Sindrom Distres Pernapasan Akut: Mekanisme dan Perspektif Pendekatan Terapeutik

The Acute Respiratory Distress Syndrome: Mechanisms and Perspective Therapeutic

Approaches
JN Gonzales,1,2,* R Lucas,1,3 and AD Verin1,2

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Abstract
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Acute Respiratory Distress Syndrome (ARDS) is a severe lung inflammatory disorder with a
3050% mortality. Sepsis and pneumonia are the leading causes of ARDS. On the cellular
level there is pulmonary capillary endothelial cell permeability and fluid leakage into the
pulmonary parenchyma, followed by neutrophils, cytokines and an acute inflammatory
response. When fluid increases in the interstitium then the outward movement continues and
protein rich fluid floods the alveolar spaces through the tight junctions of the epithelial cells.
Neutrophils play an important role in the development of pulmonary edema associated with
acute lung injury or ARDS. Animal studies have shown that endothelial injury appears within
minutes to hours after Acute Lung Injury (ALI) initiation with resulting intercellular gaps of
the endothelial cells. The Endothelial Cell (EC) gaps allow for permeability of fluid,
neutrophils and cytokines into the pulmonary parenchymal space. The neutrophils that
infiltrate the lungs and migrate into the airways express pro-inflammatory cytokines such as
tumor necrosis factor-alpha (TNF-), interleukin-1 beta (IL-1), and contribute to both the
endothelial and epithelial integrity disruption of the barriers.
Pharmacological treatments have been ineffective. The ARDS Network trial identified low
tidal volume mechanical ventilation, positive end expiratory pressure and fluid management
guidelines that have improved outcomes for patients with ARDS. Extracorporeal membrane
oxygenation is used in specialized centers for severe cases. Prone positioning has recently
proven to have significantly decreased ventilator days and days in the intensive care unit.
Current investigation includes administration of mesenchymal stem cell therapy, partial fluid
ventilation, TIP peptide nebulized administration and the continued examination of
pharmacologic drugs.

Introduction
Acute Respiratory Distress Syndrome (ARDS) is a severe lung inflammatory disorder with a
3050% mortality [1,2]. Sepsis and pneumonia are the leading causes of ARDS. On the
cellular level there is pulmonary capillary endothelial cell permeability and fluid leakage into
the pulmonary parenchyma, followed by neutrophils, cytokines and an acute inflammatory
response [3]. When fluid increases in the interstitium then the outward movement continues
and protein rich fluid floods the alveolar spaces through the tight junctions of the epithelial
cells. ARDS was initially described in the 1960s by Petty and Ashbaugh [4]. In 1994 a large
clinical network was established through the National Heart, Lung and Blood Institute
(NHLBI) with the goal of efficiently testing promising agents, devices or management
strategies to improve the care of patients with ARDS (NHLBI ARDS Network website). The
ARDS Network trial identified low tidal volume mechanical ventilation, Positive End
Expiratory Pressure (PEEP) and fluid management guidelines that have improved outcomes
for patients with ARDS. Other management modalities have been tested including steroids,
antifungals, beta agonist and nitric oxide. The pharmacologic trials have not yielded a
therapeutically effective strategy. Treatment modalities include Extracorporeal Membrane
Oxygenation (ECMO), ventilator bundles and persistent evaluation of pharmacological
entities such as heparin [5]. Current research is primarily focused on the role of biological
biomarkers in early therapeutics or preventative approaches for ARDS [6] and mesenchymal
stem cell treatment [7].
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Pathophysiology
ARDS is a Non-Cardiogenic Pulmonary Edema (NCPE). The NCPE in ARDS is ultimately a
result of capillary permeability secondary to cellular damage, inflammatory cascades, and
over inflation by mechanical ventilation resulting in endothelial permeability. The endothelial
cell barrier is a single layer of continuous endothelium lining the pulmonary capillaries and
forms a single layer between blood and the pulmonary interstitium. The pulmonary
capillaries have extremely thin walls to allow rapid exchange of respiratory gases across them
[8]. In ARDS disturbances of pulmonary capillary fluid balance and pulmonary permeability
occur as a direct result of bacterial infection, endotoxins and subsequent inflammation that
cause disruption in the capillary EC barrier with barrier disruption and subsequent pulmonary
venous congestion. As the fluid overload initially enters the pulmonary interstitium it is taken
up by the lymphatic system to be returned to the vascular system. The hydrostatic forces are
then altered as a direct result of injury to the capillary endothelium. The interstitial space can
increase its volume by as much as 40% without resulting in pulmonary edema [9]. However
persistent fluid accumulation overwhelms the lymphatic drainage and tissue edema results.
Finally, when the fluid overwhelms the hydrostatic forces and the excess fluid flows into the
alveoli. The edema that is caused by the increasing fluid and vascular permeability is a
hallmark of inflammation and tissue injury [10]. The edema formation can have severe
consequences because the fluid and protein components in the edematous tissues and alveoli
increase the diffusion barrier for oxygen and carbon dioxide with subsequent disruption of
gas exchange thus precipitating hypoxia and respiratory failure. The ensuing pulmonary
edema in patients with ARDS has been shown to be a high protein pulmonary edema. In fact,
the fluid/ plasma ratio may be used to differentiate the etiology of pulmonary edema in
ARDS and cardiogenic pulmonary edema. The fluid/plasma ratio is a measurement of the
alveolar fluid obtained by Bronchial Alveolar Lavage (BAL), to the serum plasma during
acute pulmonary edema and has been shown sensitive enough to differentiate a low protein
fluid that results from cardiac pulmonary edema compared to a high protein ratio that occurs
with illness such as ARDS [11,12]. The protein concentration in the pulmonary interstitium
of ARDS exceeds 60% of the plasma value whereas the protein concentration in non ARDS
causes is less than 45% [13,14]. The result is a high permeability of the EC barrier and a high
protein in the interstitial space with the protein content similar to blood. The acute rate of
volume accumulation is another factor in the subsequent hypoxic respiratory failure and
pulmonary edema. Pulmonary alveoli, the primary sites of gas exchange with the blood, are
composed of a thin alveolar epithelium that covers 99% of the surface area in the lung and
contains thin, squamous type I cells and cuboidal type II cell. Type I cells cover 95% of the
alveolar surface. The epithelial lined alveolar spaces facilitate gas exchange and form a tight
barrier to fluid and protein movement from the interstitial and vascular spaces maintaining
relatively dry alveoli. Tight junctions connect adjacent epithelial cells near the apical surfaces
and maintain apical and basal-lateral cell polarity. The tight junctions are important elements
of the permeability barrier necessary to maintain normal gas exchange. The alveolar type II
cell that secretes surfactant contributes to the vectorial transport of sodium. Active transport
of sodium provides a major driving force for fluid removal from the alveolar space.
Amiloride sensitive sodium channels on the apical surface, mainly the Epithelial Sodium
Channel (ENaC) are involved in fluid transport with the driving force represented by the
sodium/potassium adenosine triphosphatase (Na+/K+-ATPase) on the basolateral surface [15].
Injury of the alveolo-capillary barrier alters active Na+ transport, leading to impaired edema
fluid clearance from the alveolar spaces. The primary force driving fluid reabsorption from
the alveolar space into the interstitium and the pulmonary circulation is active Na+ transport.
Sodium is taken up on the apical surface of the alveolar epithelium by Amiloride-sensitive
and insensitive Na+ channels and is subsequently pumped out of the cell by Na+/K+-ATPase
on the basal-lateral side (Gene Therapy in Critical Care
Medicine http://dx.doi.org/10.5772/52701, by Moreno-Gonzalez and Zarain-Herzberg, 2013).
Pulmonary edema is caused by a dysregulated function of the ion channels in type II alveolar
epithelial cells [15].
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The Role of Neutrophils ALI/ARDS

