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					                                          Clin Chest Med 27 (2006) 579–589




 Mechanisms of Acute Lung Injury/Acute Respiratory
                Distress Syndrome
              Benjamin T. Suratt, MDa,b,*, Polly E. Parsons, MDa,b
                                 a
                                  Vermont Lung Center, Burlington, VT 05405, USA
                        b
                         Division of Pulmonary and Critical Care, Fletcher Allen Health Care,
                                            Burlington, VT 05405, USA




    In the 4 decades that have elapsed since                   changing emphasis on and controversy over the
Ashbaugh and colleagues [1] first described acute               importance of these many mechanisms. Such
lung injury/acute respiratory distress syndrome                controversy continues because of the continued
(ALI/ARDS), tremendous strides have been                       lack of clinical advances despite these many
made in dissecting the pathophysiology of this                 discoveries. The inability to find a unifying theory
disease. This understanding unfortunately has                  for ARDS pathogenesis almost certainly reflects
not translated into similar advances in the ability            the complexity of a disease with a common end
to predict, prevent, or treat this disease that af-            point but many causes.
fects nearly 200,000 patients a year in the United
States alone [2]. The American-European Consen-
sus Conference (AECC) on ARDS formally de-                     Common end point: failure of the alveolar
fined ARDS as severe arterial hypoxemia (with                   capillary membrane
a partial pressure arterial oxygen/fraction of in-                 Decades of clinical and animal research have
spired oxygen [PaO2/FIO2] ratio of 200 or less) in             established increased permeability edema as the
the presence of bilateral alveolar infiltrates with-            primary physiologic abnormality in the early stages
out evidence of elevated left atrial pressure [3].             of ALI/ARDS. Such edema differs from high-
This definition recognizes a clinical syndrome, ir-             pressure or hydrostatic edema (eg, congestive heart
respective of specific molecular, immunologic, or               failure) in that increased permeability edema is
physical events that may precede it. Thus, the def-            driven primarily by a failure of the alveolar struc-
inition reflects a common final end point in the                 tures that normally retain plasma within the alveo-
acute phase of this disease: respiratory compro-               lar capillaries (the alveolar capillary membrane
mise caused by failure of the alveolar capillary               [ACM]). Failure of the ACM in ALI/ARDS allows
barrier and the resulting development of protein-              proteinaceous fluid to flood the alveolar airspaces
aceous edema.                                                  and contributes directly to the impairment of gas
    From the formidable body of research exam-                 exchange and loss of lung compliance that charac-
ining the advent and perpetuation of this central              terize this disorder. The ACM is formed by two
injury, several pathophysiologic themes have                   separate components: the capillary endothelium and
arisen, and the history of this work reflects ever-             the alveolar epithelium; the function of both is
                                                               disrupted in ALI/ARDS (Fig. 1). The mechanisms
                                                               leading to the failure of the ACM are multiple but
   This work was supported by Grants No. HL084200
                                                               can be divided roughly into those affecting the cap-
and NCRR P20 RR15557 from the NIH.
   * Corresponding author. Vermont Lung Center, 149            illary endothelium and those affecting the alveolar
Beaumont Avenue, HSRF 230, Burlington, VT 05405.               epithelium.
   E-mail address: benjamin.suratt@uvm.edu                         Damage to the alveolar capillary endothelium
(B.T. Suratt).                                                 has long been recognized as a key feature of the
0272-5231/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.ccm.2006.06.005                                                                   chestmed.theclinics.com
580                                                SURATT & PARSONS




Fig. 1. The normal alveolus (left) and the injured alveolus in the acute phase of acute lung injury and the acute respi-
ratory distress syndrome (right). In the acute phase of the syndrome there is sloughing of both the bronchial and alveolar
epithelial cells with the formation of protein-rich hyaline membranes on the denuded basement membrane. Neutrophils
are shown adhering to the injured and activated capillary endothelium and marginating through the interstitium into the
air space, which is filled with protein-rich edema fluid. In the airspace an alveolar macrophage is secreting cytokines,
interleukin-1b, -6, -8, and -10, (IL-1b, 6, 8, and 10) and tumor necrosis factor-a (TNF-a), which act locally to stimulate
chemotaxis and activate neutrophils. Neutrophils can release oxidants, proteases, leukotrienes, and other proinflamma-
tory molecules. The influx of protein-rich edema fluid into the alveolus has led to the inactivation of surfactant. (From
Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000;342(18):1339; with permission.
