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Castellana G, Castellana R, Fanelli C, Lamorgese V, and Florio C
(2003) La microlitiasi alveolare polmonare: decorso clinico e
radiologico, convenzionale e HRCT, in tre casi. Ipotesi di classificazione radiologica della malattia. La Radiologia Medica 106:
160–168.
Castellana G, Gentile M, Castellana R, Fiorente F, and Lamorgese
V (2002) Pulmonary alveolar microlithiasis: clinical features,
evolution of the phenotype, and review of the literature. American Journal of Medical Genetics 111: 220–224.
Castellana G and Lamorgese V (1997) La microlitiasi endoalveolare
polmonare. Caso clinico a sostegno dell’ipotesi ereditaria. Rassegna Di Patologia Dell’Apparato Respiratorio 12: 247–251.
Castellana G and Lamorgese V (1998) La microlitiasi alveolare
polmonare: rivisitazione della casistica italiana. Rassegna Di
Patologia Dell’Apparato Respiratorio 13: 405–407.
Castellana G and Lamorgese V (2003) Pulmonary alveolar microlithiasis. World cases and review of the literature. Respiration
70: 549–555.
Chang YC, Yang PC, Luh KT, Tsang YM, and Su CT (1999)
High-resolution computed tomography of pulmonary alveolar
microlithiasis. Journal of Formosan Medical Association 98:
440–443.
Chinachoti N and Tangchai P (1957) Pulmonary alveolar microlithiasis associated with inhalation of snuff in Thailand. Diseases of the Chest 32: 687–689.
Edelman JD, Bavaria J, Kiaser LR, et al. (1997) Bilateral sequential
lung transplantation for pulmonary alveolar microlithiasis.
Chest 112: 1140–1144.
Mariotta S, Ricci A, Papale M, et al. (2004) Pulmonary alveolar
microlithiasis: report on 576 cases published in the literature. Sarcoidosis, Vasculitis, and Diffuse Lung Diseases 21:
173–181.
Moran CA, Hochholzer L, Hasleton PS, Johnson FB, and Koss
MN (1997) Pulmonary alveolar microlithiasis. A clinicopathologic and chemical analysis of seven cases. Archives of Pathology & Laboratory Medicine 121: 607–611.
Perosa L and Ramunni M (1959) La microlitiasi endoalveolare del
polmone. Recenti Progressi in Medicina 26: 353–429.
Senyigit A, Yaramis A, Gurkan F, et al. (2001) Pulmonary alveolar
microlithiasis: a rare familial inheritance with report of six cases
in a family. Respiration 68: 204–209.
Sosman MC, Dodd GD, Jones WD, and Pillmore GU (1957) The
familial occurrence of pulmonary alveolar microlithiasis. American Journal of Roentgenology 77: 947–1012.
Sosman MC, Dodd GD, Jones WD, and Pillmore GU (2004) The
familial occurrence of pulmonary alveolar microlithiasis. Lung
Disease 21: 173–181.
Ucan ES, Keyf AI, Aydilek R, et al. (1993) Pulmonary alveolar microlithiasis: review of Turkish reports. Thorax 48:
171–173.
PULMONARY CIRCULATION
L A Shimoda, Johns Hopkins School of Medicine,
Baltimore, MD, USA
Anatomy, Structure, Histology of
the Pulmonary Circulation
& 2006 Elsevier Ltd. All rights reserved.
Abstract
The pulmonary vasculature is unique, both in volume and function. The pulmonary circulation, a low-pressure vascular bed
that accommodates the entire cardiac output, carries the mixed
venous blood to the alveoli, where gas exchange occurs, and
then back to the left heart for distribution of oxygenated blood
to the rest of the tissues in the body. As compared with the
systemic circulation, the pulmonary arteries have thinner walls
with much less vascular smooth muscle. Moreover, in order to
maintain the low pulmonary arterial pressure, normal pulmonary vascular resistance is approximately one-tenth that of the
systemic circulation. Factors that control pulmonary blood flow
include vascular structure, gravity, mechanical effects of breathing, and the influence of neural and humoral factors. A unique
aspect of the pulmonary circulation is the pressor response to
hypoxia, as the systemic circulation dilates in response to decreased oxygen concentrations. In addition to gas exchange, the
pulmonary circulation also serves to filter the blood, removing
microemboli, and participates in the metabolic regulation of a
variety of vasoactive hormones. Several diseases can affect the
function of the pulmonary circulation, including primary and
secondary pulmonary hypertension, arteriovenous malformation, embolism, and fibrotic lung disease.
