144

Acute Respiratory Distress Syndrome:

Pathogenesis
Michael A. Matthay

I. PATHOPHYSIOLOGY OF PULMONARY EDEMA Role of Inflammation

IN ACUTE LUNG INJURY Role of Direct Toxicity
Vascular Fluid and Protein Exchange Biologic Markers
Increased Permeability Pulmonary Edema III. VENTILATOR-ASSOCIATED LUNG INJURY
Lung Physiology
Animal Studies
II. MECHANISMS OF ACUTE LUNG INJURY Clinical Studies
Path ological Findings IV. RESOLUTION OF LUNG INJURY
Mediators
Role of Infection V. CONCLUSIONS

This chapter focuses on the pathogenesis of acute lung injury where

(ALI) and the acute respiratory distress syndrome (ARDS).
Chapter 145 discusses clinical features and clinical manage-
ment.
PATHOPHYSIOLOGY OF PULMONARY
EDEMA IN ACUTE LUNG INJURY
Pulmonary edema occurs when fluid is filtered into the lungs
faster than it can be removed. Accumulation of fluid may have
major consequences on lung function because efficient gas
exchange cannot occur in fluid-filled alveoli. Lung structure
relevant to edema formation and the forces governing fluid
and protein movement in the lungs has been the subject of
classic and more recent reviews and chapters, as noted in the
“Suggested Reading” included at the end of this discussion.
Vascular Fluid and Protein Exchange
The essential factors that govern fluid exchange in the lungs
are expressed in the Starling equation for the microvascular
barrier:
Jv = LpS[(Pc − Pi) − σd(πc − πi)] (1)
Jv = the net fluid-filtration rate (volume flow) across
the microvascular barrier
Lp = the hydraulic conductivity (“permeability”) of the
microvascular barrier to fluid filtration (a mea-
sure of how easy it is for water to cross the barrier)
S = the surface area of the barrier
Pc = the pulmonary capillary (microvascular) hydro-
static pressure
Pi = the interstitial (“perimicrovascular”) hydrostatic
pressure
πc = the capillary (microvascular) plasma colloid
osmotic (or oncotic) pressure
πi = the interstitial (perimicrovascular) fluid osmotic
pressure
σd = the average osmotic reflection coefficient of the
barrier (a measure of the effectiveness of the bar-
rier in hindering the passage of solutes from one
side of the barrier to the other)
The Starling equation predicts the development of two differ-
ent kinds of pulmonary edema. Increased pressure pulmonary
edema occurs when the balance of the driving forces increases,

Copyright © 2008, 1998, 1988, 1980 by The McGraw-Hill Companies, Inc. Click here for terms of use.
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Part XVII Acute Respiratory Failure
forcing fluid across the barrier at a rate that can no longer be
accommodated by lymphatic drainage. Increased permeability
pulmonary edema occurs in the presence of ALI that damages
the normal barriers to fluid filtration and allows increased flux
of liquid and protein into the extravascular compartments of
the lungs.
Thus, pulmonary edema results from increases in ei-
ther hydrostatic driving pressures (increased pressure edema)
or barrier conductance (increased permeability edema), or
both. What distinguishes the two types is barrier permeability,
which is normal in increased pressure edema, but abnormal
in increased permeability edema. Fluid flow into the lungs
is driven across the barrier in both types of edema by the
balance of pressures. ALI or ARDS results primarily from an
increase in lung vascular permeability, although some cases
may be made worse by the presence of elevated lung vascular
hydrostatic pressures.
Increased Permeability Pulmonary Edema
Increased permeability pulmonary edema is caused by an in-
crease in liquid and protein conductance across the barriers
in the lungs. The essential feature is that the integrity of the
barrier to fluid and protein flow into the lung interstitium and
the alveoli is altered. Increased permeability edema is some-
times called noncardiogenic pulmonary edema, and the re-
sulting clinical syndromes in humans are commonly lumped
together as acute lung injury or the acute respiratory distress
syndrome.
Accumulation of fluid and protein increases when the
lung endothelial and epithelial barriers are injured. If the rate
of fluid accumulation exceeds the rate at which it can be re-
moved, increased permeability edema occurs. Because the
barriers limiting fluid and protein flow into the lungs do not
function normally when the lungs are injured, the lungs are
not protected against edema by the usual safety factors. Al-
though increases in fluid and protein filtration across the lung
endothelium can be removed by lymphatics and drained away
from the alveolar walls as in increased pressure edema, much
more fluid and protein are filtered at any given sum of driv-
ing pressures because the barriers to their flow are much less
restrictive than normal. Edema formation in injured lungs is
very sensitive to hydrostatic driving pressures. Driving pres-
sures are often increased when the lungs are injured because of
the vasoconstrictive effects of inflammatory mediators such
as thromboxanes, which may shift the main site of resistance
to postcapillary venules, thus increasing hydrostatic pressure
at the microvascular fluid exchange sites, or because of effects
on the heart as well as on the circulation. For example, ele-
vated left atrial pressure, pulmonary venoconstriction, or an
increase in cardiac output in sepsis can increase hydrostatic
pressure at the microvascular fluid exchange sites.
Because the barriers are leaky, the protective osmotic
pressure differences across them are lost; driving pressure is
unopposed by osmotic pressure, and even normal hydrostatic
pressure results in significant fluid and protein extravasation
into the interstitial and alveolar spaces. The ability of the lym-
phatics to pump the excess filtrate away is increased when the
lungs are injured. Maximal lung lymph flow increases more
when the microvascular wall has been injured than when hy-
drostatic pressure alone is increased, but even this augmented
lymphatic-pumping capability is taxed at lower driving pres-
sures. If the epithelial barrier is injured, edema may accumu-
late readily in alveoli, because most of the resistance to fluid
and protein flow into the alveoli is in the epithelial barrier.
Increased permeability edema is often rapid in onset and pro-
gression because injured barriers offer much less resistance to
flow and because hydrostatic driving pressure is unopposed
by increases in osmotic pressure difference. Clinically, many
patients with increased permeability edema have a low in-
travascular hydrostatic pressure, commonly measured as a
low or normal pulmonary capillary wedge pressure. In some
cases, this reflects the low intravascular pressures associated
with the underlying disease process, such as sepsis.
Lung Physiology
The effects of increased permeability edema on lung mechan-
ics and gas exchange depend, in part, on the magnitude of
edema accumulation. As with increased pressure edema, the
major effects on pulmonary mechanics occur with alveolar
flooding. In experimental lung injury, functional residual ca-
pacity is decreased as a consequence of alveolar flooding; the
loss of units which can be ventilated accounts for most of the
decrease in static lung compliance. Computed tomography
has provided new insights into structure-function relation-
ship in human ALI. In the early stage of lung injury, when
alveolar edema predominates, the lungs are characterized by
a more homogeneous alteration of vascular permeability, and
edema can accumulate evenly in all lung regions with a non-
gravitational distribution.
Measurements of pulmonary mechanics in mechani-
cally ventilated patients with ALIs show a decrease in static
lung compliance as a consequence of the loss of ventilated
lung units. In addition, airflow resistance is increased as a re-
sult of decreased lung volume. Bronchospasm may add to the
increase in airflow resistance and may be partially reversed
in some patients by administration of inhaled bronchodila-
tors. Chest wall compliance is reduced, probably because of
alterations in the intrinsic mechanical properties of the chest
wall by abdominal distention, chest wall edema, and pleural
effusion. Some investigators have reported differing respira-
tory mechanics and response to positive end-expiratory pres-
sure (PEEP) during mechanical ventilation in patients with
ARDS originating from pulmonary disease (e.g., pneumonia,
which causes consolidation) versus ARDS due to extrapul-
monary disease (which causes edema and subsequent alveolar
collapse).
Although the effects of surface forces on decreased lung
compliance in ALI were once believed to be small, results of
experiments in isolated rabbit lungs indicate that increased
permeability edema may produce more severe mechanical