Neutrophils play an important role in the development of pulmonary edema associated with
ALI/ARDS [16]. Initially pulmonary macrophages are activated and recruit neutrophils to the
injured capillaries where they are found leaking into the pulmonary parenchymal interstitium.
Here they sequester and initiate an important component of the inflammatory response in
endotoxin induced ALI/ARDS. This activation and migration of neutrophils is a characteristic
event in the progression of ALI and ARDS. Animal studies have shown that endothelial
injury appears within minutes to hours after ALI initiation with resulting intercellular gaps of
the EC. The EC gaps allow for permeability of fluid, neutrophils and cytokines into the
pulmonary parenchymal space [17]. The neutrophils that infiltrate the lungs and migrate into
the airways express pro-inflammatory cytokines such as TNF-, IL-1, and contribute to both
the endothelial and epithelial integrity disruption of the barriers [16,18]. It has also been well
documented that the percentage of neutrophils correlates directly with the alveolar-arterial
partial pressure of oxygen (PO2) difference in ALI/ARDS pulmonary edema [19]. Neutrophil
sequestration is aided by chemotactic factors and by the adhesion molecules on both the
neutrophils and capillary endothelial cells [20,21].The activated neutrophils expressing IL-1
produce other pro-inflammatory cytokines after endotoxin administration. In fact the removal
of neutrophils after endotoxin administration almost entirely prevents an increase of IL-1
expression and attenuates endotoxin induced TNF-. Neutrophils are the major source of IL-
1 in murine models of the lung in ALI [18]. Another feature of the neutrophils that
accumulate in the lung of murine models is increased activation of the transcriptional
regulatory nuclear factor cappa B(NF-B). NF-B is a protein complex that controls
transcription of DNA and is involved in cellular responses to stimuli such as pulmonary
edema due to ALI/ARDS. It is key in regulating the endotoxin induced immune response in
neutrophils and produces increased amounts of pro-inflammatory cytokines whose
transcription is dependent on NF-B [22]. Neutrophils also become an increasing liability in
the edematous pulmonary interstitium as they release free radicals
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The Molecular Mechanisms of the Pulmonary Barrier Injury in ALI/ARDS