Ó 2000, Massachusetts Medical Society.)


acute phase of ALI/ARDS. Ultrastructural stud-                  to localized inflammation or injury (eg, bacterial
ies demonstrate endothelial cell swelling and                   pneumonia), this process becomes dysregulated
widening of the intercellular junctions [4], and ra-            and uncontrolled in ALI/ARDS [6]. Among the
dionuclide studies have confirmed the presence of                phenotypic and functional changes that occur,
profound capillary leak in these patients [5]. More             endothelial cell contraction and deranged vaso-
recent work, however, has established that endo-                motor response contribute to the development
thelial structure and function may be altered in-               of capillary leak; the expression of adhesion mol-
dependently of cellular injury in a process                     ecules and cytokines promulgates alveolar injury,
called ‘‘endothelial activation’’ that seems to pre-            as discussed later [7].
cede and promote such injury. Endothelial acti-                    As with alveolar endothelial injury, the pres-
vation may occur in response to a wide range                    ence of epithelial damage, characterized by necro-
of stimuli implicated in ALI, including cytokines,              sis and often profound disruption, has been
thrombin, lipopolysaccharide, and other micro-                  appreciated as a cardinal finding of ALI/ARDS
bial products, and extreme changes in blood                     for many years [4]. The multiple consequences of
pressure. Whereas endothelial activation seems                  this injury and their central importance to the de-
to be part of a limited and reversible response                 velopment of edema in ALI have been recognized
                                                MECHANISMS OF ALI/ARDS                                               581

only more recently. The alveolar epithelial lining              endothelial and epithelial components of the alve-
is composed predominantly of flat type I epithelial              olar membrane and represents a loss of both bar-
cells that provide a thin surface for gas exchange              rier function and fluid resorption.
and a tight barrier against fluid extravasation
into the airspace. This epithelial barrier function
                                                                Pathophysiologic mechanisms
seems to be even more critical than that played
by the endothelial surface of the ACM [8]. Type                    Although increased permeability edema is the
II alveolar epithelial cells, although relatively               central physiologic event in the development of
few in number, provide another crucial protection               ALI/ARDS, the events leading to the failure of
against edema formation: the resorption of air-                 the alveolar capillary membrane are numerous
space fluid [9]. The degree of loss of this function             and complex (Fig. 2). This diversity of pathways
in ALI/ARDS has been shown to correlate with                    invoked by the many inciting injuries leading to
poorer prognosis [10]. This same study found                    ALI/ARDS and influenced by multiple host fac-
that increased rates of alveolar fluid clearance in              tors is the basis for much of the heterogeneity of
patients who had ALI/ARDS were associated                       disease manifestations and outcomes. One of the
with female sex, nonsmoking status, and ALI/                    more intuitive examples of the potential differ-
ARDS risk factors other than sepsis, suggesting                 ences among pathways leading to ALI is reflected
that some clinical heterogeneity may result from                by the AECC categorization of risk factors for the
varying rates of alveolar fluid clearance. Taken to-             development of ALI/ARDS, which groups these
gether, the dual functions of the alveolar epithe-              factors into direct and indirect (or pulmonary
lium underscore the dynamic nature of edema                     and extrapulmonary) injuries to the lung [3]. Ap-
formation in which increases in ACM permeabil-                  parent differences in the radiographic and physio-
ity rapidly overtake the diminished resorptive                  logic manifestations of ALI caused by direct
capacity of the alveolus, and alveolar flooding oc-              versus indirect insults (and possibly in response
curs. Thus, the proteinaceous edema that charac-                to some therapies) have led to ongoing contro-
terizes ALI/ARDS results from disruption of both                versy about whether these groupings should be




Fig. 2. Pathophysiologic mechanisms of acute lung injury and the acute respiratory distress syndrome. In this schema-
tized view of the pathophysiologic pathways of ALI/ARDS, direct injuries to the lung damage the alveolar capillary
membrane and initiate local and subsequently systemic inflammatory cascades. Indirect injuries initiate the pathophys-
iologic pathways of ALI/ARDS primarily through release of systemic cytokines. Following both direct and indirect ini-
tiators of ALI/ARDS, the release of systemic inflammatory mediators activates circulating neutrophils and the vascular
endothelium of the lung, leading to pulmonary microvascular sequestration of neutrophils and inflammatory injury to
the ACM. Such injury results in failure of ACM barrier function and flooding of the alveoli with proteinaceous edema
fluid. Both ACM injury and alveolar edema cause surfactant loss and dysfunction, which promote alveolar instability
and collapse, driving further edema formation and alveolar injury, particularly in the setting of mechanical ventilation.