The pulmonary circulation encompasses the circuit
by which deoxygenated blood from the right heart
enters the lungs via the pulmonary arteries, is channeled through the alveolar/capillary units where the
blood is oxygenated, and is returned to the left side
of the heart by the pulmonary veins for distribution
to the systemic circulation.
The anatomy of the pulmonary circulation differs in
several respects from that of the systemic circulation.
Blood exits the right ventricle into the main pulmonary artery, the diameter of which is similar to that of
the aorta, but it has thinner walls. During gestation
and immediately following birth, the pulmonary artery is nearly identical to that of the aorta, but, postnatally, the elastic tissue gradually diminishes.
The main pulmonary artery divides into the right
and left main branches. Each main branch further
divides to supply each lobe before entering the lung.
Within the lung, each lobar artery subdivides into
rather irregular branches corresponding to the bronchial tree. The close proximity of the pulmonary
arteries and airways underscores the relationship
538 PULMONARY CIRCULATION
between ventilation and perfusion that defines the
normal function of the lung. The large pulmonary
arteries (43000 mm in diameter) are classified as
elastic, with the media comprised primarily of elastic
fibers and some smooth muscle. As vascular diameter
decreases these elastic arteries gradually give rise to
vessels with increased smooth muscle content. In
general, arteries between 3000 and 150 mm in diameter can be considered muscular arteries, but are
still more thin walled than systemic arteries of the
same diameter. Pulmonary arteries also exhibit a thin
intima comprised of endothelial cells, collagen, and
fibroblasts and a longitudinal elastic lamina, which
allows for expansion during inspiration.
The small arterioles have a nonuniform smooth
muscle cell layer, giving way to the small nonmuscular preacinar arterioles, which are located proximal to terminal bronchi. At the alveoli, the terminal
arterioles break into a network of pulmonary capillaries within the alveolar walls. The capillaries have a
very thin wall (approximately 2 mm) consisting of a
single layer of endothelial cells and contain most
of the surface area of the pulmonary vasculature.
Indeed, the maximal surface area of the capillary
network is approximately 20 times that of the rest of
the pulmonary circulation.
Gas exchange between the alveolar gas and blood
takes place within the pulmonary capillary bed after
which the blood flows into venules, which are indistinguishable in structure from arterioles. However,
while each small arteriole supplies a specific unit of
respiratory tissue, the venules drain several portions
of the lung. Venules do not follow the bronchial tree
and unite to form the pulmonary veins, which conduct the oxygenated blood into the left ventricle.
Although 99% of the lung blood flow passes
through the pulmonary circulation, 1% is carried by
the bronchial circulation, which supplies oxygenated
blood from the systemic circulation to the lung. Similar to the pulmonary circulation, branching of the
intrapulmonary bronchial arteries along the length
of the bronchial tree results in a vast network of
capillaries, which form extensive anastomoses with
the pulmonary vasculature. Owing to these multiple
connections with the pulmonary circulation, the
deoxygenated bronchial venous blood drains via pulmonary veins to the left heart, producing an anatomic right-to-left shunt.
The small pulmonary vessels, including the capillaries, can be subdivided into extra-alveolar or alveolar based on the pressures to which they are
subjected. In addition to the intravascular pressure,
vessels in the lung are exposed to alveolar pressure
and pressure exerted by lung tissue connections. Both
of these forces increase with lung inflation; however,
they act in opposite directions, with alveolar pressure
directed inward and tissue pressure directed outward. The alveolar vessels are surrounded by alveolar pressure, due to localization within the septal
wall. The extra-alveolar vessels are surrounded by
septa and are typically contained in a sheath of connective tissue. In addition to the effects of alveolar
pressure, the connection of these vessels to lung parenchyma subjects them to substantial tissue forces.
These vessels include a subset of the pulmonary capillaries called the corner vessels, which are located in
the alveolar parenchyma at the alveolar corners.
Pulmonary Circulation in Normal Lung
Function
Physiological Function
The pulmonary vasculature is unique, both in capacity and function. Responsible for several physiological functions, the primary function of the pulmonary
circulation is exchange of gases, adding oxygen and
removing carbon dioxide from mixed venous blood.
