The Acute Respiratory Distress Syndrome:
From Mechanism to Translation
SeungHye Han and Rama K. Mallampalli
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References
J Immunol 2015; 194:855-860; ;
doi: 10.4049/jimmunol.1402513
http://www.jimmunol.org/content/194/3/855
The
Brief Reviews
Journal of
Immunology
The Acute Respiratory Distress Syndrome: From
Mechanism to Translation
SeungHye Han* and Rama K. Mallampalli*,†,‡
T
he acute respiratory distress syndrome (ARDS) is
a form of hypoxemic respiratory failure that is characterized by severe impairment of gas exchange and
lung mechanics, with a high case fatality rate. It is defined
by acute hypoxemia (the ratio of partial pressure of arterial
oxygen/the fraction of inspired oxygen # 300 mm Hg on
positive end-expiratory pressure $ 5 cm H2O), with bilateral
infiltration on chest imaging that cannot be explained fully by
cardiac failure or fluid overload (1). Acute lung injury (ALI),
a term that has been widely used in experimental lung injury
models, is categorized as a mild form of the human disorder
ARDS per the recent Berlin definition (1). The incidence of
this clinical syndrome has been on the rise and now reported
up to 86.2/100,000 person-years (2), which equals ∼200,000
cases annually in the United States. The hospital mortality is
high, at 38.5% (2), and has not significantly improved for the
past several decades. The most common risk factor is severe
sepsis with either a pulmonary or nonpulmonary source,
explaining 79% of the cases (2). Other risk factors include
aspiration, toxic inhalation, lung contusion, acute pancreati-
*Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine,
Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213;
†
Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, PA
15213; and ‡Medical Specialty Service Line, Veterans Affairs Pittsburgh Healthcare
System, Pittsburgh, PA 15240
Received for publication October 2, 2014. Accepted for publication November 12,
2014.
This work was supported by a Merit Review Award from the U.S. Department of
Veterans Affairs and National Institutes of Health Grants R01 HL096376, R01
HL097376, R01 HL098174, R01 HL081784, 1UH2HL123502, and P01 HL114453
(to R.K.M.). This material is based upon work that was supported in part by
the Biomedical Laboratory Research and Development, Office of Research and
Development, Veterans Health Administration, U.S. Department of Veterans
Affairs.
www.jimmunol.org/cgi/doi/10.4049/jimmunol.1402513
tis, trauma, transfusion, burn injury, and cardiopulmonary
bypass surgery (3).
Existing treatments
Numerous treatment measures aiming to modulate inflammation or its physiological consequences have been investigated
for the treatment of ARDS. However, current anti-inflammatory
therapies [corticosteroids (4), neutrophil elastase inhibitors (5),
GM-CSF (6), statins (7), and omega-3 fatty acid (8)] and
therapies targeted at improving lung mechanics [surfactant
(9), inhaled b agonists (10), and NO (11)] failed to show
a mortality benefit. Only supportive therapies that minimize
pressure-induced lung injury (barotrauma) during mechanical
ventilation, such as lung-protective ventilation (12) with the
use of neuromuscular blockers (13) or prone positioning (14),
improved mortality; thus, these treatments remain the mainstay
of care.
Fundamentals of pathophysiology (inflammation and
immunosuppression)
The innate immune response plays a profound role in the
pathophysiology of ARDS. Multiple immunologic processes
involving neutrophils, macrophages, and dendritic cells partake in mediating tissue injury. Inflammatory insults, either
locally from the lungs or systemically from extrapulmonary
sites, affect bronchial epithelium, alveolar macrophages, and
vascular endothelium, causing accumulation of protein-rich
edema fluid into the alveoli and, subsequently, hypoxemia
due to impaired gas exchange. Alveolar macrophages play
a central role in orchestrating inflammation, as well as the
resolution of ARDS (15). Once alveolar macrophages are
stimulated, they recruit neutrophils and circulating macrophages to the pulmonary sites of injury. These cells partake in
the elaboration of a diverse array of bioactive mediators, including proteases, reactive oxygen species, eicosanoids, phospholipids, and cytokines, that perpetuate inflammatory
responses. One profound effect of these mediators is to
The content of this publication does not necessarily represent the views of the Department of Veterans Affairs or the U.S. Government.