changes than equivalent degrees of increased pressure edema.
In contrast, experiments in awake sheep have demonstrated
that similar degrees of pulmonary edema, regardless of mech-
anism, cause similar changes in compliance and gas exchange.
Other studies indicate that dynamic and static lung compli-
ances are decreased early in evolving lung injury.
Surfactant is strongly thromboplastic, and coagulation
may compound surfactant depletion when plasma proteins
enter the airspaces. The injured lung may release substances
that can interfere with the normal, low surface tension in the
alveoli. In addition, activated neutrophils may impair surfac-
tant function in vitro and degrade major surfactant apopro-
teins through a combination of proteolysis and oxidant-
radical–mediated mechanisms. In studies using bronchoalve-
olar lavage, human lung surfactant obtained from patients at
risk for ALI and from those with established ALIs has been
reported to be abnormal in chemical composition and func-
tional activity. Abnormalities may also be caused by inter-
actions between surfactant and edema proteins, since plasma
proteins (especially fibrin monomers, but also fibrinogen and
albumin) interfere with surfactant function. Proteinaceous
edema fluid has been associated with surfactant inhibition in
several experimental models.
Gas exchange is severely compromised in increased per-
meability edema because of both intrapulmonary shunting of
blood and ventilation-perfusion inequalities. New evidence
indicates that patients with early ALI have a marked increase
in pulmonary dead space fraction. This finding indicates that
many ventilated lung units are not well perfused, although
intrapulmonary shunting may also contribute to the elevated
dead space. Not surprisingly, minute ventilation is typically
twice normal (approximately 12 L/min) at the onset of ARDS.
MECHANISMS OF ACUTE LUNG INJURY
This section focuses on the characteristic pulmonary
pathological findings in patients with ALI and ARDS and
the mechanisms responsible for ALI.
Pathological Findings
Based on several studies that included a preponderance of
postmortem pathology, the light and electron microscopic
appearances of human and animal lung tissue in ALI have
been described. Exudative, proliferative, and fibrotic changes
usually appear in sequence.
The earliest changes are marked by widespread alve-
olar and interstitial edema and hemorrhage. Hyaline mem-
branes, composed of precipitated plasma proteins, fibrin, and
necrotic debris are frequently found (Fig. 144-1). The alveo-
lar epithelium may be more extensively damaged than is the
vascular endothelium, even if the underlying insult is blood-
borne. Widespread, local areas of destruction of type I alve-
olar epithelial cells alternate with normal-appearing alveoli.
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Chapter 144 Acute Respiratory Distress Syndrome: Pathogenesis
The injured alveolar epithelium is swollen, disorganized, dis-
continuous, and, frequently, detached from basement mem-
branes, which may be otherwise intact. The alveolar surface
may be covered by hyaline membranes. Type I cells are more
severely damaged than type II cells. The thin cytoplasmic ex-
tensions of cells far from the nucleus, which cover the thin
side of the alveolar-capillary barrier, may be most severely
affected. The interstitium is widened by edema (especially
in peribronchovascular cuffs) and may be filled with leuko-
cytes, platelets, red blood cells, fibrin, and debris (especially
near the alveolar walls). The microvascular endothelium is
relatively preserved; it usually shows little other than irregu-
lar, focal thickening due to cytoplasmic swelling or vacuoles
and greater numbers of luminal leukocytes.
After about 5 to 10 days, the exudative phase is fol-
lowed by a proliferative phase. The relative contributions of
the original insult, repair processes, and effects of therapies
on this and subsequent phases are not well known. Some ab-
normalities occurring after the initial exudative phase appear
to be related to effects of traditional modes of mechanical
ventilation that used tidal volumes between 12 and 15 ml/kg
predicted body weight.
Reabsorption of some of the edema fluid character-
izes the proliferative phase. Fibrin may be prominent in alve-
oli and interstitium, and infiltration with inflammatory cells
and fibroblasts, which may have been activated very early in
the course of lung injury, may be seen. The alveolar epithe-
lium is often cuboidal and made up largely of proliferating
type II cells. The air-blood barrier may be thickened by in-
terstitial and epithelial enlargement. The pulmonary vascular
bed may be partially or completely disrupted, and structural
alterations may reduce its surface area.
Approximately 2 weeks after the initial insult, a final
stage may be observed in which fibrotic changes of the alveo-
lar ducts, alveoli, and interstitium predominate. Alveoli may
be obliterated, alveolar walls coalesced, and functional lung
units lost. The lungs may be emphysema-like, with extensive
bullous changes. Notably, even severe changes at any stage
may be reversible during a slow recovery back toward normal
lung function.
Mediators
The most common clinical disorders associated with the
development of ALI are pneumonia, sepsis, gastric aspi-
ration, and major trauma. Other, less common causes in-
clude transfusion-associated lung injury, drug overdose, se-
vere acute pancreatitis, and near drowning. The initiating
insult to the lungs occurs either via the airways or the blood-
stream.
The exact mechanisms by which the lungs are injured
have been the subject of intense investigation in humans, an-
imals, and cellular systems. Human studies have provided
descriptive data about the events that occur in the airspaces
before and after the onset of lung injury. Studies using bron-
choalveolar lavage or collection of pulmonary edema fluid
2526
Part XVII Acute Respiratory Failure

