and, if severe enough,
may cause hypoventilation. This is why emphysema is classiﬁ ed,
as noted earlier in this chapter, as a “chronic
nary disease.” The airway obstruction in emphysema is caused by
the collapse of the lower airways. To understand this, recall that
two physical factors passively holding the airways open are the
transpulmonary pressure and the lateral traction of connective-
bers attached to the airway exteriors. Both of these fac-
tors are diminished in emphysema because of the destruction
of the lung elastic tissues, so the airways collapse.
increased airway resistance, decreased total area available for
diffusion, and ventilation-perfusion inequality. The result,
particularly of the ventilation-perfusion inequality, is always
some degree of hypoxia. As explained above, an increase in
will not occur until the disease becomes exten-
sive and prevents increases in alveolar ventilation.
Acclimatization to High Altitude
Atmospheric pressure progressively decreases as altitude increases.
Thus, at the top of Mt. Everest (approximately 29,000 ft, or
9000 m), the atmospheric pressure is 253 mmHg, compared to
760 mmHg at sea level. The air is still 21 percent oxygen, which
means that the inspired
is 53 mmHg (0.21
Therefore, the alveolar and arterial
must decrease as persons
ascend unless they breathe pure oxygen. The highest villages
permanently inhabited by people are in the Andes at 19,000 ft
(5700 m). These villagers work quite normally, and the only
major precaution they take is that the women descend to lower
altitudes during late pregnancy.
The effects of oxygen deprivation vary from one individ-
ual to another, but most people who ascend rapidly to altitudes
above 10,000 ft experience some degree of
). This disorder consists of
breathlessness, headache, nausea, vomiting, insomnia, fatigue,
and impairment of mental processes. Much more serious is the
appearance, in some individuals, of life-threatening pulmo-
nary edema, which is the leakage of ﬂ uid from the pulmonary
capillaries into the alveolar walls and eventually the airspaces
themselves. Brain edema can also occur. Supplemental oxygen
and diuretic therapy are used to treat mountain sickness.
Over the course of several days, the symptoms of mountain
sickness usually disappear, although maximal physical capacity
remains reduced. Acclimatization to high altitude is achieved
by the compensatory mechanisms listed in
Acclimatization to the Hypoxia
of High Altitude
1. The peripheral chemoreceptors stimulate ventilation.
2. Erythropoietin, a hormone secreted by the kidneys,
stimulates erythrocyte synthesis, resulting in increased
erythrocyte and hemoglobin concentration in blood.
3. DPG increases and shifts the hemoglobin dissociation curve
to the right, facilitating oxygen unloading in the tissues.
However, this DPG change is not always adaptive and may
be maladaptive. For example, at very high altitudes, a right
shift in the curve impairs oxygen
in the lungs,
an effect that outweighs any beneﬁ t from facilitation of
in the tissues.
4. Increases in capillary density (due to hypoxia-induced
expression of the genes that code for angiogenic factors),
number of mitochondria, and muscle myoglobin occur, all
of which increase oxygen transfer.
5. The peripheral chemoreceptors stimulate an increased loss
of sodium and water in the urine. This reduces plasma
volume, resulting in a concentration of the erythrocytes and
hemoglobin in the blood.