Address correspondence and reprint requests to Dr. Rama K. Mallampalli, Division of
Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of
Pittsburgh, UPMC Montefiore, NW 628, Pittsburgh, PA 15213. E-mail address:
[email protected]
Abbreviations used in this article: ALI, acute lung injury; ARDS, acute respiratory distress
syndrome; DAMP, danger (or damage)-associated molecular pattern; ENaC, epithelial Na+
channel; HIF, hypoxia-inducible factor; MSC, mesenchymal stem cell; NET, neutrophil
extracellular trap; NLR, nucleotide-binding oligomerization domain-like receptor; NLRP,
NLR, pyrin domain containing; PAMP, pathogen-associated molecular pattern; PMN,
polymorphonuclear neutrophil; PRR, pattern recognition receptor.
Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00
Downloaded from http://www.jimmunol.org/ by guest on June 18, 2017
The acute respiratory distress syndrome (ARDS) is
a form of severe hypoxemic respiratory failure that is
characterized by inflammatory injury to the alveolar
capillary barrier, with extravasation of protein-rich
edema fluid into the airspace. Although many modalities to treat ARDS have been investigated over the past
several decades, supportive therapies remain the mainstay of treatment. In this article, we briefly review
the definition, epidemiology, and pathophysiology of
ARDS and present emerging aspects of ARDS pathophysiology that encompass modulators of the innate
immune response, damage signals, and aberrant proteolysis that may serve as a foundation for future therapeutic targets. The Journal of Immunology, 2015,
194: 855–860.
856
FIGURE 1. Acute exudative phase of ARDS. Low-magnification photomicrograph showing alveolar inflammatory infiltration and filling of air sacs
with protein-rich fluid (H&E, low magnification) (16).
Emerging aspects of ARDS pathophysiology
Pattern recognition receptors: TLRs and nucleotide-binding
oligomerization domain-like receptors. Pattern recognition
receptors (PRRs) are critical to surveillance in innate immunity, detecting components of foreign pathogens referred to as
pathogen-associated molecular patterns (PAMPs). TLRs are
one of the transmembrane PRR proteins and are highly
conserved molecules throughout vertebrates (27). Ten
functional TLRs have been identified in humans (28).
They recognize nonendogenous PAMPs and trigger a rapid
response to cause proinflammatory signaling. Recently, some
TLRs were found to recognize endogenous danger (or
damage)-associated molecular patterns (DAMPs) as well.
Unlike TLRs, nucleotide-binding oligomerization domainlike receptors (NLRs) are cytosolic PRRs that respond to
the various PAMPs and DAMPs to trigger proinflammatory
responses.
Development and resolution of ARDS seems to be related to
TLR signaling pathways. Hyaluronan, an extracellular matrix
glycosaminoglycan produced after tissue injury, initiates the
inflammatory response in ARDS through engagement of
TLR2 and TLR4; at the same time, it promotes recovery from
ARDS (29). TLR4 was described as playing a pivotal role in
the induction of ARDS in various murine models (30). TLR3
mediates hyperoxia-induced ARDS (31), and TLR2 mediates
hemorrhage-induced ARDS (32).
Recent studies showed that NLRs are responsible for sterile
inflammation in ALI. One of them, NLRP (NLR family, pyrin
domain containing) is an important component of the inflammasome, a large multiprotein complex. This complex is
activated by pore-forming toxins or hypoxic cellular injury
when conditions are primed with microbial ligands or endogenous cytokines (33). Specifically, the NLRP3 inflammasome is made up of three components: NLRP3, ASC, and
procaspase 1. Once assembled, inflammasomes cleave pro–IL1b and pro–IL-18, generating active IL-1b and IL-18. The
NLRP3 inflammasome and its interaction with extracellular
histones (34) was found to be required for the development of
hypoxemia in a murine ARDS model (35). Also, inflammasome-regulated cytokines are associated with worse outcomes in ARDS subjects (36).