Not depicted is the role of the coagulation cascade, which promotes alveolar collapse, capillary obstruction with micro-
thrombi, and further release of inflammatory mediators.
582                                             SURATT & PARSONS


considered separate entities for the purposes of           indirect causes of ALI/ARDS have confirmed
further research and clinical trials [11,12].              the critical role of neutrophil recruitment in the in-
    It seems logical that a direct injury to the           jury to the alveolar membrane [21], and although
ACM, such as aspirated stomach acid, would                 studies in neutropenic patients have demonstrated
differ from an indirect mechanism, such as extra-           the occurrence of ALI/ARDS in the apparent ab-
thoracic trauma, and in fact ALI/ARDS mortality            sence of neutrophils [22,23], it is widely recognized
from these two mechanisms differs substantially             that such patients worsen dramatically with the
[2]. There also, however, are significant differences        resolution of neutropenia [24]. The mechanisms
in mortality among indirect causes themselves: for         governing neutrophil trafficking to the lung in
instance, sepsis with an extrapulmonary source             ALI have been investigated intensely. Neutrophils
has a greater risk of mortality than extrathoracic         are recruited to the lung through the release of sol-
trauma [2]. Furthermore, there seems to be no              uble mediators that activate these cells through
overall difference in mortality between direct and          cell surface receptors. Some soluble factors, such
indirect causes of ALI/ARDS [12,13]. In animal             as lipopolysaccharide (as seen in gram-negative
models examining direct injuries such as aspiration,       sepsis), are triggers of the innate immune system,
the direct chemical injury to the ACM is only a small      whereas others are endogenous signaling mole-
component of the resultant pathophysiologic pro-           cules such as complement fragments, lipid factors,
cess [14]. Thus, the relationship between inciting in-     and, most importantly, cytokines.
jury and ALI/ARDS pathophysiology (at least as                 The role of cytokine signaling in ALI/ARDS is
reflected by mortality) seems to be more complex.           vast and complex [25], but it can be schematized
Recent epidemiologic studies of ALI/ARDS have              using the paradigm of the innate immune response
suggested that additional factors such as age, sex,        [26]. The cascade of cytokine release that occurs
and race may influence both the risk of developing          during such a response begins with the activation
the disease and subsequent mortality, and these            of monocytes and macrophages in the lung (in di-
findings probably also reflect differences in the             rect injury) or in blood or other tissues (in indirect
pathophysiology of the disease as manifested in            injury). This activation stimulates the release of
these patients [2,15–17]. Therefore, any apprecia-         the first wave of cytokine signal: tumor necrosis
tion of ALI/ARDS pathophysiology must take                 factor-a (TNF-a) and interleukin-1b (IL-1b),
in to account the numerous underlying pathways             also known as ‘‘early-response cytokines.’’ These
thus far implicated in this disease and the grow-          key pleiotropic cytokines act upon leukocytes
ing number of host and other factors that seem             and other cell types (such as the alveolar epithe-
to influence their expression.                              lium and endothelium and lung fibroblasts) to ini-
                                                           tiate a cascade of secondary cytokines and to
                                                           release other soluble mediators, diversifying and
                                                           amplifying the inflammatory signal. Critical
Leukocytes and soluble mediators
                                                           among these secondary cytokines are those acting
   Much of the evolved understanding of ALI/               primarily on neutrophils (CXC cytokines, the
ARDS pathophysiology has centered on the role              most important of which is IL-8) and monocytes
of leukocytes and, most recently, the numerous             (CC cytokines, eg, macrophage inflammatory
soluble mediators that both drive their recruit-           protein-1), which serve both to activate and to
ment and influence their behavior (see Fig. 1). As          recruit these cells. Recent evidence suggests that
with the initial appreciation of alveolar epithelial       inflammation in ALI/ARDS results not so much
and endothelial injury in ALI/ARDS, early histo-           from the unopposed actions of these proinflam-
logic studies also identified neutrophils as a likely       matory cytokines as from the net balance of a mi-
key participant in this injury [1,4]. Since this ob-       lieu of both pro- and anti-inflammatory mediators
servation was made, studies have demonstrated              (eg, IL-10, soluble TNF-a receptor, and IL-1 re-
neutrophils to be the predominant cell type in             ceptor antagonist) [27]. Also crucial during this
bronchoalveolar lavage of patients who have                inflammatory cascade are cytokines (including
ALI/ARDS, and the persistence of this finding               TNF-a and IL-1b) that activate the vascular
seems to correlate with increased mortality                endothelium, particularly that of the lung, leading
[18,19]. Examination of bronchoalveolar lavage             to expression of leukocyte adhesion molecules [6].