The thin alveolar-capillary barrier allows oxygen-carbon dioxide (CO2) exchange for normal
respiration. The major consequence of pulmonary edema is impaired gas exchange that
interrupts the normal fluid exchange balance. The alveoli epithelium removes fluid by
molecular mechanisms of sodium transport however the capillary endothelial barrier function
has only incompletely defined pathways affecting the concurrent barrier disruption.
Permeability of the EC in the capillaries with concurrent alveolar-capillary membrane
damage and with leakage of fluid, neutrophils, proteases, cytokines and free radicals that all
contribute to the ensuing pulmonary edema is a prominent feature of permeability edema and
ALI/ARDS [23]. The alveolar liquid clearance from the alveolus into the interstitium is based
on active sodium transport largely through the highly regulated apical Amiloride sensitive
Epithelial Sodium Channel Complex (ENaC) with concomitant passive water transport and
the Na+, K+ ATPase exchange [24,25]. The Na+, K+ ATPase exchange transports the alveolar
liquid into the interstitium and ultimately into the lymphatic and blood vessels [26,27].
However these transport processes are often impaired in ALI or ARDS. It is likely that the
induction of increased permeability of the pulmonary capillary bed is directly linked to
reversible physical modifications of the pulmonary capillary endothelium [28]. The capillary
endothelial regulation of endothelial permeability involves various pathways such as those
involving (ROS), Rho Guanosine Triphosphate Enzymes (GTPases), and tyrosine
phosphorylation of junctional proteins that all converge to regulate junctional permeability.
They either affect the stability of junctional proteins or modulate their interactions [27]. The
regulation of permeability at the junctions is mediated by active communication between the
proteins of the adherens junctions and the Actin cytoskeleton. Actin mediated endothelial cell
contraction is the result of Myosin Light Chain (MLC) phosphorylation by MLC kinase
(MLCK) in a Ca2+/calmodulin- dependent manner. RhoA also potentiates MLC
phosphorylation by inhibiting MLC phosphatase activity through its downstream effector
Rho kinase (ROCK). As the Actin/myosin driven contraction generates a contractile force it
pulls Vascular Endothelial (VE)-cadherin inward. This contraction will force VE-cadherin to
dissociate from its adjacent partner causing endothelial gaps the basic pathology in
permeability pulmonary edema [27]. It is increasingly recognized that the injured lung cells
release inflammatory mediators into the systemic circulation contributing to the deleterious
effect on other organs. One study showed that, in the septic patient with ARDS, human
epithelial pulmonary cells stimulated with bacterial Lipopolysaccharide (LPS) release
inflammatory mediators that are able to induce a translational clinically relevant and harmful
response in brain cells [1].
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Biomarkers
One of the challenges in ARDS is to identify patients at risk of developing ARDS or to
predict mortality once the disease is established. The ARDS net Clinical trial network looked
at the biologic index of biomarkers combined with clinical risk factors. This clinical trial
looked at markers that had been shown to be increased in ARDS. The result showed
significant changes in inflammatory cytokines interleukins (IL-6 and IL-8), coagulation
proteins Plasminogen Activator Inhibitor-1(PAI-1), protein C, epithelial proteins, a serologic
biomarker for interstitial lung disease (KL-6), Surfactant Protein (SP-D), Receptor For
Advanced Glycation End Products (RAGE) and Endothelial Proteins Angiopoietin-2 (ANG-
2), Intercellular Adhesion Molecule 1 (ICAM-1), von Willebrand Factor (vWF) [6,29]. They
found the two best performing biomarkers were IL-8, a potent Neutrophil chemo-attractant
and SP-D, produced by type 2 alveolar epithelial cells [29]. Endocan, an endothelial cell
specific molecule-1 secreted from pulmonary and kidney vascular endothelial cells has
recently been shown to be significantly increased in moderate or severe ARDS non-survivors.
Endocan levels predicted the mortality of patients with ARDS. Procalcitonin (PCT) was also
significantly increased in the same study in ARDS [6]. Clara Cell Protein (CC16) performed
well as a potential biological marker for ARDS in patients with ventilator associated
pneumonia and ARDS [30]. It is likely that no one biomarker will be able to predict with
complete accuracy the risk of development, diagnosis and prognostic course of ARDS in
patients. Rather it is projected that there will be a panel of the best potential markers to select
these patients.
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Management
Current management of ARDS is unchanged since the ARDSnet trials revealed the only
strategy that improved survival is Mechanical Ventilation (MV) with low tidal volumes of
6mg/kg ideal body weight. Other trials revealed that days on the ventilator and in the
intensive care unit are shortened by a conservative fluid strategy and that restricting fluid
intake and promoting fluid excretion is more effective that a liberal fluid strategy in patients
with ARDS [31]. There are clear guidelines for the treatment of the two most common
underlying causes of ARDS. The standard for pneumonia classification with the severity
CURB-65 score (confusion, uremia, respiratory rate, blood pressure, age greater than 65) or
the Pneumonia Severity Index (PORT) scores to admit the appropriate patients to the hospital
ward or intensive care unit based on the models that have been shown to predict mortality.
Sepsis bundles with early goal directed therapy for patient with sepsis of any source have
improved the outcomes for patients with sepsis and also likely reduced cases of ARDS. These
criteria for common causes of ARDS have likely decreased the development of ARDS in
some cases by improved care of these underlying causes. However the incidence, prevalence
and mortality are too high and there is an intensive search for a healing therapy. Alternative
ventilation modes of ventilation are utilized when conventional low tidal volume MV is
unsuccessful. Airway Pressure Release Ventilation (APRV) and High Frequency Oscillatory
Ventilation (HFOV) are modes designed to prevent or minimize Ventilator Induced Lung
Injury (VILI). The goal of both of these modes is to use an open lung strategy to improve
oxygenation while keeping the lungs uniformly open. APRV, a high continuous positive
airway pressure is delivered for a long duration and then falls to a lower pressure for a shorter
duration. Alveolar recruitment is maximized by the high continuous positive airway pressure.
There is no proof that APRV improves mortality, however, there are ongoing studies that
may reveal further information about this mode of ventilation [32,33]. HFOV uses an
oscillatory pump to deliver a respiratory rate of 3 to 15 Hertz (up to 900 breaths per minute)
through the endotracheal tube. The constant mean airway pressure maintains alveolar
recruitment, avoids low end-expiratory pressures and avoids high peak pressures. Although
HFOV is initially associated with improved oxygenation it has not been associated with
improved survival [34]. Another MV mode that has been utilized is Partial Liquid Ventilation
(PLV) is a technique of MV in which the lungs are insufflated with oxygenated
Perfluorochemical (PFC) liquid rather than oxygen-containing gas mixture. The lungs are
slowly filled with a volume of PFC close to the functional residual capacity during gas
ventilation. The PFC in the lungs is oxygenated and carbon dioxide is removed by means of
gas breaths cycling in the lungs with traditional MV [35]. In ARDS some studies have shown
that PLV can improve gas exchange in ARDS by recruitment of the atelectatic, consolidated
dependent regions of the lungs that contribute to physiologic shunt during gas ventilation
Pulmonary blood flow is also redistributed to less severely injured and/or atelectatic regions
of the lung thus improving ventilation perfusion matching [36]. The most recent Cochrane
Database Systematic Review update shows that in spite of trials and persistent research with
two new trials there is not enough evidence that supports the use of PLV in ARDS and some
evidence suggests an increased risk of adverse events associated with its use [37]. A non-
pharmacologic application for treatment of severe ARDS that is not being effectively treated
by the current clinical types of mechanical ventilation is Extracorporeal Membrane
Oxygenation (ECMO). ECMO is a form of partial cardiopulmonary bypass that can be
employed in longer term support of respiratory and/or cardiac function [38]. ECMO offers
artificial temporary and respiratory support that is maintained until the patient recovers from
severe respiratory failure [39]. ECMO use for respiratory failure was first described in 1972,
however the technology was primitive and knowledge about acute lung injury was limited
with the terminology of shock lung used in the articles description [40]. Despite initial
problems ECMO use continued in some centers and there was renewed interest as a treatment
for ARDS when ECMO was proposed as a rescue therapy in the 2009 H1N1 pandemic, and
had good outcomes [39]. The main indication for the use of ECMO is in refractory
hypoxemia and the risk of mortality is 80% or greater. The Extracorporeal Life Support
Organization (ELSO) has published guidelines that address personnel, training, resources, use
of ECMO and quality assurance. According to the ELSO guidelines for ARDS the criteria for
consideration are as follows: (A) a 50% mortality risk that is associated with a PaO2/FiO2 <
150 on FiO2 > 90% and/or Murray score 23 and(B) an 80% mortality risk that is associated
with a PaO2/FiO2 < 100 on FiO2> 90% and/or Murray score 34 despite optimal care for 6
hours or more and CO2 retention on mechanical ventilation despite high Pplat (>30cm H2O)
and severe air leak syndromes (ELSO
guidelines http://www.elsonet.org/index.php?option=com_phocadownload). There are no
absolute contraindications of ECMO however there are some conditions that may be relative
contraindications. The main adverse outcome is bleeding including CNS hemorrhage. Prone
positioning in ARDS has recently been evaluated in a multicenter, prospective, randomized,
controlled trial with 466 patients with severe ARDS with a PaO2/FIO2 ratio of < 150 mm
Hg, FIO2 of > 0.6 and a PEEP of > 5 cm H2O. The patients who underwent prone-
positioning were left in sessions of at least 16 hours or the controls were left in supine
position throughout their ICU stay. Survival after severe ARDS was significantly higher
(32.8%) in the prone group than in the supine group (16%) despite the fact that the mortality
in the supine group was lower than anticipated (P<0.001) [41]. Prior Meta analysis suggested
that survival was improved with prone positioning compared with supine positioning
however with the most recent results in a well conducted trial prone positioning may be
integrated into the standard of care for the severe ARDS patient.
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New Treatment Strategies