Under normal conditions, gas exchange occurs primarily in the alveolar capillaries, where blood flow
rapidly equilibrates with the alveolar air. The average
transit time for red blood cells within the capillary
network is approximately 0.5–1 s. Since the volume
of the capillary bed is roughly equal to stroke volume, the entire capillary volume is exchanged with
each heartbeat.
In addition to gas exchange, the lung also filters
the blood, preventing thrombi and other microemboli from entering the systemic circulation. Moreover, since the entire circulating blood flow passes
through the lungs, the pulmonary circulation plays
an important role in performing metabolic functions.
For example, the pulmonary endothelium contains
an abundance of angiotensin-converting enzyme, and
is the major site in the body for conversion of angiotensin I to the active vasopressor angiotensin II
(ANG II) and, conversely, for inactivation of the
vasodilator bradykinin. Other functions include supplying nutrients to the alveoli and acting as a blood
reservoir to transiently support left ventricle output
during periods of decreased right ventricular output.
Regulation of Blood Flow
Vascular resistance The pulmonary circulation is
the only circulation in the body to conduct the entire
cardiac output, and the only one in which the arteries
carry oxygen poor blood. In utero, oxygen is delivered to the fetus via the placenta and the pulmonary
circulation is a high-resistance circuit, with little
blood flow. Perinatally, with the commencement of
PULMONARY CIRCULATION 539
ventilation, pulmonary vascular resistance falls, and
blood flow increases 10-fold. In the adult, normal
pulmonary artery pressures are approximately 25
mmHg systolic and 10 mmHg diastolic, while pulmonary venous pressure is approximately 9 mmHg.
Given the relationship between blood flow, pressure,
and resistance, which by Ohm’s law is defined as:
pulmonary arterial venous pressure
¼ pulmonary blood flow=pulmonary
vascular resistance
and the large volume of blood flow that must be
accommodated (approximately 5 l min 1 at rest), the
low pulmonary arterial pressure required to maximize the efficiency of the right ventricle work load
must be maintained by low pulmonary vascular resistance, which is approximately one-tenth that of
the systemic circulation.
In the normal lung, significant increases in cardiac
output have very little effect on pulmonary artery
pressure. Indeed, a rapid 30% change in volume in
moving from lying to standing, or a doubling of
blood flow during exercise, can be accommodated
with little rise in pulmonary arterial pressure. In order
to maintain this low-pressure system, increases in
cardiac output must be balanced by a reduction in
pulmonary vascular resistance (Figure 1). This is possible because the pulmonary vasculature is highly
distensible and possesses a significant reserve capacity. Decreases in pulmonary vascular resistance in response to increases in blood flow are not mediated by
alterations in vascular tone, but are due to two passive processes: recruitment and distension (Figure 2).
With an increase in blood flow, pressure rises transiently and opens or recruits capillaries and other
small vessels that had been closed during resting
conditions due to insufficient intravascular pressure.
This increase in vascular pressure also causes distension or expansion of individual capillaries. Both of
these processes reduce pulmonary vascular resistance
and minimize any flow-induced increase in pulmonary vascular pressure.
Lung volume The resistance of both the alveolar
and extra-alveolar vessels is affected by alveolar volume. Since these vessels are exposed to different surrounding pressures, their resistance is differentially
regulated by changes in lung volume, leading to a
complex relationship between lung volume and pulmonary vascular resistance (Figure 3). The extraalveolar vessels are positioned such that they become
enlarged with increased lung volume (i.e., during inspiration) due to the fall in pleural pressure, which
results in increased transmural pressure, and the pull
exerted by the alveolar septa. Conversely, the increase in alveolar volume during inspiration results
in greater air pressure compared to vascular pressure
Distension
Recruitment
Pulmonary vascular
resistance
Figure 2 Schematic demonstrating the effects of recruitment
and distension on capillary flow.
Pulmonary vascular
resistance
Total
Alveolar
Extra-alveolar
Mean pulmonary arterial
pressure
Figure 1 Diagram illustrating the inverse relationship between
pulmonary arterial pressure and resistance.
Lung volume
Figure 3 Variation in pulmonary vascular resistance as a function of lung volume.