Mitochondrial DAMPs. Further compounding the inflammation
from sepsis-induced ARDS is the release of mitochondrial
components from cellular damage into the circulation. These
mitochondrial-derived products include mitochondrial DNA,
formyl peptides, and cardiolipin, which serve as DAMPs to
other cells (37, 38), triggering sterile inflammation and
a clinical phenotype, the systematic inflammatory response
syndrome (39). Both traumatic and operative injuries (40),
which are risk factors for ARDS, release mitochondrial
DAMPs into the circulation and activate polymorphonuclear
neutrophils (PMNs) as a proinflammatory response. Mitochondrial DAMPs are present in blood-transfusion products,
suggesting a possible link with transfusion-related ARDS
(41). Increased permeability of endothelial cells, which is
a critical event causing hypoxemia in ARDS, is triggered by
fragmented mitochondria (mitochondrial DAMP) in PMNdependent and PMN-independent fashions (42). Elevated
mitochondrial DNA levels in plasma also are associated
with higher mortality in patients with or without ARDS
in the surgical and trauma (43), as well as the medical (44),
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damage or induce distal cell death, specifically alveolar type 2
epithelial cells. These cells serve vital functions by synthesizing
and secreting pulmonary surfactant, which is an indispensable
material that lines the inner lung surface to lower alveolar
surface tension. Type 2 cells also actively partake in ion
transport to control lung fluid. Together, these inflammatory
events lead to histological changes typical of an acute exudative phase that results in significant impairment of lung mechanics and gas exchange (Fig. 1) (16). During the initial
inflammatory and/or resolution phases of ARDS, alveolar
macrophages also coordinate in a paracrine manner to interact
with other cells, including epithelial cells (17), lymphocytes
(18), and mesenchymal stem cells (19), which can result in
augmentation of the inflammatory response or accentuation
of tissue injury. Prolonged M1 (classically activated macrophages) or M2 (alternatively activated macrophages) phenotypes appear to be associated with nonhealing chronic ARDS
(20).
ARDS is a systemic inflammatory disease with bidirectional
involvement between the lungs and other organ systems, rather
than a local pulmonary process. Inflammatory cytokines, such
as IL-1b, TNF-a, IL-6, and IL-8, are elevated both in
bronchoalveolar lavage fluid and circulating plasma in ARDS
subjects (21). Interestingly, systemic immunosuppression is
also observed in prolonged nonresolving ARDS patients, even
though pulmonary inflammation is present simultaneously.
An observational study in humans showed that peripheral
blood samples from 23 subjects with ARDS secondary to
trauma or surgery had decreased cytokine release after LPS
exposure (22). Also, autoantibodies are produced rapidly
during ARDS (23). Although ARDS is characterized by lung
inflammation, it is worth noting that many risk factors for
ARDS can induce organ-specific inflammation. For example,
traumatic brain injury (24), sepsis (25), and burn injury (26)
cause robust inflammation in lungs, as well as systemic immunosuppression. Further studies are necessary to clarify
whether ARDS contributes to this differential inflammation
independently of these risk factors.
BRIEF REVIEWS: INFLAMMATION AND ARDS
The Journal of Immunology
(60). Neutrophil extracellular traps (NETs) are produced by
neutrophils and are released to the extracellular space to trap
pathogens, such as bacteria, fungi, viruses, and protozoa (61),
a process known as NETosis. In a murine ARDS model,
NETs are formed in lung tissue, directly inducing the cell
death of lung epithelia and endothelia (62). NETs are
found in a variety of ARDS models, including both
infection-related injury [influenza (63), bacterial endotoxin
(64), and fungi (65)] and sterile lung injury [transfusionrelated ARDS (66)]. The lower levels of surfactant proteins
A and D that are commonly observed in ARDS appear to be
responsible for excessive NETs in ARDS, because surfactant
proteins are involved in clearing NET nucleic acid (64).
Potential new therapeutic targets in ARDS
Targeting the ubiquitin proteasome system. Recently, proteasome
inhibitors, such as bortezomib (67) and carfilzomib (68), were
approved for the treatment of multiple myeloma by the U.S.
Food and Drug Administration. Several new proteasome
inhibitors are now in development as anticancer therapies.
There is mounting evidence that inhibiting the proteasome
may induce anti-inflammatory effects (69). Hypoxia-inducible
factor (HIF)-1a, a transcription factor that controls the expression of numerous genes, is targeted for ubiquitin
proteasomal degradation. HIF-1a appears to be protective
against ARDS, because pharmacologic stabilization of HIF1a lessens ALI severity in preclinical models (70). Inhibiting
the proinflammatory protein Fbxo3 effectively decreases the
severity of viral pneumonia, septic shock, cytokine-driven
systemic inflammation, and ARDS in preclinical models,
underscoring the potential for targeting of the ubiquitin
proteasome system in ARDS (51, 71).