A B

Figure 144-1 A. A low-power light micrograph of lung biopsy specimen collected 2 days after onset of ALI/ARDS
secondary to gram-negative sepsis demonstrates key features of diffuse alveolar damage, including hyaline mem-
branes, inflammation, intra-alveolar red blood cells and neutrophils, and thickening of the alveolar-capillary mem-
brane. B . High-power view of a different field illustrates dense hyaline membrane and diffuse alveolar inflammation.
Polymorphonuclear leukocytes are imbedded in the proteinaceous hyaline membrane structure (black arrows). The
white arrow points to the edge of an adjacent alveolus, which contains myeloid leukocytes. (Histological sections in
A and B courtesy of Dr. K. Jones, University of California, San Francisco). C. Electron micrograph from a classic analysis
of ALI/ARDS showing injury to capillary endothelium and alveolar epithelium. LC = leukocyte within the capillary
lumen; EC = erythrocytes; EN = blebbing of the capillary endothelium; BM = exposed basement membrane where
the epithelium has been denuded; C = capillary; A = alveolar space. (From The ARDS Network: Ventilation with lower
tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome.
N Engl J Med 342:1301–1308, 2000, with permission.)

in patients following the onset of ALI have demonstrated a
major acute inflammatory response beginning prior to clin-
ical recognition of ALI. The response peaks during the first
1 to 3 days of clinically defined ALI and resolves slowly over
7 to 14 days in patients who remain intubated. These stud-
ies have shown the complexity of the evolving inflamma-
tory responses, characterized by accumulation of acute re-
sponse cytokines and their naturally occurring inhibitors,
oxidants, proteinases and antiproteinases, lipid mediators,
growth factors, and the collagen precursors involved in the
repair process.
Hypotheses regarding the mechanisms of lung injury
have been tested in animal models and in vitro studies, and
several reviews have summarized the findings. The existing
animal models do not completely reproduce all of the aspects
of ALI in humans, in part because human ALI evolves over a
longer period of time than can be studied in the laboratory.
In addition, the lungs of humans are exposed not only to the
initial injurious insult, but also to the therapies that are used to
treat ALI, such as mechanical ventilation. Experiments using
isolated cells have been helpful in testing specific concepts, but
the complexity and redundancy of intact biologic systems is
not reproduced in simplified experimental systems. By design,
most experimental work limits study to one causative agent,
thereby reducing actual clinical complexity to the simplicity of
a single experimental pathway. Increased permeability edema
in humans is likely to be caused by interactions among a
number of different pathways acting in parallel or series.