540 PULMONARY CIRCULATION
and stretches the alveolar walls, causing the pulmonary capillaries to be compressed and elongated, thus
increasing the resistance of these vessels. During
expiration, lung volume falls and the process is reversed. Below functional residual capacity (FRC),
extra-alveolar resistance is high due to lack of tension in the parenchyma, while above FRC the alveolar vessels collapse and the net effect of alveolar and
extra-alveolar changes is that pulmonary vascular
resistance increases with lung inflation. Thus, pulmonary vascular resistance is lowest near FRC and
progressively rises with both increasing and decreasing lung volume.
Blood flow heterogeneity Within the lung, blood
flow is not uniform. The distensibility, compressibility, and low intravascular pressure that characterize
the pulmonary circulation cause pulmonary blood
flow and pulmonary vascular resistance to be influenced by factors that are independent of vascular
smooth muscle tone, including both gravitational
and structural factors. For example, within a column
of fluid, the weight of the fluid exerts a higher pressure at the bottom than near the top. Similarly, in
upright individuals, the vertical height of the lung is
approximately 24 cm (at FRC), and while alveolar
pressure is fairly uniform throughout the lung,
intravascular pressure increases in the bottom (dependent) portions of the lungs due to gravity-dependent hydrostatic effects. This pressure gradient
causes progressive vascular distension, decreased resistance, and increased flow at the bottom (base) of
the lung.
Based on the relationship between pulmonary arterial pressure (PPA), pulmonary venous pressure
(PV), and alveolar pressure (Palv), the lung can be
divided into three zones (Figure 4). In zone 1,
hydrostatic effects cause both arterial and venous
pressures to fall below alveolar pressure such that
Palv4PPA4PV and the alveolar vessels are completely collapsed, restricting blood flow to only the
corner vessels. Under zone 2 conditions, PPA4
Palv4PV and the alveolar vessels are partially collapsed and the driving force for flow is the pressure
gradient between arterial and alveolar pressures
(PPA–Palv). In zone 3, PPA4PV4Palv, all of the alveolar blood vessels are fully open, and blood flow is
driven by the difference between pulmonary arterial
and venous pressure (PPA PV). In a seated or standing normal subject, zone 1 conditions are typically
absent but, if present, will be found at the apex of
the lung. Conversely, at the bottom of the lung,
blood flow is greatest and zone 3 conditions are
present, while zone 2 conditions can be found in the
mid-lung.
In addition to gravitational forces, the extent and
location of the lung zones vary with body position. In
a supine subject, zone 1, if present, will be in the
ventral portion of the lungs while flow increases to
the anatomically dependent (dorsal) regions of the
lungs, resulting in zone 3. When a subject lies on their
side, blood flow increases to the dependent lung. In
certain cases, alveolar pressure may exceed vascular
pressure in the nondependent portions of the lung.
For example, zone 1 and 2 regions can be created
and/or increased during hemorrhage or hypovolemia,
Zone 1
Palv>PPA>PV
PPA>Palv>PV
Height
Zone 2
Zone 3
PPA>PV>Palv
Blood flow
Figure 4 Diagram illustrating the zone 3 model describing regional variation in pulmonary blood flow. PPA, arterial pressure; PV,
venous pressure; Palv, alveolar pressure. Adapted from West JB, Dollery CT, and Naimark A (1964) Distribution of blood flow in isolated
lung: relation to vascular and alveolar pressures. Journal of Applied Physiology 19: 713–724.
PULMONARY CIRCULATION 541
which result in low intravascular pressures, or during
positive pressure ventilation or forced expiration,
where alveolar pressure is increased.
Regional blood flow differences can exist even between alveoli with similar vertical position, indicating that blood flow heterogeneity is not entirely
dependent on the effects of gravity. At the microvascular level, the branching nature of the pulmonary
vascular tree results in structural heterogeneities
within isogravitational planes, producing variations
in local driving pressures and resistances. This heterogeneity in driving pressure creates gravity-independent differences in regional pulmonary blood flow.
Regulation of Pulmonary Vascular Tone
Factors that influence vascular smooth muscle cell
tone, including neural and circulating factors and
oxygen concentration, are potent regulators of both
pulmonary vasomotor responses and vascular caliber.
Nervous control The pulmonary circulation is supplied with both sympathetic and parasympathetic innervation. In general, increased sympathetic activity
leads to release of catecholamines (e.g., dopamine,
norepinephrine, epinephrine, and neuropeptide Y)
that cause vasoconstriction and an increase in pulmonary vascular resistance. Pulmonary arteries contain fewer cholinergic than adrenergic nerve fibers.