Mesenchymal Stem Cells (MSCs) are a potential new approach for treatment of ARDS.
MSCs are multipotent, self-renewing cells initially isolated from bone marrow that can
differentiate into a variety of cell types. The interest in a cell based therapy has been piqued
since the ineffectiveness of specific pharmacologic therapies has evolved. Numerous studies
have demonstrated that the soluble factors or products derived from human MSCs generate a
local immunosuppressive microenvironment by secreting cytokines [42,43]. As a result there
is intense study focusing on the paracrine properties of MSCs [7]. It also appears that MSCs
do not generate allo-responsiveness and this makes MSCs an attractive treatment [43]. It has
been found that Bone Marrow Derived (BMD) MSC markers are negative for cluster of
differentiation 45 and 11b (CD45 and CD11b) and are capable of differentiating into a variety
of cell types, including endothelial, epithelial and neuronal cells. When BMDMSCs are
infused into mice they can be found with the phenotypic characteristics of cells in the organ
where they reside. In the lung, BMDMSCs have been detected as type I and type II alveolar
epithelial cells, endothelial cells, fibroblasts and bronchial epithelial cells. It seems certain
that these cells have the capacity to localize into injured lung and differentiate into specific
cell types [44]. In a study with bleomycin-induced lung injury in mice it was found that
transplanted MSCs localized to the injured lung and assumed parenchymal cell phenotypes.
In this model of lung injury MSCs transplant prevented increased lung expression of immune
related inflammatory cytokines interleukin (IL)-1, interferon (IFN)-, IL-2, IL-4 that may
provide an environment beneficial to lung repair. MSCs were also shown to induce
production of anti-inflammatory prostaglandins and IL-10 and this may be the mechanism of
the suppressive inflammatory effect. In addition to MSCs suppression of the local
microenvironment [44]. The administration of MSCs in an endotoxin model of acute lung
injury via administration of MSC directly into the airspaces of the lung 4 h after the
intrapulmonary administration of lipopolysaccharide significantly decreased lung water, a
measure of pulmonary edema and bronchoalveolar lavage protein, a measure of endothelial
and alveolar epithelial permeability and increased survival compared with phosphate buffered
saline-treated mice. The protection was shown to be mediated by a shift from a
proinflammatory to an anti-inflammatory response to endotoxin that includes enhanced
production of IL-10 [45]. Based on in vitro and in vivo studies multiple studies suggesting
MSC benefits in various clinical disorders including acute lung injury there has been a
randomized, placebo-controlled pilot study with the objective to examine the possible adverse
events after systemic administration of allogeneic adipose-derived MSCs in ARDS patients
and to determine potential efficacy of MSCs on ARDS. Twelve adult patients with ARDS
with a partial pressure of arterial oxygen to fraction inspired oxygen (PaO2/FiO2) ratio of <
200 were randomized to receive allogeneic MSCs or placebo. There were no infusion
toxicities or serious adverse events between the two groups. The conclusion was that
administration of allogeneic MSCs appeared to be safe in the treatment of ARDS. However
there were no significant differences in the levels of inflammatory cytokines with the dose of
MSCs that was used. Further optimization of the strategy will be required to reach the goal of
reduced lung injury in ARDS [46]. A Phase 1, open label, dose escalation, multi-center trial
of allogeneic bone marrow-derived human MSCs to treat ARDS is recruiting patients
(http://clinicaltrials.gov/ct2/show/NCT01775774). Tumor necrosis factor is a potent pro-
inflammatory cytokine produced by many cell types. It is involved in systemic inflammation
and is a member of a group of cytokines that stimulate the acute phase reaction. It is
principally produced by activated macrophages although it can be produced by other cell
types. TNF is also able to reduce lung edema in different inflammatory processes such as
non-cardiogenic pulmonary edema. The lectin-like domain of TNF, mimicked by a circular
seventeen amino acid peptide, TIP peptide, is responsible for the reduction in lung edema
clearance in murine models of non-cardiogenic pulmonary edema [24,47,15,48]. Studies of
lung injury induced in 16 pigs by BAL lavage followed by injurious ventilation received
either nebulized TIP or water. The Extravascular Lung Water Index (EVLWI), the
PaO2/FIO2 ratio and the pulmonary shunt fraction were assessed. The inhalation of TIP
induced an amelioration of clinical surrogate parameters of the lung function in a porcine
lung injury model demonstrating the TIP peptide as an innovative approach as supportive
therapy in ARDS [48]. Based on these findings the TIP peptide is now in clinical trials in
Europe with the findings yet to be published. Pharmacologic therapies continue to be
investigated although most are still in the early development stage. Some of these include
adenosine [49], heparin and low anticoagulant heparins [5051], growth hormones [52], Heat
Shock Protein 90 inhibitors [53]. Effective pharmacotherapy for ARDS remains extremely
limited [54].
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Conclusion
The most common causes of adults with severe ARDS are sepsis and pneumonia and
mortality rates continue to be high. The underlying pathology includes local and systemic
inflammation. Biomarkers are identified however the emergence of a single biomarker has
not surfaced and will likely have a panel of biomarkers to predict the severity and course of
ARDS. The use of lung protective MV, alternative modes of ventilation, ECMO and prone
positioning can improve mortality. Active research includes mesenchymal cells installation,
TIP peptide and persistent evaluation for a pharmacologic therapy to benefit patients in
severe ARDS.
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Acknowledgement
This work was supported by NIH PO1-HL101902 and GRU Extramural Success Award
(ADV), NHLBI R01HL094609 (RL) and the generous support of the Georgia Regents
Department of Medicine and Dr. Madaio (JG).
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Abbreviations

ARDS Acute Respiratory Distress Syndrome

ALI Acute Lung Injury

EC Endothelial Cell

TNF- Tumor Necrosis Factor-Alpha

IL 1 Interleukin 1 Beta

PEEP Positive End Expiratory Pressure

ECMO Extracorporeal Membrane Oxygenation

NHLBI National Heart, Lung, Blood Institute

NCPE Non-Cardiogenic Pulmonary Edema

BAL Bronchial Alveolar Lavage

ENaC Epithelial Sodium Channel

Na+/K+-ATPase Sodium/Potassium Adenosine Triphosphatase

PO2 Partial Pressure Of Oxygen

NF-Kb Nuclear Factor-Kappa B

DNA Deoxyribonucleic Acid

CO2 Carbon Dioxide

ROS Reactive Oxygen Species

GTPases Guanosine Triphosphate Enzymes

MLC Myosin Light Chain

MLCK Myosin Light Chain Kinase

ROCK Rho Kinase

VE Vascular Endothelial

LPS Lipopolysaccharide

IL Interleukin

Plasminogen Activator Inhibitor-1, a serological biomarker for interstitial

PAI-1
lung disease (KL-6)