has also implicated the release of injurious neutro-           Activation of both circulating neutrophils
phil contents, such as proteases and oxidants, in          and the vascular endothelium leads to rapid
the process [20]. Animal models of direct and              sequestration of neutrophils to the microvascular
                                            MECHANISMS OF ALI/ARDS                                         583

beds of the lung (Fig. 2). Unique among the tissues       converts plasminogen to the fibrinolytic factor,
of the body, the lung uses both classic leukocyte         plasmin. Plasmin, in turn, cleaves the small
adhesion mechanisms in this process (selectin-            amount of fibrin that is formed through the co-
and integrin-mediated endovascular adhesion and           agulation cascade, which is largely quiescent in
diapedesis [28]) and also a filter-like form of me-        the resting lung. In the setting of injury to the al-
chanical arrest, in which neutrophils stiffen after        veolar capillary membrane, this balance is over-
activation and can no longer pass through the             whelmed by the leakage of coagulation factors
small capillaries of the alveoli [29,30]. This mecha-     into the interstitium and airspace of the alveolus.
nism seems to be accentuated by the release of im-        This imbalance, coupled with the expression of
mature marrow neutrophils, which are larger and           procoagulant molecules (such as tissue factor)
less deformable [31,32], and may in part explain          by the injured endothelial and epithelial compo-
the elevated risk of ALI/ARDS in patients during          nents of the ACM and an increase in inhibitors
the recovery from neutropenia [24,33].                    of fibrinolysis (such as plasminogen activator-1,
    Given the importance of the innate immune             or as plasminogen-activator inhibitor type 1 [PAI-
system in the development of ALI/ARDS, it is              1]), leads to unopposed procoagulant activity
easy to appreciate how genetic variation involving        [37]. The resulting formation of fibrin-platelet
cytokines and their receptors might lead to               microthrombi in the capillaries and fibrin-rich
significant variability in the expression of ALI/          proteinaceous casts in the airspaces of the lung
ARDS after a given injury. For example, poly-             contributes significantly to ventilation-perfusion
morphisms in the gene for TNF-a have been                 mismatching in this disease. What has only re-
shown to be associated with increased susceptibil-        cently been appreciated is the interaction be-
ity to and mortality from ALI/ARDS [34], and              tween this imbalance of alveolar coagulation
multiple other polymorphisms in both pro- and             and fibrinolysis and the inflammatory processes
anti-inflammatory mediators and receptors such             of ALI/ARDS.