Studies in isolated organs and small animals in which
hemodynamic variables are not measured can be difficult to
evaluate. Indices of lung injury, usually measured by the ap-
pearance of markers in lungs, lavage fluid, or perfusate, are
not determined solely by the barrier function of the microvas-
culature. Indeed, when vascular endothelium is injured, fluid
and protein movement from the vascular space into the lungs
is sensitive to hydrostatic driving pressures and filtration sur-
face area. Hence, the effects of experimental interventions
may be caused by changes in these parameters and not by
changes in microvascular barrier function.
The effects of microvascular driving pressures and sur-
face area can be difficult to evaluate, even in large, instru-
mented animals. In sheep and goats, interpretation of lung
lymph fluid and protein flow changes are further compli-
cated by contributions of extrapulmonary lymphatics, physi-
cal forces acting on lymphatics, and possible intranodal mod-
ification of lymph. Data from experimental animal models
suggest that at least two broad categories of mechanisms of
ALI are operative: (1) those that are indirect (i.e., require
the participation of intermediary mechanisms, e.g., host de-
fenses); and (2) those that are direct (i.e., do not require in-
termediary mechanisms; injury probably occurs as a result
of contact between an offending substance and lung tissue).
These categories overlap, since once the lungs are injured,
inflammatory responses occur, which may compound the
primary mechanism of injury. Three major hypotheses re-
garding the mechanism of ALI are discussed below. Although
discussed separately, they are interrelated.
Role of Infection
ALI develops in 20 to 45 percent of patients with severe sepsis.
Increased microvascular permeability to albumin has been
shown to accompany human sepsis, and infection and the
sepsis syndrome are major causes of ALI in humans. Patients
who develop shock in response to known or suspected in-
fection have a particularly high incidence of ALI, and the
mortality of patients with ALI associated with infection (i.e.,
sepsis syndrome) is increased. ALI also appears to predispose
the lungs to infection, and delayed infection is an important
cause of morbidity in patients who survive the initial lung
insult.
The mechanism by which infection and sepsis syn-
drome injure the lungs is not certain. The lung injury is likely
related to factors other than direct damage by bacteria or
other microorganisms, since the prognosis appears unrelated
to documented bacteremia or pneumonia. In experimen-
tal animals, intravenous infusions of live Pseudomonas aeru-
ginosa or endotoxins from Escherichia coli or surgically in-
duced peritonitis result in increased permeability pulmonary
edema. Instillation of endotoxin into the airways of sheep
also leads to lung inflammation with variable degrees of lung
injury. P. aeruginosa produces lung injury in pigs, and E. coli
endotoxin administration injures the lungs of baboons and
dogs; neutrophilic alveolitis is observed in rats and mice. ALI
caused by endotoxin in sheep is thought to be an inflamma-
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Chapter 144 Acute Respiratory Distress Syndrome: Pathogenesis
tory response mediated, at least in part, by neutrophils and
tumor necrosis factor (TNF). Endotoxin may also affect the
clotting system and metabolic functions of the lungs, as well as
predispose the lungs to development of pulmonary infections
by increasing adherence of bacteria to injured endothelium.
Exoproducts of bacteria, such as elastase and Pseudomonas
exoenzyme U, also have been shown to injure the lungs.
In addition to a direct role in the pathogenesis of lung
injury, bacterial products may also have an indirect role by
sensitizing the lungs to the effects of mechanical stretch.
Gram-negative lipopolysaccharide causes an acute inflam-
matory response in the lungs of humans. Bacterial endotoxin
enhances the responses of human alveolar macrophages to
positive pressure ventilation; pretreatment of rats with in-
travenous endotoxin enhances cytokine production in the
lungs during mechanical ventilation ex vivo. Furthermore,
mechanical ventilation using moderate or large tidal volumes
increases the sensitivity of lung macrophages to endotoxin
in vitro and the expression of the endotoxin recognition
molecule, CD14, on lung cells in vivo. Endotoxin recognition
pathways are increased in the lungs of patients with ARDS,
and the biologic effects of endotoxin are amplified in the
lungs of patients with lung injury. The synergism between
bacterial products and mechanical stretch suggests that in-
terrupting these pathways might limit some forms of ALI in
humans.
Increased permeability edema is associated with im-
paired antibacterial defenses. In animal models, bacterial in-
fections worsen ALI. The cause of impaired bacterial defenses
in acute ALI is not known. Bactericidal properties of the alve-
olar lining material might be altered in injured or flooded
lungs, and alterations in surfactant concentration and func-
tion may be important. Although neutrophils may be present
in large numbers in the bronchoalveolar lavage fluid of pa-
tients with ALI, evidence indicates that the function of the
neutrophils is compromised.
Role of Inflammation
Substantial evidence implicates host defenses and inflamma-
tory responses in the underlying mechanism of many ALIs.
Neutrophils are a vital component of host defenses, and pa-
tients with severe neutropenia are at increased risk of bacterial
and fungal infections. On the other hand, neutrophils release
toxic oxygen radicals, proteases, and other biologically active
mediators that initiate inflammation. Other important cells
in pathogenesis include alveolar and pulmonary intravascular
macrophages, and eosinophils.
Normally, the pulmonary circulation contains a very
large pool of marginated neutrophils that change shape in
order to squeeze through the lung capillaries. When neu-
trophils are activated, they stiffen and become less disten-
sible. These neutrophils are retained for longer periods of
time in the pulmonary microcirculation. Endothelial acti-
vation leads to increased expression of leukocyte adhesion
molecules, providing a second mechanism to slow the transit
of neutrophils. Trapped neutrophils respond to chemotactic