SP-D Surfactant Protein-D

RAGE Receptor For Advanced Glycation End Products

ANG-2 Angiopoietin-2

ICAM-1 Intercellular Adhesion Molecule1

vWF Von Willebrand Factor

PCT Procalcitonin

CC16 Clara Cell Protein 16

CURB-65 Confusion, Blood Urea Nitrogen, Respiratory Rate, Blood Pressure, Age 65

PORT Pneumonia Severity Index Score

APRV Airway Pressure Release Ventilation

HFOV High Frequency Oscillatory Ventilation

VILI Ventilator Induced Lung Injury

MV Mechanical Ventilation

PLV Partial Liquid Ventilation

PFC Perfluorochemical

ELSO Extracorporeal Life Support Organization

PaO2/FIO2 Partial Pressure Of Arterial Oxygen To Fraction Inspired Oxygen

Pplat Plateau Pressure

CNS Central Nervous System

Hg Mercury
cm Centimeters

H2O Water

ICU Intensive Care Unit

MSCs Mesenchymal Stem Cells

BMD Bone Marrow Derived

CD 45 or CD
Cluster Of Differentiation
11b

IFN- Interferon Gamma

TNF Tumor Necrosis Factor

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Terjemahan
Abstrak
Tertekan sindrom ( ards saluran pernapasan akut ) paru-paru yang sangat keras inflamasi
gangguan dengan sekitar 30 50 % kematian.Sepsis dan radang paru-paru adalah
penyebab ards terkemuka.Tingkat ada pada jaringan selular paru sel kapiler permeabilitas dan
cairan kebocoran endotel di paru-paru parenkim, diikuti oleh neutrofil, radang akut yang
sitokin dan respon.Ketika cairan kenaikan interstitium kemudian luar gerakan terus dan
protein alveolar kaya cairan ruang melalui kerap terjadi banjir yang ketat junction dari sel
epitel.Neutrofil memainkan peranan penting dalam perkembangan paru-paru akut edema paru
terkait dengan cedera atau ards. Endotel hewan berbagai studi telah menunjukkan bahwa
cedera muncul dalam beberapa menit untuk jam setelah paru-paru akut cedera ( ali ) dengan
menghasilkan antarseluler inisiasi kesenjangan dari sel-sel endotel.Endotel sel ( yang
memungkinkan terjadinya ec ) kesenjangan permeabilitas cairan, neutrofil dan sitokin ruang
parenchymal di paru-paru.Orang-orang neutrofil yang menyusup paru-paru dan bermigrasi ke
dalam airways mengungkapkan pro-inflammatory sitokin seperti ( tnf- nekrosis tumor factor-
alpha ), beta ( il-1 interleukin-1 ), baik dan berkontribusi pada epitel endotel dan
integritas terganggunya berbagai hambatan yang.
Pengobatan farmakologi telah efektif .Jaringan yang diidentifikasi rendah ards uji coba
pasang surut volume ventilasi mekanis , tekanan akhir positif ekspirasi dan cairan yang telah
mengalami perbaikan pedoman pengelolaan hasil untuk pasien dengan ards .Extracorporeal
kadar oksigen dalam membran ini digunakan dalam khusus centers for kasus yang parah
.Rawan posisi baru baru ini terbukti telah secara signifikan menurun ventilator hari dan hari
di ruangan intensive care unit
Penyelidikan termasuk saat ini administrasi mesenchymal terapi sel induk , cairan parsial
ventilasi , tip peptida nebulized administrasi dan dengan terus pemeriksaan pharmacologic
obat-obatan .

Pengantar
Acute Respiratory Distress Syndrome (ARDS) adalah gangguan inflamasi paru yang parah
dengan mortalitas 30-50% [1,2]. Sepsis dan pneumonia adalah penyebab utama ARDS. Pada
tingkat sel ada permeabilitas sel endotel paru kapiler dan kebocoran cairan ke dalam
parenkim paru, diikuti oleh neutrofil, sitokin dan respons inflamasi akut [3]. Ketika cairan
meningkat di interstitium maka gerakan keluar berlanjut dan cairan kaya protein membanjiri
ruang alveolar melalui persimpangan ketat sel epitel. ARDS awalnya digambarkan pada
tahun 1960an oleh Petty dan Ashbaugh [4]. Pada tahun 1994 sebuah jaringan klinis besar
didirikan melalui National Heart, Lung and Blood Institute (NHLBI) dengan tujuan untuk
secara efisien menguji agen, perangkat, atau strategi manajemen yang menjanjikan untuk
memperbaiki perawatan pasien ARDS (situs jaringan NHLBI ARDS Network). Uji Jaringan
ARDS mengidentifikasi ventilasi mekanis volume tidal rendah, Positive End Expiratory
Pressure (PEEP) dan pedoman pengelolaan fluida yang memiliki hasil yang lebih baik untuk
pasien ARDS. Modalitas pengelolaan lainnya telah diuji termasuk steroid, antijamur, agonis
beta dan oksida nitrat. Percobaan farmakologis belum menghasilkan strategi terapeutik yang
efektif. Modalitas perawatan meliputi Extracorporeal Membrane Oxygenation (ECMO),
bundel ventilator dan evaluasi persisten entitas farmakologis seperti heparin [5]. Penelitian
saat ini terutama berfokus pada peran biomarker biologis pada terapi dini atau pendekatan
pencegahan ARDS [6] dan pengobatan sel induk mesenchymal [7].
Patofisiologi
ARDS adalah Edema Paru Tidak Kardiogenik (NCPE). NCPE di ARDS pada akhirnya
merupakan hasil permeabilitas kapiler sekunder akibat kerusakan sel, peradangan, dan lebih
dari inflasi oleh ventilasi mekanik yang mengakibatkan permeabilitas endotel. Hambatan sel
endotel adalah satu lapisan endotelium kontinyu yang melapisi kapiler paru dan membentuk
satu lapisan antara darah dan interstitium paru. Kapiler pulmonal memiliki dinding yang
sangat tipis sehingga memungkinkan pertukaran gas pernafasan yang cepat melintasi mereka
[8]. Pada gangguan ARDS pada keseimbangan cairan kapiler paru dan permeabilitas paru
terjadi sebagai akibat langsung dari infeksi bakteri, endotoksin dan peradangan selanjutnya
yang menyebabkan terganggunya penghalang EC kapiler dengan gangguan penghalang dan
kemacetan vena pulmonal berikutnya. Karena kelebihan cairan biasanya masuk ke
interstitium paru, sistem limfatik diambil kembali ke sistem vaskular. Kekuatan hidrostatik
kemudian diubah sebagai akibat langsung dari luka pada endothelium kapiler. Ruang
interstisial dapat meningkatkan volumenya sebanyak 40% tanpa menghasilkan edema paru
[9]. Namun akumulasi cairan persisten menguasai drainase limfatik dan hasil edema jaringan.
Akhirnya, ketika cairan menguasai kekuatan hidrostatik dan kelebihan cairan mengalir ke
alveoli. Edema yang disebabkan oleh peningkatan permeabilitas cairan dan vaskular adalah
ciri khas radang dan cedera jaringan [10]. Pembentukan edema dapat memiliki konsekuensi
parah karena komponen cairan dan protein pada jaringan edematous dan alveoli
meningkatkan penghalang difusi untuk oksigen dan karbon dioksida dengan gangguan
pertukaran gas selanjutnya sehingga memicu hipoksia dan gagal napas. Edema paru
berikutnya pada pasien ARDS telah terbukti menjadi edema paru protein tinggi. Faktanya,
rasio cairan / plasma dapat digunakan untuk membedakan etiologi edema paru pada ARDS
dan edema paru kardiogenik. Rasio cairan / plasma adalah pengukuran cairan alveolar yang
diperoleh dengan Bronchial Alveolar Lavage (BAL), ke plasma serum selama edema paru
akut dan telah terbukti cukup sensitif untuk membedakan cairan protein rendah yang
dihasilkan dari edema paru kardiak dibandingkan dengan Rasio protein tinggi yang terjadi
dengan penyakit seperti ARDS [11,12]. Konsentrasi protein di interstitium paru ARDS
melebihi 60% dari nilai plasma sedangkan konsentrasi protein pada ARDS non penyebab
kurang dari 45% [13,14]. Hasilnya adalah permeabilitas yang tinggi dari penghalang EC dan
protein tinggi di ruang interstisial dengan kandungan protein yang mirip dengan darah.
Akumulasi volume akut adalah faktor lain dalam kegagalan pernafasan hipoksia berikutnya
dan edema paru. Alveoli paru, situs utama pertukaran gas dengan darah, terdiri dari epitel
alveolar tipis yang mencakup 99% luas permukaan di paru-paru dan mengandung sel-sel
kurus tipe skuamosa dan sel cuboidal tipe II. Sel tipe I menutupi 95% permukaan alveolar.
Ruang alveolar berjajar epitel memfasilitasi pertukaran gas dan membentuk penghalang ketat
gerakan fluida dan protein dari ruang interstisial dan vaskular yang mempertahankan alveoli
yang relatif kering. Sambungan yang kencang menghubungkan sel epitel yang berdekatan di
dekat permukaan apikal dan mempertahankan polaritas sel apikal dan basal. Persimpangan
yang ketat merupakan elemen penting penghalang permeabilitas yang diperlukan untuk
mempertahankan pertukaran gas normal. Sel alveolar tipe II yang mengeluarkan surfaktan
berkontribusi pada transportasi vektor natrium. Pengangkutan natrium yang aktif memberikan
kekuatan pendorong utama untuk menghilangkan cairan dari ruang alveolar. Saluran sodium
sensitif amiloride pada permukaan apikal, terutama Epochial Sodium Channel (ENaC) yang
terlibat dalam transportasi fluida dengan motor penggerak yang ditunjukkan oleh natrium /
potassium adenosine triphosphatase (Na + / K + -ATPase) pada permukaan basolateral [15].
Cedera penghalang alveolo-kapiler mengubah transport Na + aktif, yang menyebabkan
kebocoran cairan edema edema dari ruang alveolar. Gaya utama yang mendorong reabsorpsi
cairan dari ruang alveolar ke interstitium dan sirkulasi pulmonal adalah transport Na + aktif.
Sodium diambil di permukaan apikal epitel alveolar oleh saluran Na + Amiloride yang
sensitif dan tidak sensitif dan kemudian dipompa keluar dari sel oleh Na + / K + -ATPase di
sisi lateral lateral (Terapi Gen di Pengobatan Kritis Pengobatan http: /
/dx.doi.org/10.5772/52701, oleh Moreno-Gonzalez dan Zarain-Herzberg, 2013). Edema paru
disebabkan oleh fungsi yang disregulasi dari saluran ion pada sel epitel alveolar tipe II [15].