Parasympathetic stimulation causes the release of
acetylcholine and vasoactive intestinal polypeptide,
which mediate vascular dilation and a decrease in
pulmonary vascular resistance. The lung also contains nonadrenergic, noncholinergic nerves that can
be excitatory (e-NANC) or inhibitory (i-NANC). Release of vasoactive intestinal peptide, calcitonin generelated peptide, substance P, and nitric oxide from
i-NANC nerves mediates vasodilation, while the
e-NANC nerves mediate vasoconstriction, although
the neurotransmitter involved remains unclear.
Curiously, in contrast to the systemic vasculature,
there appears to be minimal nervous control in the
pulmonary circulation with respect to basal vascular
caliber. Moreover, while the existence and activity of
e-NANC and i-NANC nerves have been demonstrated in vitro, regulation of tone in vivo by these
nerves has not been demonstrated. However, stimulation of adrenergic nerves may modulate pulmonary
vascular resistance and blood flow during exercise
and cold exposure and may increase in regulatory
contribution during pathological states, particularly
during pulmonary edema and embolism.
Humoral factors A number of humoral factors
can participate in active regulation of pulmonary
vascular tone. Some of these factors are endogenous,
derived from the vascular endothelium, while others
are produced by circulating cells or in other vascular
beds. If the changes in vasomotor tone induced by
these factors are not uniform, significant redistribution of blood flow can occur.
Vasodilators Factors that induce pulmonary vasodilation include nitric oxide and nitrites, adenosine,
bradykinin, atrial natriuric factor (ANP), and the
eicosanoids prostaglandin E1 (PGE1) and PGI2 (prostacyclin). Nitric oxide and PGI2 are produced by the
endothelium and are the most studied of the pulmonary vasodilators. Both have a short half-life and are
quickly metabolized. Thus, neither is suited for action as a circulating factor and instead, once released
by endothelial cells, quickly diffuse to the underlying
smooth muscle and cause relaxation via stimulation
of cGMP and cAMP. Bradykinin, a product of the
renin–angiotensin system, exerts its dilatory influence by stimulating nitric oxide release. Indeed,
in vitro, removal of the endothelium results in a loss
of dilation in response to bradykinin, with vasoconstriction observed in some cases due to activation of
receptors on the smooth muscle.
ANP is a peptide produced primarily by stretch of
the right heart, as occurs with an increase in pulmonary artery pressure. Given that the pulmonary circulation is the first vascular bed to see ANP, it is not
surprising that plasma levels of ANP are 30% greater
in the pulmonary than systemic circulation. Additionally, pulmonary arteries appear to be significantly more sensitive to the vasodilatory effects of
ANP than arteries from other vascular beds.
Although all of the aforementioned factors have
been demonstrated to produce changes in vasomotor
tone, only PGI2 and nitric oxide appear to regulate
basal pulmonary vascular tone in the normal lung.
Under pathological conditions, however, modulation
of tone may be more pronounced.
Vasoconstrictors Pulmonary vasoconstriction is
caused by serotonin, endothelin-1 (ET-1), ANG II,
histamine, and prostaglandins. Several of these factors are derived from the vascular endothelium. For
example, arachidonic acid, which is readily taken up
in the pulmonary circulation, is metabolized into a
number of vasoactive eicosanoids, including PGE2,
PGF2a, thromboxane, and leukotrienes, all of which
diffuse to the smooth muscle and cause contraction.
The lung endothelium is also the primary site of
metabolism of angiotensin I, with approximately 60–
80% of plasma angiotensin I converted to ANG II,
the vasoactive form of the peptide, in a single pass
through the pulmonary circulation. ET-1 is perhaps
542 PULMONARY CIRCULATION
2% O2
PPA (mmHg)
30
25
20
15
10
15
PPA
10
Pt
5
0
Hypoxia One of the most unique aspects of the
pulmonary circulation is the hypoxic pressor response. Unlike the systemic vasculature, which dilates in response to hypoxia in order to increase
blood flow and oxygen delivery to tissues, alveolar
hypoxia causes profound pulmonary vasoconstriction. Pulmonary vascular resistance rapidly increases
as oxygen tension decreases, beginning within 1–
2 min after a drop in oxygen levels and reaches maximal response within 5 min (Figure 5). Hypoxic
pulmonary vasoconstriction is maintained for the
duration of hypoxia, and rapidly reverses (within
1 min) with a return to normoxia. When hypoxia is
localized, this mechanism is thought to divert blood
flow from regions of the lung that are poorly ventilated, helping to maintain arterial oxygen tension.