as IL-1 receptor antagonist and toll-like recep-              Recent studies have emphasized the multiple
tor-4 (the receptor for lipopolysaccharide) have          effects of thrombin and fibrin deposition on local
been shown to influence the clinical manifesta-            and systemic cellular activation and cytokine
tions of sepsis and possibly ALI/ARDS [17]. Fur-          production [38]. Fibrin and thrombin seem to ac-
thermore, the pivotal role of neutrophils and their       tivate both neutrophils and the vascular endothe-
cytotoxic contents in ALI/ARDS may explain, in            lium directly, leading to augmented expression of
part, the epidemiologic observations that chronic         adhesion molecules on both cell types and, in the
alcoholism, which is associated with a profound           case of the endothelium, to increased capillary
deficiency in the antioxidant glutathione, is associ-      permeability [39]. Such activation also drives the
ated with increased susceptibility to and mortality       further release of TNF-a and IL-1b and of other
from ALI/ARDS [35], whereas diabetic patients,            cytokines, such as IL-8, which further propagate
who manifest defects in neutrophil activation             the inflammatory response [38]. Platelets seem to
and function, are at a lower risk of developing           have similar proinflammatory actions in ALI/
ALI/ARDS [36].                                            ARDS but also may have some ameliorating ef-
                                                          fects on the capillary leak, making their net effect
                                                          in this process unclear [21]. Although trials of sev-
                                                          eral anticoagulant therapies for ALI/ARDS have
Coagulation and platelets
                                                          yielded mixed results [40], recent success with acti-
   The appearance of intra-alveolar hyaline mem-          vated protein C in the treatment of sepsis has sug-
branes and microvascular thrombi has been rec-            gested that this therapy may have a role in the
ognized as a histologic hallmark of acute ALI/            treatment of ALI/ARDS and has confirmed that
ARDS for decades (see Fig. 1) [1,4], but the full         such an approach may indeed attenuate both the
implications of these findings for the pathophys-          thrombotic and inflammatory events of ALI/
iology of ALI/ARDS have been appreciated only             ARDS [41,42]. Furthermore, studies of genetic
recently. Both findings reflect the exuberant de-           polymorphisms of coagulation proteins, such as
position of fibrin in the lung and represent a pro-        PAI-1 and thrombospondin, have related these
found imbalance in production and degradation             polymorphisms to variations in both proinflam-
of this molecule. In the uninjured lung a net fi-          matory cytokine levels and clinical outcomes for
brinolytic state is maintained through the action         patients who have sepsis and ALI/ARDS
of urokinase plasminogen activator, which                 [43,44]. This finding also suggests that genetic
584                                            SURATT & PARSONS


variation may influence the clinical expression of         mortality in those who had ALI/ARDS caused by
ALI/ARDS through polymorphisms of the cyto-               indirect injury [51]. Furthermore, genetic studies
kines themselves and of the coagulation pathways          have suggested that certain polymorphisms in
as well [45].                                             the SP-B protein may confer a greater risk for
                                                          the development of ALI/ARDS, particularly after
                                                          direct lung injury [52]. Thus, the importance of
                                                          surfactant dysfunction may be influenced by the
Surfactant
                                                          mechanism of injury and by host factors.
    One of the earliest theories about the patho-
physiology of ALI/ARDS concerned lung surfac-
tant and its dysfunction during ALI/ARDS [1].             Ventilator-induced lung injury
The role of surfactant in this disease has since
been appreciated to be complex and, as regards               Since the early observations of Webb and
possible therapeutic applications, somewhat per-          Tierney [53] that high tidal volume ventilation in
plexing. Surfactant is a lipoprotein complex,             rats leads to proteinaceous lung edema and
composed of phospholipids, neutral lipids, and            histologic findings consistent with ALI/ARDS,
surfactant proteins (SP-A, B, C, and D), that is se-      mechanical ventilation has been suspected to in-
creted by the type II alveolar epithelium and lines       fluence the manifestation of ALI/ARDS in hu-
the alveolar surfaces. Its functions are both bio-        mans. How such an interaction might be
physical and immunologic, in that it serves to de-        particularly accentuated in ALI/ARDS during
crease surface tension at the air/liquid interface        even physiologic levels of ventilation was sug-
(maintaining alveolar patency), and participates          gested subsequently by radiographic studies dem-
in critical elements of innate host defense [46].         onstrating the extreme heterogeneity of alveolar
Studies of bronchoalveolar lavage in patients             patency in this disease [54]. These studies revealed
who have ALI/ARDS have demonstrated that                  that aeration of the lung varies markedly, not only
surfactant is altered quite early in the course of        by lung region (with widespread patchy consolida-
the disease: the composition and form of surfac-          tion, particularly in the more dependent areas) but
tant changes, and it develops abnormal surface            also by the respiratory cycle. Thus, in the course
tension properties [47,48]. These changes seem to         of cyclic tidal volume delivery, three areas may
be driven by the influx of edema fluid and serum            be considered to exist [55]:
proteins into the alveoli and worsened by injury
                                                            1. Fluid-filled or collapsed areas in which the al-
to the type II epithelium (as described previously),
                                                               veoli never inflate during the respiratory cycle
ultimately leading to alveolar instability and col-
                                                               and which lead to a decrease in total lung
lapse, as well as to altered immune function (see
                                                               capacity
Fig. 1). Alveolar collapse decreases lung compli-
                                                            2. Patent areas in which alveoli may become
ance, worsens hypoxemia, and draws additional
                                                               overdistended during inspiration because of
edema fluid in to the alveoli [49], driving a vicious
                                                               shunting of delivered breath away from col-
cycle of further surfactant dysfunction and alveo-
                                                               lapsed areas
lar edema (see Fig. 2).