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Part XVII Acute Respiratory Failure
gradients generated by chemokines produced by alveo-
lar macrophages and mesenchymal cells and migrate into
the airspaces. Activated neutrophils generate and release
toxic substances (e.g., oxygen metabolites and granular con-
stituents, such as proteases, and cationic lysosomal enzymes)
that disrupt the function of the microvascular and epithe-
lial barriers. Normally, these barriers limit liquid and protein
flow out of the vascular space and into the alveolar spaces,
mitigating development of permeability edema.
Inflammatory responses also have the potential to in-
duce lung cell injury by activating cell death pathways, leading
to apoptosis. Bacterial products, such as Pseudomonas Exoen-
zyme U and mechanical stretch, may lead to direct cellular
necrosis. Apoptosis is mediated by a family of death receptors,
including TNF and Fas receptors. The Fas ligand (FasL) is a 45
kD peptide that is shed from the cell surface by the action of
metalloproteinases. Biologically active soluble FasL (sFasL)
accumulates in the lungs of patients with ARDS, inducing
apoptotic death of human lung epithelial cells in vitro. Hu-
man sFasL induces epithelial cell death in the lungs of rabbits;
a monoclonal antibody that activates membrane Fas causes
alveolar wall apoptosis and fibrosis in the lungs of mice.
Apoptosis and inflammation pathways intersect, as
stimulation of membrane Fas induces cytokine production
in human macrophages and inflammation in the lungs of
rabbits and mice. In addition, lung injury may be able to
trigger apoptosis pathways in distant organs, such as the kid-
ney, perhaps by increasing the concentrations of circulating
sFasL. Thus, inflammatory responses may trigger cell death
pathways, and cell death pathways triggered by sFasL may in-
duce inflammation in the lung alveolar environment. Recent
human studies implicate apoptosis in human lung injury.
Role of Direct Toxicity
Inflammation is not required for all forms of ALI. ALI or
ARDS can develop in neutropenic patients. A clinical trial
using granulocyte colony-stimulating factor to increase the
number and activation state of circulating neutrophils in pa-
tients with severe pneumonia was not associated with an in-
creased incidence of ARDS. Lung injuries that do not require
the participation of neutrophils have been described in animal
models.
Direct lung injury is also thought to occur in humans.
Putative agents that directly injure the lungs include mechan-
ical forces during mechanical ventilation, toxic and corro-
sive chemicals and gases (e.g., hydrochloric and other acids,
ozone, ammonia, chlorine, phosgene, nitrogen dioxide, the
vapors of cadmium and mercury, combustion products, and
oxygen, especially at high concentrations), ionizing radiation,
aspiration of fresh water (near drowning) or hydrocarbon
compounds (e.g., kerosine, gasoline, and dry-cleaning fluid),
high temperatures (parenchymal lung burns from fires or ex-
plosions), and mechanical injuries (e.g., lung contusion from
nonpenetrating chest trauma or blast injury from explosions
or lightning). Many of these injuries develop rapidly, support-
ing the idea that injury is caused directly by contact with the
respiratory epithelium in the airways and/or alveolar walls.
Inflammatory pathways are likely to be rapidly acti-
vated following many types of direct lung injury, as proba-
bly occurs following aspiration of gastric secretions—one of
the most common clinical causes of ALI. Lung injury occurs
rapidly, especially to the epithelium. The injury is probably
related, in part, to the low pH of the aspirated stomach con-
tents (aspiration of gastric contents with pH greater than 2.5
is relatively benign; aspiration of gastric contents with pH
less than 2.5 causes severe pulmonary injury). Aspirated acid
is almost immediately neutralized. However, within hours,
proinflammatory mediators are released, the injured lung is
infiltrated with neutrophils, fibrin accumulates in the alveolar
spaces, and further structural damage is seen on histological
examination.
Biologic Markers
Considerable interest exists in finding a simple test of blood,
urine, or bronchoalveolar lavage fluid that would identify
patients at risk for, or in the earliest stages of, ALI, or that
might predict clinical outcome.
Although products of complement activation have been
proposed as markers, their serum levels correlate poorly with
lung injury. Measurement of circulating endotoxin is not ap-
propriately sensitive or specific for the presence or risk of
developing lung injury. The same is true for measurements
of release or activity of angiotensin-converting enzyme. Von
Willebrand factor (VWF) antigen may be useful as a plasma
marker of impending ALI in patients with nonpulmonary
sepsis. Recent work confirms that VWF levels are elevated in
the edema fluid and plasma of patients with ALI and cor-
relate with poor clinical outcomes. While increases in other
biochemical and inflammatory markers, including surfactant
protein D and interleukin-6, correlate somewhat with lung
injury and mortality, no simple biologic marker currently
serves in the same diagnostic capacity as do cardiac enzymes
in evaluation of suspected acute myocardial infarction.
Because neutrophils are implicated in the mechanism
of many lung injuries, their detection in the lungs, assess-
ment of their function, or assay of the toxic metabolites they
release might be useful. For example, increased hydrogen per-
oxide levels have been measured in the breath and urine of
patients with ALI, presumably reflecting the presence of oxy-
gen metabolites in the injured lungs. Evidence of increased
oxidant activity has been reported in bronchoalveolar lavage
fluid in patients with lung injury.
Finally, other mediators of inflammation in ALI have
been studied. For example, increased levels of TNF are de-
tected in blood and bronchoalveolar lavage fluid in lung in-
jury, but an association between TNF levels and development
of ARDS has not been found. Furthermore, elevated TNF
levels are found in patients with severe congestive heart fail-
ure. Lipoxygenase products of arachidonic acid metabolism
have been detected in pulmonary edema fluid, bronchoalve-
olar lavage fluid, plasma, and urine, and elastase has been
 2529
Chapter 144 Acute Respiratory Distress Syndrome: Pathogenesis