However, in chronic lung disease, where alveolar
hypoxia is global and prolonged, pulmonary hypertension develops.
The exact mechanism underlying the hypoxiainduced increase in pulmonary vascular tone is unknown. Several factors have been shown to modulate
the response, including prostaglandins, ANG II, serotonin, and leukotrienes, although these have all
been ruled out as mediators of the response. Hypoxia
has a direct effect on pulmonary vascular smooth
muscle, although the maximal contractile response
requires alterations in the release of the endothelial
cell-derived mediators nitric oxide (decreased) and
ET-1 (increased). Hypoxic pulmonary vasoconstriction is not mediated through the autonomic nervous
system, as the response can be observed in isolated,
perfused lungs that lack nervous input.
Although the large pulmonary arteries are capable
of responding to hypoxia, it is generally accepted
5 min
(a)
P (mmHg)
the most potent endogenous vasoconstrictor in the
lung. While ET-1 can elicit nitric oxide production
and transient dilation when receptors on the endothelial cells are activated, its main action is vasoconstriction mediated by receptors on the smooth
muscle cells. Synthesized in the pulmonary endothelium, ET-1 secretion has been shown to increase in
response to shear stress and hypoxia. Indeed, enhanced ET-1 levels are believed to contribute to the
development of pulmonary hypertension.
Circulating cells are also an important source of
vasoconstrictors that can act on the pulmonary circulation, including serotonin, a primary product of
activated platelets, and histamine, produced by mast
cell granules. While these factors do not appear to be
involved in basal regulation of tone, vasoconstrictors
can modulate tone under pathological conditions,
such as in pulmonary hypertension induced by anorexic agents, where serotonin uptake is impaired.
10 s
(b)
Figure 5 (a) Effect of hypoxia on pulmonary arterial pressure in
an isolated perfused rat lung model. In this preparation, left atrial
pressure is negative and changes in pulmonary arterial pressure
reflect changes in pulmonary vascular resistance. (b) Expanded
scale showing the effect of ventilation on pulmonary arterial
pressure. PPA, arterial pressure; Pt, tracheal pressure. Courtesy
of J T Sylvester.
that the main site of increased resistance during
hypoxic pulmonary vasoconstriction is in the small,
muscular arterioles. There is evidence that postcapillary hypoxic venoconstriction may also occur, although the magnitude of the contribution of these
vessels to the increase in total pulmonary vascular
resistance is uncertain.
Our understanding of the pulmonary circulation
has been greatly aided by evaluation of pulmonary
function in a variety of species, including sheep, rats,
dogs, cats, ferrets, mice, cattle, guinea pigs, goats,
and rabbits. Despite the obvious size differences, the
pulmonary circulation across species is quite similar.
For example, all mammals respond to hypoxic challenge with HPV, although the degree of the response
varies from minor (rabbits) to robust (cattle). In developing animal models of human disease, the most
widely used is the mouse. Although the mouse appears to lack a bronchial circulation, major advantages of this model include small size and ease of
maintenance, quick availability, and reduced genetic
variability. Perhaps the most important advantage of
murine models is the ability to alter gene expression,
providing a powerful tool to explore the functional
role of specific proteins in physiological and pathophysiological conditions.
PULMONARY CIRCULATION 543
Pulmonary Circulation in Respiratory
Diseases
obstructive sleep apnea, may also result in pulmonary hypertension.
Primary Pulmonary Hypertension
Interstitial Lung Disease
Pulmonary vascular disease may be primary or secondary to other disorders of the lung or other organs.
Primary pulmonary hypertension (PPH), also known
as idiopathic pulmonary arterial hypertension, is
a disease of unknown etiology, although certain cases
have been linked to appetite suppressants. PPH is
characterized by an elevated resting pulmonary artery pressure that increases dramatically during exercise. Increased pulmonary vascular resistance, due
in part to pulmonary arteriolar obstruction with
hypertrophy of wall elements, necrotizing arteritis,
and/or endothelial cell lesions increases pulmonary
arterial pressure, causing right ventricular hypertrophy in the absence of any other cardiac abnormality.