                                                            3. Atelectatic areas in which the alveoli repeat-
    Given the importance of surfactant in the
                                                               edly open and close with the respiratory cycle
pathophysiology of ALI/ARDS, the use of re-
                                                               because of alveolar instability, particularly
combinant surfactant to treat ALI/ARDS has
                                                               at lower levels of positive end-expiration
been of great interest [50,51]. Unlike the positive
                                                               pressure
results seen in neonatal respiratory distress syn-
drome (nRDS), however, trials of surfactant in               Therefore, mechanical ventilation in ALI/
ALI/ARDS have been disappointing. These re-               ARDS may lead to recurrent overdistension of
sults seem to underscore the relatively greater im-       the patent alveoli and to shear injury in the areas
portance of impaired surfactant production in             exposed to cyclic atelectasis.
nRDS versus surfactant function in ALI/ARDS                  Alveolar overdistension and shear seem to
[21]. Post hoc analysis of the most recent trial of       perpetuate and augment lung injury in three
surfactant replacement for ALI/ARDS suggested             important ways: local and systemic inflammatory
that such therapy reduced mortality in patients           signaling, direct disruption of the ACM, and
who had ALI/ARDS secondary to direct injury               impairment of alveolar fluid clearance (see
(pneumonia or aspiration) but may have increased          Fig. 2). Animal studies have shown that
                                            MECHANISMS OF ALI/ARDS                                         585

mechanical ventilation, particularly at high tidal        as much by these corrective responses as by the
volumes, leads to both pulmonary and systemic             initiating and ongoing injuries discussed previously.
release of inflammatory cytokines, including               Resolution of ALI/ARDS involves the termination
TNF-a, IL-1b, and IL-6, and the recruitment of            of the inflammatory response, the clearance of both
neutrophils to the lung. This process seems to be         fluid and debris from the alveoli, and the repair of
driven, in part, by cyclical stretching of lung mac-      the ACM (see Fig. 1). Clinical and animal studies
rophages and type II pneumocytes, which pro-              have suggested that an imbalance of corrective
motes activation of these cells [56,57]. Clinical         and injurious forces or dysregulation of the repair
studies confirm that inflammatory cytokines, in-            process itself may lead to pathophysiology in the
cluding IL-6 and IL-8, are released into the lung         later phase of ALI/ARDS and to poor outcome
and blood during mechanical ventilation of pa-            from this disease [21].
tients who have ALI/ARDS, and that this effect                 Fluid resorption from the alveolar airspace
is attenuated by the use of lower tidal volumes           and interstitium is dependent on the active trans-
(6 mL/kg) than traditionally used (10–12 mL/kg)           port of sodium (and with it, water) by the type II
[58–60]. In addition to the possible proinflamma-          epithelium and reconstitution of the ACM barrier.
tory effects of mechanical ventilation, direct me-         Failure of fluid resorption, even as measured quite
chanical injury to the ACM may occur at high              early in the disease process, is predictive of
tidal volumes as the result of cell membrane dis-         mortality from ALI/ARDS [10]. Thus, regenera-
ruption [61,62] and mechanically transduced acti-         tion of the alveolar epithelium structure and func-
vation of the alveolar endothelium [63]. These            tion, as described later, is a critical event in the
processes seem to be exacerbated by concomitant           recovery from ALI/ARDS. The removal of cellu-
ALI/ARDS, so that even tidal volumes consid-              lar and other debris from the airspace is also im-
ered to be physiologic may provoke significant di-         portant, both in the restoration of gas exchange
rect injury to the lung [64]. Last, mechanical            and in the resolution of inflammation and repair
ventilation in ALI/ARDS may reduce airspace               of the damaged epithelium. Apoptosis (or con-
edema clearance further through alteration of             trolled cell death) is the central mechanism of
type II pneumocyte function [65].                         cell clearance for both injured alveolar epithelium
    The observation that mechanical ventilation,          and recruited inflammatory cells. Apoptosis seems
even at physiologic tidal volumes, may compound           to be a double-edged sword in ALI/ARDS: al-
the severity of lung injury in ALI/ARDS led to            though the induction of apoptosis may contribute
a series of clinical trials examining low tidal           to epithelial injury in early ALI/ARDS [66], it also
volume ventilation strategies for this disease.           is critical in the removal of neutrophils by airspace
The largest of these trials demonstrated that a           macrophages [67]. Furthermore, the clearance of
6-mL/kg (ideal body weight) tidal volume strategy         apoptotic cells from the airspace seems to alter
led to a reduction in ALI/ARDS mortality from             the cytokine milieu and attenuate the inflamma-
40% to 31% compared with a conventional tidal             tory response in the lung [68]. In addition to the
volume strategy of 12 mL/kg [59]. The significance         removal of cellular debris, the clearance of insolu-
of this finding cannot be overemphasized, because          ble proteinaceous debris, particularly hyaline
to date it represents the only specific intervention       membranes, is essential for gas exchange and for
ever shown in a large-scale trial to reduce mortal-       restoration of the normal architecture of the
ity from this disease significantly. It also suggests      alveolus.