Inflammasomes: modification of the upstream and downstream
pathways. As reviewed earlier, inflammasomes play a critical
role in the development of sterile inflammation during ARDS.
Several agents to modify NLRP3 inflammasome signaling have
been studied. Antioxidants (72) and glyburide (73) block
upstream signaling of the NLRP3 inflammasome in vitro.
P2X7R antagonists (74) also inhibit upstream pathways before inflammasomes are assembled, but they have not been
tested for lung inflammation. In contrast, a caspase-1
inhibitor decreases the release of IL-1b and IL-18 in rat
endotoxemia (75), targeting a downstream pathway to
inhibit the products of inflammasome activation. Anti–
IL-1 therapy is another approach to limit inflammasome
activation. A mAb against human IL-1b (canakinumab) is
licensed to treat cryopyrin-associated periodic syndrome
(76), a rare genetic disease caused by autosomal-dominant
mutations of the NLRP3 gene. Recombinant IL-1Ra
(anakinra) and IL-1 Trap (rilonacept) are approved to treat
rheumatoid arthritis and cryopyrin-associated periodic
syndromes, respectively (77). However, the purported role
of these agents as anti-inflammatory therapy for ARDS has
not been evaluated in preclinical settings. New chemical
entities directly targeting the inflammasome (NLRs) have
not been identified.
Modulating inflammation. Numerous anti-inflammatory agents
have failed to show any mortality benefit in ARDS subjects.
Currently untested alternatives for the treatment and prevention of ARDS in human randomized controlled trials are
inhaled corticosteroids, angiotensin-converting enzyme inhibitors,
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intensive care unit. Finally, a mitochondrial-targeted inhibitor
was shown to mitigate the apoptosis of mouse lung endothelial
cells after irradiation (45). These mitochondrial DAMPs
also may be the cause of the differential inflammation observed in trauma, sepsis, and ARDS (46), but further
studies are necessary to confirm the mechanistic basis for
these findings.
Ubiquitin biology in lung injury. Ubiquitin is a small regulatory
molecule found universally in most tissues in eukaryotic
organisms. Ubiquitination is a posttranslational modification
process whereby ubiquitin is attached to a substrate protein,
usually serving as the signal for its degradation via the proteasome or lysosome. Ubiquitination is carried out in three
main steps performed by one or two ubiquitin-activating
enzymes, several ubiquitin-conjugating enzymes, and hundreds
of ubiquitin ligases (E3 ligases). In the ubiquitination cascade,
the ability of E3 ligases to target a specific substrate for its
degradation provides an elegant mechanism for protein disposal
in cells but also opens up attractive opportunities for relatively
selective therapeutic intervention.
ARDS is characterized by activation of the ubiquitin proteasome system (47), increased expression of ubiquitin within
alveolar (type II) epithelia (48), and release of ubiquitin proteasome components into lung fluid (49). Ubiquitin components (E3 ligases) are also activated by endotoxin (50). An
endotoxin-responsive ubiquitin E3 ligase component, termed
Fbxo3, is elevated in subjects with sepsis. It profoundly stimulates cytokine release when expressed in human PBMCs by
mediating the degradation of another E3 ligase subunit, Fbxl2.
Fbxl2 acts as an anti-inflammatory protein, inhibiting TNF
receptor-associated factors (51). Ubiquitination also was reported to play an important role in regulating the Na, KATPase and epithelial Na+ channel (ENaC) functions during
ARDS (47). Specifically, the E3 ubiquitin ligase Cblb negatively
regulates TLR4 signaling to prevent hyperactivation of NF-kB
in a sepsis-induced ARDS murine model (52). The disruption
of the alveolar–capillary barrier is one of the key pathophysiologic events causing lung edema and hypoxemia in ARDS. The
Na, K-ATPase is located in the basolateral surface of alveolar
type 2 epithelial cells (53), contributing to lung liquid clearance.
During hypoxia, the Na, K-ATPase is internalized and degraded
by endocytosis via ubiquitination, resulting in alveolar epithelial
barrier dysfunction and, consequently, decreased alveolar fluid
clearance (54, 55). ENaC is responsible for salt and fluid absorption in lung epithelia, and its cellular abundance is regulated
by the E3 ligase Nedd4-2 (56). Interestingly, hypoxia inhibits
expression of the ENaC subunit at the apical membrane of
murine alveolar epithelial cells, which may occur via Nedd4-2–
mediated ubiquitination (57). Furthermore, Nedd4-2–knockout mice develop sterile lung inflammation with some similarities to an ARDS phenotype (58). The emerging role of these
protein-degradation factors in ARDS presents the opportunity
for identification of unique therapeutic targets.