Peran Neutrofil ALI / ARDS

Neutrofil memainkan peran penting dalam pengembangan edema paru yang terkait dengan
ALI / ARDS [16]. Awalnya makrofag paru diaktifkan dan merekrut neutrofil ke kapiler yang
cedera dimana mereka ditemukan bocor ke interstitium parenkim paru. Di sini mereka
mengasingkan dan memulai komponen penting dari respons inflamasi pada endotoksin yang
menginduksi ALI / ARDS. Aktivasi dan migrasi neutrofil ini merupakan peristiwa yang khas
dalam perkembangan ALI dan ARDS. Penelitian pada hewan menunjukkan bahwa cedera
endothelial muncul beberapa menit sampai beberapa jam setelah inisiasi ALI dengan celah
antar sel EC yang dihasilkan. Kadar EC memungkinkan permeabilitas cairan, neutrofil dan
sitokinin ke dalam ruang parenkim paru [17]. Neutrofil yang menginfiltrasi paru-paru dan
bermigrasi ke saluran udara mengekspresikan sitokin pro-inflamasi seperti TNF-, IL-1, dan
berkontribusi pada gangguan integritas endotel dan epitel hambatan [16,18]. Ini juga telah
didokumentasikan dengan baik bahwa persentase neutrofil berkorelasi langsung dengan
tekanan parsial alveolar arterial terhadap perbedaan oksigen (PO2) pada edema paru ALI /
ARDS [19]. Neutrophil sequestration dibantu oleh faktor kemotaktik dan oleh molekul adhesi
pada neutrofil dan sel endotel kapiler [20,21]. Neutrofil aktif yang mengekspres IL-1
menghasilkan sitokin pro-inflamasi lainnya setelah pemberian endotoksin. Sebenarnya
penghapusan neutrofil setelah pemberian endotoksin hampir seluruhnya mencegah
peningkatan ekspresi IL-1 dan mengurangi endotoksin yang diinduksi TNF-. Neutrofil
adalah sumber utama IL-1 pada model murine paru-paru pada ALI [18]. Fitur lain dari
neutrofil yang terakumulasi di paru-paru model murine adalah peningkatan aktivasi peraturan
transkripsional faktor nuklir cappa B (NF-B). NF-B adalah kompleks protein yang
mengendalikan transkripsi DNA dan terlibat dalam respons seluler terhadap rangsangan
seperti edema paru akibat ALI / ARDS. Ini adalah kunci dalam mengatur respon imun yang
diinduksi endotoksin pada neutrofil dan menghasilkan peningkatan jumlah sitokin pro-
inflamasi yang transkripsi bergantung pada NF-B [22]. Neutrofil juga menjadi
pertanggungjawaban yang meningkat pada interstitium paru edematous saat mereka
melepaskan radikal bebas.

Mekanisme Molekul dari Pulmonary Barrier Injury di ALI / ARDS

Hambatan kapiler alveolar tipis memungkinkan pertukaran oksigen-karbon dioksida (CO2)

untuk respirasi normal. Konsekuensi utama edema paru adalah gangguan pertukaran gas yang
mengganggu keseimbangan pertukaran cairan normal. Epitel alveoli menghilangkan cairan
dengan mekanisme molekuler transportasi natrium namun fungsi penghalang endothelial
kapiler hanya memiliki jalur yang tidak lengkap yang mempengaruhi gangguan penghalang
bersamaan. Permeabilitas EC di kapiler dengan kerusakan membran alveolar-kapiler
bersamaan dan dengan kebocoran cairan, neutrofil, protease, sitokin dan radikal bebas yang
semuanya berkontribusi pada edema paru berikutnya adalah ciri menonjol edema
permeabilitas dan ALI / ARDS [23] . Isolasi cairan alveolar dari alveolus ke interstitium
didasarkan pada pengangkutan natrium aktif sebagian besar melalui kompartemen epilen
kompleks Sodium Channel Complex (AmaC) Amiloride sensitif dengan transpor air pasif
bersamaan dan pertukaran Na +, K + ATPase [24,25]. Penukaran Na +, K + ATPase
mengangkut cairan alveolar ke interstitium dan akhirnya ke dalam pembuluh darah limfatik
dan darah [26,27]. Namun proses transportasi ini sering terganggu pada ALI atau ARDS.
Kemungkinan induksi permeabilitas meningkat dari tempat tidur kapiler pulmonal
berhubungan langsung dengan modifikasi fisik reversibel dari endothelium kapiler paru [28].
Pengaturan endothelial kapiler dari permeabilitas endotel melibatkan berbagai jalur seperti
yang melibatkan (ROS), Rho Guanosine Triphosphate Enzim (GTPases), dan fosforilasi
tirosin protein junctional yang semuanya berkumpul untuk mengatur permeabilitas junctional.
Mereka juga mempengaruhi stabilitas protein junctional atau memodulasi interaksi mereka
[27]. Regulasi permeabilitas di persimpangan dimediasi oleh komunikasi aktif antara protein
persimpangan adheren dan sitoskeleton Actin. Actin memediasi kontraksi sel endotel adalah
hasil mitososforilasi Myosin Light Chain (MLC) oleh MLC kinase (MLCK) dengan cara Ca2
+ / calmodulin. RhoA juga mempotensiasi fosforilasi MLC dengan menghambat aktivitas
MLC phosphatase melalui penghambat hilir Rho kinase (ROCK). Saat kontraksi yang
disebabkan Actin / myosin menghasilkan kekuatan kontraktil, ia menarik Vascular
Endothelial (VE) -kulit ke dalam. Kontraksi ini akan memaksa VE-kadherin untuk
memisahkan diri dari pasangannya yang berdekatan yang menyebabkan sel endotel menjadi
patologi dasar pada permeabilitas edema paru [27]. Hal ini semakin diakui bahwa sel-sel
paru-paru yang terluka melepaskan mediator inflamasi ke dalam sirkulasi sistemik yang
berkontribusi terhadap efek buruk pada organ lain. Satu studi menunjukkan bahwa, pada
pasien septik dengan ARDS, sel paru-paru epitel manusia yang distimulasi dengan bakteri
Lipopolysaccharide (LPS) melepaskan mediator inflamasi yang mampu menginduksi respons
translasi klinis yang relevan dan berbahaya pada sel otak [1]