that yet another factor may dramatically influence             Repair of the ACM is a complex process
the pathophysiology and outcome of ALI/ARDS:              involving local cellular proliferation and, proba-
physician practice.                                       bly, the recruitment of circulating progenitor cells.
                                                          As the clearance of airspace edema and debris
                                                          progresses, repair of the alveolar structure occurs
                                                          through the orderly replacement of its cellular
Late-phase pathophysiology: dysregulated
                                                          constituents. The denuded alveolar epithelium is
and maladaptive repair
                                                          replaced through a proliferation of the remaining
    Even as the multiple pathophysiologic processes       type II pneumocytes, which spread to cover the
of early ALI/ARDS promulgate alveolar injury and          exposed basement membrane and subsequently
edema, reparative processes are initiated within the      transdifferentiate into type I cells. At the same
lung that drive toward resolution of the disease.         time, the alveolar interstitium is restored through
Thus, the course of ALI/ARDS may be determined            the orderly expansion of fibroblasts and
586                                           SURATT & PARSONS


deposition of extracellular matrix proteins, the         The frustration of generations of clinicians and
alveolar microcirculation is recanalized, and the        researchers in developing consistent paradigms for
damaged endothelium is replaced. Although re-            the understanding and treatment of ALI/ARDS
pair to the damaged lung in ALI/ARDS can lead            underscores the fundamental variability of mech-
to substantial, although incomplete, restoration of      anisms that underlie this condition. Recent prog-
lung function in survivors [69], divergence from         ress in the fields of immunology, molecular
this choreographed sequence of events may lead           biology, genetics, and epidemiology has allowed
to severe consequences. The best described of            greater appreciation of the multiple factors influ-
these consequences is the ‘‘fibroproliferative            encing this disease. In the end, each individual
phase’’ of ALI/ARDS that may develop approxi-            affected by ALI/ARDS must be seen as represent-
mately 5 to 7 days into the disease course and is        ing a unique combination of genetics, comorbid
characterized by an exuberant fibrotic response           conditions, inciting events, and factors yet to be
[4] that has been likened to wound healing in the        discovered that drive the process of ALI with
alveolar airspace [70]. This maladaptive repair re-      variable contributions from the many pathophys-
sponse seems to be promoted by severe injury to          iologic mechanisms elucidated in the past 40
the ACM and extensive hyaline membrane forma-            years.
tion, which lead to migration of myofibroblasts
into the alveoli and subsequent formation of gran-
ulation tissue with physiologic compromise [70].
                                                         References
Recent studies indicate that these migrating cells
may, in fact, be recruited from the bone marrow           [1] Ashbaugh DG, Bigelow DB, Petty TL, et al. Acute
[71], suggesting that blockade of this cytokine-me-           respiratory distress in adults. Lancet 1967;2(7511):
diated recruitment might represent a future thera-            319–23.
peutic approach to this devastating complication          [2] Rubenfeld GD, Caldwell E, Peabody E, et al. Inci-
[72].                                                         dence and outcomes of acute lung injury. N Engl
                                                              J Med 2005;353(16):1685–93.
    Circulating precursor cells also seem to be
                                                          [3] Bernard GR, Artigas A, Brigham KL, et al. The
critical in the normal restoration of the ACM.                American-European Consensus Conference on
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