Figure 144-2 Multiple cellular responses and mediators contribute to alveolar-capillary membrane injury (right-
hand side) and the transition from normal alveolar structure and function (left-hand side) in the acute phase of
ALI/ARDS. Original investigations of the pathogenesis of ALI/ARDS searched for single mediators that provided final
common pathways to inflammation and alveolar edema. Current concepts of pathogenesis involve multiple molecu-
lar factors of several classes, a variety of responding cells, and an imbalance between injurious and reparative signals
and pathways. See text and Ware & Matthay (2000) and Matthay & Zimmerman (2005). (Reprinted from Matthay MA,
Zimmerman GA: Acute lung injury and the acute respiratory distress syndrome: Four decades of inquiry into pathogenesis
and rational management. Am J Respir Cell Mol Biol 33:319–327, 2005, with permission.)

detected in bronchoalveolar lavage fluid in the setting of lung
injury.
ALI follows a wide variety of insults of varying sever-
ity. Furthermore, many abnormalities detected in ALI are
found in other diverse, severe illnesses that do not involve the
lungs. Therefore, the likelihood that any single marker that
unequivocally identifies the risk or the presence of ALI will
be found seems remote. An investigative focus on particular
subgroups of patients with common causes of injury, coupled
with study of much larger groups of more definitively diag-
nosed patients, might prove helpful. An approach that has
not received much attention is investigation of the sensitivity
and specificity of combinations of biologic markers. The new
field of proteomics will expand this type of investigation and,
perhaps, identify patterns of protein abnormalities that can
be found in plasma, urine, edema fluid, and bronchoalveolar
lavage in patients with ARDS.
Figure 144-2 depicts multiple pathways involved in the
pathogenesis of ALI and ARDS in the context of normal
and injured alveoli. Emphasis is placed on potential path-
ways for injury across the vascular endothelium and alveolar
epithelium.
VENTILATOR-ASSOCIATED LUNG INJURY
The most important development of the last 10 years in our
understanding of the pathogenesis and treatment of ALI is
recognition that the long-standing practice of mechanically
ventilating patients with ALI or ARDS using high tidal vol-
umes and airway pressures actually worsens the injury. An-
imal studies first suggested the potential contributory role
of high tidal volumes and elevated airway pressures in the
2530
Part XVII Acute Respiratory Failure
pathogenesis of lung injury; subsequently, clinical trials con-
firmed the findings.
Animal Studies
Animal experiments have shown that ventilation using high
tidal volumes may increase vascular filtration pressures; pro-
duce stress fractures of microvascular endothelium, alveolar
epithelium, and basement membranes; and cause lung rup-
ture (so-called ventilation-induced lung injury). The injury
appears to be due to increased lung excursions at high vol-
umes (“volutrauma”), rather than the high-airway pressure,
per se, since it can be prevented by limiting thoracic motion
(e.g., by placing the chest in a cast). The concept of volu-
trauma was first established in 1974 when investigators found
that modestly elevated tidal volumes, especially in the absence
of PEEP, caused lung edema in rats. Several years later, ad-
ditional animal studies further demonstrated the potential
injurious role of high tidal volumes and elevated airway pres-
sures, an effect termed ventilator-induced lung injury (VILI).
Subsequent experiments demonstrated that VILI could also
induce release of several proinflammatory cytokines, injur-
ing the lung and other organs—a process referred to as
“biotrauma.” These animal studies stimulated clinical inves-
tigation that revolutionized the care of patients with ALI or
ARDS.
Clinical Studies
The compelling evidence from animal experiments and small
clinical trials prompted clinical studies aimed at testing the
potential benefit of lower tidal volumes and reduced airway
pressures in management of ALI or ARDS. In a large, mul-
ticenter, National Heart Lung and Blood–sponsored trial of
861 patients, mortality was reduced from 40 to 31 percent
using a tidal volume of 6 ml/kg/ideal body weight and a lim-
ited plateau airway pressure of less than 30 cm H2 O. In this
trial, use of small tidal volumes was associated with a lower
incidence of nonpulmonary organ failure. The protocol for
carrying out the lung protective ventilatory strategy is de-
scribed in detail in Table 144-1. The results of the trial have
transformed the management of patients with ALI or ARDS.
A follow-up clinical trial has shown that ventilation using
the limited tidal volume and plateau pressure of the original
study is associated with an overall reduction of mortality to
26 percent. In the follow-up study, although elevated levels
of PEEP did not decrease mortality, the basic lung protective
strategy was validated as effective.
The beneficial mechanism underlying the low tidal vol-
ume strategy is unclear. An Italian study has shown that use
of low tidal volumes in patients with ARDS attenuates the
inflammatory response in both lungs and bloodstream, as
measured by reductions in neutrophil and cytokine concen-
trations in bronchoalveolar lavage and cytokines in circulat-
ing blood. Other studies have confirmed a number of these
findings. In addition, a reduction in alveolar epithelial injury
appears likely, based on a decline in plasma surfactant protein
D levels. Additional clinical and experimental studies are un-
derway. A reduction in lung endothelial and epithelial injury,
attenuated inflammatory responses, reduced edema forma-
tion, and more rapid resolution of lung edema are likely part
of the mechanism(s).
RESOLUTION OF ACUTE LUNG INJURY
In the last two decades, considerable progress has been made
in understanding the mechanisms responsible for resolution
of lung edema. More limited progress has been made in un-
derstanding the resolution of lung inflammation.
Considerable advances have been made in our under-
standing of the clearance of fluid and solute from alveoli.
Active sodium and chloride transport across the alveolar and
distal airway epithelial barriers into the interstitium drives
edema fluid removal from the airspaces. The uninjured alve-
olar epithelium has a remarkable ability to rapidly clear fluid
from the airspaces. Even when mild-to-moderate alveolar in-
jury occurs, salt and water transport capacity is often pre-
served. In severe injury, when the barrier is disrupted, the
capacity to clear edema is lost. The vascular endothelium be-
comes the limiting barrier between the vascular space and
airspace. Clinically, the capacity to remove some alveolar
edema fluid (as indicated by increase in edema fluid to plasma
protein concentration ratio) in the first 12 hours following
ALI is a favorable prognostic finding; the associated mortal-
ity rate is only 20 percent. In contrast, an inability to resorb
alveolar edema fluid early in the course of injury is associated
with a mortality of nearly 80 percent. Thus, the function of
the alveolar epithelial barrier early in the course of ALI may be
a useful prognostic index, serving as a marker of the severity
and extent of injury.
In uninjured, ex vivo human lungs, alveolar fluid clear-
ance is increased by administration of salmeterol. In addition,
experimental studies have shown that even in the presence of
ALI and alveolar edema, alveolar fluid clearance can be in-
creased pharmacologically (e.g., by catecholamines), thereby
representing a potential therapeutic intervention.
Clearance of protein from flooded alveoli is much
slower (1 to 2 percent per hour) than clearance of fluid (10 to
20 percent per hour), resulting in an increased concentration
of protein in airspaces. If the alveolar edema formed during
increased lung vascular permeability clots, its removal from
flooded alveoli may be slowed. Clotting may occur because
extravasation of plasma into airspaces can lead to clotting
system activation by surfactant or macrophage-derived pro-
coagulants.
Most of the interstitial water in pulmonary edema lies
in the peribronchovascular loose connective-tissue spaces,
rather than in alveolar walls. Because the lymphatic capillaries
are arranged to drain only the alveolar wall interstitium, this
route for edema removal is not significant for most interstitial
edema. A study in goats showed that lung lymph originates
mainly from alveolar wall interstitial fluid. The contribution
 2531
Chapter 144 Acute Respiratory Distress Syndrome: Pathogenesis