Biomarker

Salah satu tantangan dalam ARDS adalah untuk mengidentifikasi pasien yang berisiko
terkena ARDS atau untuk memprediksi kematian setelah penyakit ini terbentuk. Jaringan
percobaan klinis ARDS net melihat indeks biologis biomarker dikombinasikan dengan faktor
risiko klinis. Uji coba klinis ini melihat tanda-tanda yang telah terbukti meningkat pada
ARDS. Hasilnya menunjukkan adanya perubahan yang signifikan pada sitokin interleukin
inflamasi (IL-6 dan IL-8), protein koagulasi Inhibitor Plasminogen Inhibitor-1 (PAI-1),
protein C, protein epitel, biomarker serologis untuk penyakit paru interstisial (KL-6) , Protein
Surfaktan (SP-D), Reseptor Untuk Produk Akhir Glycasi Lanjutan (RAGE) dan Protein
Endotel Angiopoietin-2 (ANG-2), Molekul Pemberian Intercellular Molekul 1 (ICAM-1),
Faktor von Willebrand (vWF) [6,29 ]. Mereka menemukan dua biomarker berkinerja terbaik
adalah IL-8, atraktan kemoterapi nanotrofil kuat dan SP-D, diproduksi oleh sel epitel alveolar
tipe 2 [29]. Endocan, molekul spesifik sel endotel-1 yang disekresikan dari sel endotel
vaskular paru dan ginjal baru-baru ini terbukti meningkat secara signifikan pada ARDS non-
survivors sedang atau berat. Tingkat endoklas memprediksi angka kematian pasien ARDS.
Procalcitonin (PCT) juga meningkat secara signifikan pada studi ARDS yang sama [6]. Clara
Cell Protein (CC16) dilakukan dengan baik sebagai penanda biologis potensial untuk ARDS
pada pasien dengan ventilator associated pneumonia and ARDS [30]. Kemungkinan tidak ada
satu biomarker yang bisa memprediksi dengan akurasi lengkap risiko pengembangan,
diagnosis dan jalur prognostik ARDS pada pasien. Melainkan diproyeksikan akan ada panel
penanda potensial terbaik untuk memilih pasien ini.

Pengelolaan

Pengelolaan ARDS saat ini tidak berubah sejak uji coba ARDSnet menunjukkan satu-satunya
strategi yang meningkatkan kelangsungan hidup adalah Mechanical Ventilation (MV) dengan
volume tidal rendah dengan berat tubuh ideal 6mg / kg. Uji coba lainnya menunjukkan bahwa
hari di ventilator dan di unit perawatan intensif dipersingkat oleh strategi cairan konservatif
dan yang membatasi asupan cairan dan meningkatkan ekskresi cairan lebih efektif sehingga
strategi cairan liberal pada pasien ARDS [31]. Ada pedoman yang jelas untuk pengobatan
dua penyebab utama ARDS yang paling umum. Standar klasifikasi pneumonia dengan skor
keparahan CURB-65 (kebingungan, uremia, laju pernafasan, tekanan darah, usia di atas 65)
atau skor Pneumonia Severity Index (PORT) untuk memberi pasien yang tepat ke bangsal
rumah sakit atau unit perawatan intensif. berdasarkan model yang telah ditunjukkan untuk
memprediksi angka kematian. Sepsis bundel dengan tujuan awal diarahkan terapi untuk
pasien dengan sepsis dari sumber manapun telah memperbaiki hasil untuk pasien dengan
sepsis dan juga kemungkinan mengurangi kasus ARDS. Kriteria untuk penyebab umum
ARDS ini cenderung menurunkan perkembangan ARDS dalam beberapa kasus dengan
memperbaiki asuhan penyebab ini. Namun kejadian, prevalensi dan mortalitasnya terlalu
tinggi dan ada pencarian intensif untuk terapi penyembuhan. Modus ventilasi ventilasi
alternatif digunakan saat MV volume tidal rendah konvensional tidak berhasil. Ventilasi
Pelepasan Ventilasi Jalan napas (APRV) dan Ventilasi Osilasi Tinggi (HFOV) adalah mode
yang dirancang untuk mencegah atau memperkecil Ventilator Induced Lung Injury (VILI).
Tujuan kedua mode ini adalah dengan menggunakan strategi paru terbuka untuk
memperbaiki oksigenasi sambil menjaga paru-paru tetap terbuka secara seragam. APRV,
tekanan saluran udara positif kontinu yang tinggi disampaikan untuk durasi yang lama dan
kemudian jatuh ke tekanan yang lebih rendah untuk durasi yang lebih pendek. Perekrutan
alveolar dimaksimalkan dengan tekanan udara positif kontinu yang tinggi. Tidak ada bukti
bahwa APRV memperbaiki angka kematian, bagaimanapun, ada studi berkelanjutan yang
dapat mengungkapkan informasi lebih lanjut tentang mode ventilasi ini [32,33]. HFOV
menggunakan pompa osilasi untuk menghasilkan laju pernafasan 3 sampai 15 Hertz (sampai
900 napas per menit) melalui tabung endotrakea. Tekanan saluran napas rata-rata konstan
mempertahankan rekrutmen alveolar, menghindari tekanan ekspirasi rendah dan menghindari
tekanan puncak yang tinggi. Meskipun HFOV pada awalnya dikaitkan dengan peningkatan
oksigenasi, namun belum dikaitkan dengan peningkatan ketahanan hidup [34]. Modus MV
lain yang telah digunakan adalah Partial Liquid Ventilation (PLV) adalah teknik MV dimana
paru-paru tidak tercampur dengan cairan Perfluorokimia (KLB) berlebih oksigen daripada
campuran gas yang mengandung oksigen. Paru-paru perlahan diisi dengan volume PFC yang
mendekati kapasitas residu fungsional selama ventilasi gas. PFC di paru-paru teroksigenasi
dan karbon dioksida dikeluarkan dengan cara gas napas bersepeda di paru-paru dengan MV
tradisional [35]. Di ARDS beberapa penelitian telah menunjukkan bahwa PLV dapat
memperbaiki pertukaran gas di ARDS dengan melakukan perekrutan di daerah-daerah
dependen atelektrik dan terkonsolidasi di paru-paru yang berkontribusi pada shunt fisiologis
selama ventilasi gas Aliran darah pulmonal juga didistribusikan kembali.