Neutrophil biology/neutrophil extracellular traps. Neutrophil influx into the lungs in response to activated alveolar macrophages is associated with the severity of ARDS, and it
may directly influence the development of this disorder (59).
Several chemokines, including IL-8 (CXCL8), seem to
play a central role in regulating neutrophil recruitment
and consequent tissue damage, as well as altered alveolar–
capillary permeability in both human and animal studies
857
858
FIGURE 2. Pathophysiology of ARDS. Initial inflammatory insults, including mitochondrial DAMPs,
activate alveolar macrophages via TLR and NLR signaling
pathways. Activated alveolar macrophages release proinflammatory cytokines and recruit circulating macrophages
and neutrophils to injured sites. Excessive neutrophils and
persistently activated macrophages cause extensive damage
to lung epithelia and endothelia, resulting in an impaired
alveolar–capillary barrier. Disruption of this barrier allows protein-rich fluid to enter the alveoli, causing fluid
accumulation in alveolar spaces (pulmonary edema) that
interferes with gas exchange. Ubiquitination (Ⓤ) plays an
important role in modulating the abundance of key
proteins in ARDS, resulting in secretion of cytokines,
lower levels of surfactant proteins, and decreased function
of ion channels (Na, K-ATPase and ENaC). ARDS is
associated with surfactant depletion, leading to increased
NETosis, a process that alters lung cell viability. Mitochondrial DAMPs can directly increase microvascular
permeability independently of leukocytes. MF, macrophage.
easy to isolate and propagate and do not generate the ethical
issues associated with embryonic stem cells. Preclinical studies
showed that MSCs reduced lung inflammation and mortality
in a murine ARDS model (85). This beneficial effect of MSC
therapy was reproduced in ex vivo–perfused human lungs
(86); this seems to be primarily due to the release of
keratinocyte growth factor by MSCs. There was no toxicity
in a recently published phase I clinical trial (87). Another
phase I trial started enrolling subjects to receive MSCs
(START; NCT01775774) (88).
Conclusions
In summary, the highly complex signaling and cellular networks that mediate tissue injury in ARDS present significant
challenges in devising novel therapies for this disorder (Fig. 2).
However, this pathobiologic model provides a mechanistic
platform offering unique opportunities to identify new targets
for intervention. The pathobiology of ARDS involves cellular,
biochemical, and organelle-based mediators, with activation of components within the innate immune response that
incites significant pulmonary inflammation. The identifica-
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and peroxisome proliferator receptor agonists. Animal data
suggest that nebulized corticosteroids improve dynamic
lung compliance and oxygenation and decrease lung inflammation in sepsis-induced ARDS models (78). Angiotensin II
induces NF-kB gene expression (79); hence, blocking the
renin–angiotensin axis may be beneficial to ARDS patients
based on animal data (80) and an observational human study
(81). In contrast, peroxisome proliferator receptors and their
respective ligands negatively control proinflammatory gene
expression (82). Their agonists reduce inflammation and
vascular leakage in animal ARDS experimental models
(83). However, human randomized controlled trials are
necessary to examine the effect and efficiency of all of
these modalities.
Cell-based therapy (stem cell). An exciting area of investigation is
assessing cell-based therapy for ARDS using stem cells, because
these cells have the potential to differentiate into alveolar
epithelial or lung endothelial cells and directly replenish
the alveolar–capillary barrier during cellular injury (84).
Mesenchymal stem cells (MSC) are rapidly advancing to the
clinical setting because they have practical advantages: they are
BRIEF REVIEWS: INFLAMMATION AND ARDS
The Journal of Immunology
tion of unique druggable targets within the ubiquitin cascade
related to PRRs or stem cells holds promise in advancing
a new frontier for treating this critical illness based on the
mechanistic biology.
Disclosures
R.K.M. has an equity interest and serves as Chairman of the Scientific Advisory
Board for E3 Therapeutics.
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BRIEF REVIEWS: INFLAMMATION AND ARDS
The Journal of Immunology
Corrections
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