Although the underlying cause of PPH remains unclear, dysfunction of the pulmonary endothelium,
which is a rich source of both vasodilators and vasoconstrictors, may contribute. In the normal lung, the
balance of vasodilators to vasoconstrictors favors
low pulmonary vascular resistance. However, with
endothelial cell dysfunction, release of the vasodilators nitric oxide and PGI2 is impaired while release of
the vasoconstrictors ET-1 and thromboxane may be
augmented, resulting in a net vasoconstriction. In
addition, excessive endothelial cell proliferation may
obliterate the lumen of small arteries and alveolar
vessels, further increasing vascular resistance.
Interstitial lung disease refers to a diverse group of
diseases with the common feature of alterations in
the alveolar interstitial space, most commonly septal
destruction and fibrosis. While interstitial lung disease will produce fibrosis of the vessels, early in the
disease process only a small part of the pulmonary
arterial tree is involved, and hypoxemia during exercise, due to reduced diffusion capacity and/or ventilation–perfusion mismatch, is commonly the only
alteration in lung function. As the disease progresses
to later stages, resting hypoxemia may be observed
along with subsequent pulmonary hypertension.
Secondary Pulmonary Hypertension
Secondary pulmonary hypertension and right heart
failure are common complications of chronic lung
diseases, including emphysema, chronic bronchitis,
cystic fibrosis, and severe chronic asthma. In this
case, elevated pulmonary arterial pressure is caused
by a combination of hypoxic pulmonary vasoconstriction, polycythemia, alveolar hypercapnia and
acidosis, and raised intra-alveolar pressure during
expiration. Global hypoxemia is also a consequence
of residence at high altitude. The decrease in vascular
caliber associated with prolonged hypoxia is comprised of both a reversible and fixed component. The
reversible component is due to sustained active contraction of the pulmonary vascular smooth muscle
while the fixed component is due to structural remodeling of the pulmonary circulation, primarily
increased muscularization of the small pulmonary
arteries. In addition to chronic lung diseases that
produce continuous alveolar hypoxia, in recent
years it has become clear that prolonged exposure to intermittent hypoxic episodes, as occurs in
Pulmonary Edema
Pulmonary edema can occur as a consequence of
heart failure or lung microvascular injury and leads
to an increase in vascular resistance. With left ventricular failure, elevated diastolic pressure results in
elevated pulmonary venous pressure, which interferes with normal capillary blood flow and increases
capillary pressure. The accumulation of fluid in the
interstitial compartment around the vessels can lead
to impaired gas exchange or, more commonly, can
exaggerate the effects of lung volume on vascular
resistance and affect blood flow distribution. In more
severe cases, when the interstitial spaces are filled,
or when the endothelial lining of the lung microvasculature is injured, alveolar flooding can occur.
In either case, excess fluid in the alveoli results in
marked deterioration in gas exchange. In some cases,
alterations in vasomotor tone can cause edema, independent of microvascular injury or cardiac function. For example, excessive vasoconstriction in
response to hypoxia is believed to be the underlying
cause of high-altitude pulmonary edema.
Arteriovenous Malformation and Stenosis
A pulmonary arteriovenous malformation is a direct
communication between a pulmonary artery and a
pulmonary vein producing a right-to-left shunt. These
malformations can occur as a consequence of liver
dysfunction, genetic abnormalities, as with Osler–
Weber–Rendu disease, or are idiopathic. Pulmonary
arteriovenous malformations are not uncommon, and
in one-third of cases, are multiple. In addition to
pulmonary hypotension, capillary dilation and extensive shunting results in impaired gas exchange and
hypoxemia.
Pulmonary vascular stenoses, although rare, occur
most commonly at the bifurcation of the main
544 PULMONARY EDEMA
pulmonary artery. The increase in pulmonary vascular resistance caused by the narrowing of the artery
results in right ventricular hypertension. Stenoses in
the left heart valves lead to passive pulmonary venous hypertension. The elevation in venous pressure
results in elevated capillary and arterial pressures.