Table 144-1
National Institute of Heart, Lung, and Blood, ARDS Network:
Lung Protective Ventilatory Strategy
Ventilator mode Volume assist-control

Tidal volume ≤ 6 ml/kg PBW

Plateau pressure ≤ 30 cmH2 O

Ventilation set rate, pH goal 6–35, adjusted to achieve arterial

pH ≥7.30, if possible

Inspiratory flow, I:E Adjust flow to achieve I:E = 1:1–1:3

Oxygenation goal 55 ≤Pao2 ≤80 mmHg or 88 ≤Spo2 ≤95%

FIO2 /PEEP Combinations

Fio2 0.3 0.4 0.4 0.5 0.5 0.6 0.7 0.7 0.7 0.8 0.9 0.9 0.9 1.0

PEEP, cmH2 O 5 5 8 8 10 10 10 12 14 14 14 16 18 18, 22, 24

(Further increases in PEEP to 34 cmH2 O allowed, but not required)

Weaning Attempts to wean by pressure support required when Fio2 /PEEP ≤0.40/8

PBW = predicted body weight

Male PBW = 50 + 2.3 [height (inches) − 60] or
50 + 0.91[height (cm) − 152.4]
Female PBW = 45.5 + 2.3[height (inches) − 60] or
45.5 + 0.91[height (cm) − 152.4]

I:E = ratio of inspiratory to expiratory duration

Pao2 = partial pressure of oxygen in arterial blood
Spo2 = oxyhemoglobin saturation measured by pulse oximetry
Source: Adapted from Acute Respiratory Distress Syndrome Network: Ventilation with low tidal volumes as compared with traditional tidal volumes for acute
lung injury and the acute respiratory distress syndrome. N Engl J Med 342:1301–1308, 2000, with permission.