Strategi Pengobatan Baru

Mesenchymal Stem Cells (MSCs) adalah pendekatan baru yang potensial untuk pengobatan
ARDS. MSCs adalah multipotent, self-renewing cells yang awalnya diisolasi dari sumsum
tulang yang dapat berdiferensiasi menjadi berbagai jenis sel. Minat terhadap terapi berbasis
sel telah terganggu karena ketidakefektifan terapi farmakologis spesifik telah berevolusi.
Sejumlah penelitian telah menunjukkan bahwa faktor atau produk terlarut yang berasal dari
MSC manusia menghasilkan lingkungan mikro imunosupresif lokal dengan mensekresi
sitokin [42,43]. Akibatnya ada studi intensif yang berfokus pada sifat parakrin MSC [7].
Tampaknya MSC tidak menghasilkan responsif dan ini membuat pengobatan yang menarik
bagi MSC [43]. Telah ditemukan bahwa penanda MSC Bone Marrow Derived (BMD) negatif
untuk cluster diferensiasi 45 dan 11b (CD45 dan CD11b) dan mampu membedakan ke dalam
berbagai tipe sel, termasuk sel endotel, epitel dan neuronal. Ketika BMDMSCs dimasukkan
ke dalam tikus, mereka dapat ditemukan dengan karakteristik fenotipik sel-sel di organ
tempat mereka berada. Di paru-paru, BMDMSCs telah terdeteksi sebagai sel epitel alveolar
tipe I dan tipe II, sel endotel, fibroblas dan sel epitel bronkial. Tampaknya pasti bahwa sel-sel
ini memiliki kemampuan untuk melokalisasi paru-paru yang terluka dan berdiferensiasi
menjadi tipe sel tertentu [44]. Dalam sebuah penelitian dengan cedera paru yang diinduksi
oleh bleomycin pada tikus, ditemukan bahwa MSC transplantasi dilokalisasi ke paru-paru
yang terluka dan diasumsikan fenotip sel parenkim. Dalam model transplantasi kanker paru-
paru MSCs ini, dicegah peningkatan ekspresi paru sitokin sitokin terkait kekebalan
interleukin (IL) -1, interferon (IFN) -, IL-2, IL-4 yang dapat memberikan lingkungan yang
bermanfaat untuk perbaikan paru-paru. MSC juga ditunjukkan untuk menginduksi produksi
prostaglandin anti-inflamasi dan IL-10 dan ini mungkin mekanisme efek peradangan
penekan. Selain penekanan MSC terhadap lingkungan mikro lokal [44]. Pemberian MSC
dalam model endotoksik cedera paru akut melalui pemberian MSC langsung ke dalam ruang
udara paru-paru 4 jam setelah pemberian lipopolisakarida secara intrapulmoner secara
signifikan menurunkan air paru-paru, ukuran edema paru dan protein lavage bronchoalveolar,
ukuran endothelial dan permeabilitas epitel alveolar dan kelangsungan hidup meningkat
dibandingkan dengan tikus yang diberi perlakuan garam fosfat. Perlindungan tersebut
ditunjukkan untuk dimediasi oleh pergeseran dari proinflammatory menjadi respons anti-
inflamasi terhadap endotoksin yang mencakup peningkatan produksi IL-10 [45]. Berdasarkan
penelitian in vitro dan in vivo beberapa penelitian yang menunjukkan manfaat MSC dalam
berbagai gangguan klinis termasuk cedera paru akut, telah ada penelitian percontohan
terkontrol plasebo secara acak dengan tujuan untuk memeriksa kemungkinan kejadian buruk
setelah pemberian sistemik dari MSCs adiposa yang berasal dari adiogenik. pada pasien
ARDS dan untuk menentukan potensi kemanjuran MSC pada ARDS. Dua belas pasien
dewasa dengan ARDS dengan tekanan parsial oksigen arterial terhadap rasio oksigen
terinspirasi (PaO2 / FiO2) yang terukur <200 diacak untuk menerima MSC allogeneic atau
plasebo. Tidak ada toksisitas infus atau efek samping yang serius antara kedua kelompok.
Kesimpulannya adalah bahwa pemberian MSC allogeneic tampaknya aman dalam
pengobatan ARDS. Namun tidak ada perbedaan signifikan pada tingkat sitokin inflamasi
dengan dosis MSC yang digunakan. Optimalisasi strategi lebih lanjut akan diperlukan untuk
mencapai tujuan mengurangi cedera paru di ARDS [46]. Fase 1, label terbuka, eskalasi dosis,
percobaan multi-pusat MSC manusia sumsum tulang allogeneic yang diturunkan dari
sumsum tulang untuk mengobati ARDS adalah merekrut pasien
(http://clinicaltrials.gov/ct2/show/NCT01775774). Faktor nekrosis tumor adalah sitokin pro-
inflamasi yang manjur yang diproduksi oleh banyak tipe sel. Ini terlibat dalam peradangan
sistemik dan merupakan anggota kelompok sitokin yang merangsang reaksi fase akut. Ini
pada dasarnya diproduksi oleh makrofag aktif meskipun dapat diproduksi oleh jenis sel
lainnya. TNF juga mampu mengurangi edema paru dalam proses inflamasi yang berbeda
seperti edema paru non kardiogenik. Domain TNF mirip lincin, ditiru oleh peptida asam
amino serbaguna melingkar, peptida TIP, bertanggung jawab atas pengurangan clearance
edema paru pada model murine edema paru non kardiogenik [24,47,15,48]. Studi tentang
cedera paru-paru yang diinduksi pada 16 ekor babi oleh pembengkakan BAL diikuti oleh
ventilasi yang berbahaya menerima TIP atau air yang nebulasi. Indeks Air Paru
Ekstravaskular (EVLWI), rasio PaO2 / FIO2 dan fraksi shunt paru dinilai. Inhalasi TIP
menginduksi perbaikan parameter pengganti klinis fungsi paru pada model cedera paru-paru
babi yang menunjukkan peptida TIP sebagai pendekatan inovatif sebagai terapi suportif pada
ARDS [48]. Berdasarkan temuan ini, peptida TIP sekarang dalam uji klinis di Eropa dengan
temuan yang belum dipublikasikan. Terapi farmakologis terus diselidiki meski sebagian besar
masih dalam tahap pengembangan awal. Beberapa di antaranya adalah adenosin [49], heparin
dan heparins antikoagulan rendah [50-51], hormon pertumbuhan [52], inhibitor Heat Shock
Protein 90 [53]. Farmakoterapi yang efektif untuk ARDS tetap sangat terbatas [54)

Kesimpulan

Penyebab paling umum orang dewasa dengan ARDS berat adalah sepsis dan pneumonia dan
tingkat kematian terus tinggi. Patologi yang mendasari meliputi peradangan lokal dan
sistemik. Biomarker diidentifikasi namun kemunculan biomarker tunggal belum muncul dan
kemungkinan akan memiliki panel biomarker untuk memprediksi tingkat keparahan dan jalur
ARDS. Penggunaan MV pelindung paru-paru, moda ventilasi alternatif, ECMO dan posisi
rawan dapat memperbaiki angka kematian. Penelitian aktif meliputi pemasangan sel
mesenchymal, peptida TIP dan evaluasi persisten untuk terapi farmakologis untuk memberi
manfaat pada pasien ARDS berat.

Pengakuan

Karya ini didukung oleh NIH PO1-HL101902 dan GRU Extramural Success Award (ADV),
NHLBI R01HL094609 (RL) dan dukungan dermawan dari Departemen Kesehatan Georgia
dan Dr. Madaio (JG).