Pulmonary Embolism
Pulmonary embolism is perhaps the most common
pulmonary vascular disease. Clots originate in the
systemic veins, often in the deep veins of the lower
extremities, and formation is augmented following
injury, venous stress, and hypercoagulable states. The
thrombi detach and become lodged in the pulmonary
arterial circulation. Occasionally, the right side of
the heart is a source of a pulmonary embolus. Given
the large reserve capacity of the pulmonary capillaries, many thromboemboli can go undiagnosed, and
resolve quickly. Massive blockages produce a functional decrease in cross-sectional area of the pulmonary circulation, resulting in a significant increase in
pulmonary vascular resistance and elevated pulmonary arterial pressure. Subsequent right ventricular
strain decreases cardiac output and, if severe, can
result in death. In approximately one-tenth of patients, large thromboemboli cause local cessation of
flow and ischemic necrosis of the lung parenchyma
(pulmonary infarction).
See also: Bronchial Circulation. Diffusion of Gases.
Endothelial Cells and Endothelium. High Altitude,
Physiology and Diseases. Hypoxia and Hypoxemia.
Oxygen–Hemoglobin Dissociation Curve. Peripheral
Gas Exchange. Pulmonary Vascular Remodeling.
Smooth Muscle Cells: Vascular. Ventilation: Uneven.
Ventilation, Perfusion Matching.
Further Reading
Bakhle YS and Vane JR (1974) Pharmacokinetic function of the
pulmonary circulation. Physiological Reviews 54(4): 1007–1045.
Crofton J and Douglas A (eds.) (1975) The pulmonary circulation.
In: Respiratory Diseases, 2nd edn., pp. 34–37. Philadelphia:
Lippincott Co.
Crystal RG, West JB, Weibel ER, and Barnes PJ (eds.) (1997) The
Lung: Scientific Foundations, 2nd edn., sect. 5. New York:
Lippincott-Raven.
Dawson CA (1984) Role of pulmonary vasomotion in physiology
of the lung. Physiological Reviews 64(2): 544–616.
Hlastala MP and Glenny RW (1999) Vascular structure determines
pulmonary blood flow distribution. News in Physiological Sciences 14: 182–186.
Keith IM (2000) The role of endogenous lung neuropeptides in
regulation of the pulmonary circulation. Physiological Research
49(5): 519–537.
McMurtry IF (1986) Humoral control. In: Bergofsky EH (ed.)
Abnormal Pulmonary Circulation, pp. 83–125. New York:
Churchill-Livingstone.
Nadel JF and Nadel JA (eds.) (1988) Textbook of Respiratory
Medicine. Philadelphia: WB Saunders.
Peacock AJ (ed.) (1966) Pulmonary Circulation. London: Chapman and Hall Medical.
Sylvester JT and Brower RG (1990) Pulmonary blood flow. In:
Stein JH (ed.) Internal Medicine, 3rd edn., pp. 583–586. Boston:
Little, Brown and Co.
Ward JPT and Aaronson PI (1999) Mechanisms of hypoxic pulmonary vasoconstriction: can anyone be right? Respiratory
Physiology 115(3): 261–271.
West JB, Dollery CT, and Naimark A (1964) Distribution of blood
flow in isolated lung: relation to vascular and alveolar pressures.
Journal of Applied Physiology 19: 713–724.
PULMONARY EDEMA
M A Matthay and T E Quinn, University of California,
San Francisco, CA, USA
& 2006 Elsevier Ltd. All rights reserved.
Abstract
Pulmonary edema refers to the abnormal collection of fluid in
the extravascular spaces of the lung such as the interstitium and
the alveoli. Its two main pathophysiologic mechanisms are increased hydrostatic forces within the lung microvasculature and
increased microvascular permeability. Understanding the pathophysiology of pulmonary edema requires a firm understanding
of normal lung fluid balance. The Starling equation, which describes the net flow of fluid across a semipermeable membrane,
applies to the filtration of fluid from the pulmonary microvasculature into the pulmonary interstitium. Interstitial fluid is
primarily removed by the lung lymphatic vessels, and alveolar
fluid is removed via active transport mechanisms. Pulmonary
edema occurs because of either increased hydrostatic forces or
increased vascular permeability which then causes an increase in
fluid filtration sufficient to overwhelm fluid removal mechanisms. The treatment of hydrostatic pulmonary edema targets a
reduction in pulmonary microvascular pressure with diuretics,
vasodilators, and sometimes inotropic agents. The treatment of
increased permeability pulmonary edema is mainly supportive.
Mechanical ventilation of patients with increased permeability
pulmonary edema should be performed with a low tidal volume,
lung-protective strategy.
Introduction
Pulmonary edema refers to the abnormal collection
of fluid in the extravascular spaces of the lung such
as the interstitium and the alveoli. Its two main