of the lung lymphatic system to clearance of interstitial edema
in bronchoalveolar cuffs and interlobular septa is small. The
maximum possible contribution by lung lymphatics to clear-
ance of interstitial edema liquid is less than 10 percent, with
airway loss of liquid through evaporation occurring at about
twice the rate of lymphatic clearance.
In a study of in situ perfused sheep lungs with experi-
mentally induced low- and high-protein pulmonary edema,
interstitial liquid was resorbed into the circulation in inverse
proportion to its protein concentration. Only a very small
fraction of interstitial edema was cleared by the lung lym-
phatics during recovery from either type of edema.
Some fluid from the loose peribronchovascular inter-
stitium may drain directly into the bloodstream by crossing
the walls of blood vessels in the lungs. A study of isolated
sheep lungs made edematous by raising vascular pressures
showed that the primary route of edema clearance is by vas-
cular resorption (60 percent of filtered water cleared over
3 hours, including 42 percent by resorption into the blood-
stream and 18 percent by lymphatic, pleural, and mediastinal
drainage).
Edema may also drain into the pleural space. Pleural
effusions are more common in increased pressure pulmonary
edema (25 to 50 percent of patients; usually on the right if
unilateral). However, they occur in ALI as well (35 percent of
patients). As much as 25 to 30 percent of edema fluid may leave
the lungs through the pleural space. A significant portion of
the interstitial edema probably follows the prevailing pressure
gradient in the lungs to drain into the mediastinum, where it
may be picked up by the lymphatics.
Short-term alveolar protein clearance appears to pro-
ceed primarily by paracellular diffusion. The process depends
2532
Part XVII Acute Respiratory Failure
on the size of the proteins. Most proteins are cleared in-
tact, rather than as degraded, smaller fragments. However,
a few specific proteins (e.g., vasoactive intestinal peptide and
gastrin) are degraded before being cleared.
Receptor-mediated clearance may play a role. An
albumin-binding protein (albondin) is expressed on lung mi-
crovascular endothelial cells. An antibody to this protein re-
acts with cellular proteins of alveolar epithelial cells, which
also appear to have albondinlike binding sites for albumin.
In addition, a polymeric immunoglobulin receptor has been
described. The significance of these receptors in protein clear-
ance is, however, unclear.
Finally, the general consensus is that transcytosis (trans-
port via vesicles) is not a major mechanism for clearing bulk
quantities of albumin or other proteins from the alveolar
space. Over the long term, phagocytosis and catabolism by
macrophages account for most protein clearance from the
alveolar spaces. All insoluble, precipitated proteins are re-
moved in this way. Macrophages are also ultimately respon-
sible for removing senescent and dead neutrophils and other
debris. The presence of a small, ciliated surface area of the
distal airspaces suggests that the mucociliary route accounts
for only a minor fraction of alveolar protein clearance. Com-
plete clearance of alveolar protein from pulmonary edema by
any route is slow.
Little is known about the mechanisms and signals that
regulate endothelial barrier function or how increased en-
dothelial permeability is returned to normal.
CONCLUSIONS
Among the major advances in respiratory medicine and phys-
iology over the last three decades has been the acquisition of
important new knowledge on the physiology of fluid, so-
lute, and protein transport in healthy and diseased lungs.
Pulmonary edema, defined as the abnormal accumulation
of extravascular lung fluid, is a pathological state that oc-
curs when fluid is filtered into the lungs faster than it can be
removed.
The many causes of pulmonary edema are grouped into
two main pathophysiological categories: (1) increased pres-
sure edema, which results from an increase in hydrostatic or
osmotic forces (or both) that act across the barriers that nor-
mally restrict movement of fluid and solutes in the lungs; and
(2) increased permeability edema, which is seen in ALI in
which a breakdown of the normal barrier properties of lung
endothelium or epithelium develops. Although these two dif-
ferent types of pulmonary edema share many features, usu-
ally they can be distinguished by careful clinical, radiological,
and physiological evaluation. They also differ in treatment
and prognosis.
Major advances in the treatment of ALI have occurred
because of the successful application of lung protective venti-
latory strategies early in the course of the illness (Table 144-1).
A low tidal volume (6 ml/kg/ideal body weight), coupled with
a plateau pressure limit (less than 30 cm H2 O) has resulted in
the first therapy demonstrated to reduce mortality in patients
with ALI.
Recently, the National Heart, Lung, and Blood Institute
Acute Respiratory Distress Syndrome Network published the
results of the Fluid and Catheter Treatment Trial (FACTT),
a large randomized trial comparing a liberal fluid manage-
ment strategy to a conservative fluid management strategy in
patients with ALI. Patients were also randomized to receive
either a pulmonary arterial catheter or a central venous
catheter for monitoring and fluid management. There were
no differences in clinical outcomes between the pulmonary
or central venous catheter utilization. In contrast, there was
a marked difference in outcome between the liberal and
the conservative fluid management arms of the study. Pa-
tients in the conservative fluid management arm had 2.5
more ventilator-free days than those in the liberal fluid man-
agement arm with concordant improvements in pulmonary
physiology. There was also a 2.9 percent reduction in the 60-
day mortality rate in the conservative fluid management arm
compared with the liberal fluid management arm, although
this difference did not reach statistical significance.
New insights into the pathogenesis of ALI suggest that
other therapies may also prove to be efficacious in reducing
mortality in this common form of severe acute respiratory
failure. A major development has been the ability to con-
duct large, prospective, randomized, clinical trials (e.g., those
sponsored by the National Heart, Lung, and Blood Institute)
to test a variety of therapies important in supportive patient
care, including use of mechanical ventilation, intravenous flu-
ids, and a variety of pharmacologic agents. Such trials have led
to a better understanding of the pathogenesis of human ALI
and have confirmed the importance of ventilator-associated
lung injury. In addition, ancillary pathogenetic studies car-
ried out on biologic samples from clinical trials have advanced
our understanding of underlying mechanisms. In the future,
additional human studies will be needed to explore new ther-
apeutic strategies suggested by basic investigation conducted
in animal models of ALI.
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