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Pathobiology of Acute Respiratory Distress Syndrome

Sapru, Anil MD, MAS1; Flori, Heidi MD2,3; Quasney, Michael W. MD, PhD4; Dahmer, Mary K. PhD4 for the Pediatric Acute Lung Injury Consensus Conference Group

Pediatric Critical Care Medicine: June 2015 - Volume 16 - Issue 5_suppl - p S6–S22
doi: 10.1097/PCC.0000000000000431
PARDS Supplement
Free

The unique characteristics of pulmonary circulation and alveolar-epithelial capillary-endothelial barrier allow for maintenance of the air-filled, fluid-free status of the alveoli essential for facilitating gas exchange, maintaining alveolar stability, and defending the lung against inhaled pathogens. The hallmark of pathophysiology in acute respiratory distress syndrome is the loss of the alveolar capillary permeability barrier and the presence of protein-rich edema fluid in the alveoli. This alteration in permeability and accumulation of fluid in the alveoli accompanies damage to the lung epithelium and vascular endothelium along with dysregulated inflammation and inappropriate activity of leukocytes and platelets. In addition, there is uncontrolled activation of coagulation along with suppression of fibrinolysis and loss of surfactant. These pathophysiological changes result in the clinical manifestations of acute respiratory distress syndrome, which include hypoxemia, radiographic opacities, decreased functional residual capacity, increased physiologic deadspace, and decreased lung compliance. Resolution of acute respiratory distress syndrome involves the migration of cells to the site of injury and re-establishment of the epithelium and endothelium with or without the development of fibrosis. Most of the data related to acute respiratory distress syndrome, however, originate from studies in adults or in mature animals with very few studies performed in children or juvenile animals. The lack of studies in children is particularly problematic because the lungs and immune system are still developing during childhood and consequently the pathophysiology of pediatric acute respiratory distress syndrome may differ in significant ways from that seen in acute respiratory distress syndrome in adults. This article describes what is known of the pathophysiologic processes of pediatric acute respiratory distress syndrome as we know it today while also presenting the much greater body of evidence on these processes as elucidated by adult and animal studies. It is also our expressed intent to generate enthusiasm for larger and more in-depth investigations of the mechanisms of disease and repair specific to children in the years to come.

1Division of Critical Care, Department of Pediatrics, University of California, San Francisco, San Francisco, CA.

2Pediatric Intensive Care Unit, Department of Medicine, Children’s Hospital, Oakland, CA.

3Division of Pediatric Critical Care, Research Center Oakland, Oakland, CA.

4Division of Pediatric Critical Care, Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI.

The Pediatric Acute Lung Injury Consensus Conference Group is listed in Appendix 1.

Supported, in part, by Department of Pediatrics, The Pennsylvania State University College of Medicine; Health outcome axis—Ste Justine research center, Montreal, Canada; Respiratory research network of Fonds de Recherche du Québec-Santé, Québec, Canada; Mother and children French-speaking network; French-speaking group in pediatric emergency and intensive care (Groupe Francophone de Réanimation et Urgences Pédiatriques), French-speaking intensive care society (Société de Réanimation de Langue Française); European Society for Pediatric and Neonatal Intensive Care Society for the travel support of European expert. Financial support for publication of the supplement in Pediatric Critical Care Medicine is from the Children’s Hospital Foundation of Children’s Hospital of Richmond at Virginia Commonwealth University, the Division of Pediatric Critical Care Medicine, C.S. Mott Children’s Hospital at the University of Michigan, and the Department of Anesthesia and Critical Care, Children’s Hospital of Philadelphia.

Dr. Jouvet received grants from the respiratory research network of Fonds de Recherche du Québec-Santé, Réseau mère enfant de la francophonie, and Research Center of Ste-Justine Hospital related to the submitted work; and received equipment on loan from Philips and Maquet outside the submitted work. Dr. Thomas served on the Advisory Board for Discovery Laboratories and Ikaria outside the submitted work; received a grant from United States Food and Drug Administration Office of Orphan Product Development outside the submitted work. Dr. Willson served on the Advisory Board for Discovery Laboratories outside the submitted work. Drs. Khemani, Smith, Dahmer, and Watson received grants from the National Institutes of Health (NIH) outside the submitted work. Dr. Zimmerman received research grants from the NIH, Seattle Children’s Research Institute, and ImmuneXpress outside the submitted work. Drs. Flori and Sapru received grants from the NIH related to the submitted work. Dr. Cheifetz served as a consultant with Philips and Hill-Rom outside the submitted work; and received grants from Philips, Care Fusion, Covidien, Teleflex, and Ikaria outside the submitted work. Drs. Rimensberger and Kneyber received travel support from the European Societiy of Pediatric and Neonatal Intensive Care related to this work. Dr. Tamburro received a grant from United States Food and Drug Administration Office of Orphan Product Development outside the submitted work. Dr. Emeriaud received a grant from Respiratory Health Network of the Fonds de la Recherche du Québec–Santé outside the submitted work. Dr. Newth served as a consultant for Philips Medical outside the submitted work. Drs. Erickson, Quasney, Curley, Nadkarni, Valentine, Carroll, Essouri, Dalton, Macrae, Lopez-Cruces, Santschi, and Bembea have disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: mkdahmer@umich.edu

Acute respiratory distress syndrome (ARDS) accounts for a significant proportion of the mortality observed in PICUs. The pathophysiologic basis of ARDS has been studied extensively since the initial description of this devastating condition over 40 years ago (1). Interestingly, of the 12 patients in Ashbaugh’s first case series of “adult respiratory distress syndrome” in 1967, five were between 11 and 19 years of age. Despite this, for the next 25 years, the term “adult” respiratory distress syndrome pervaded the literature despite other reports of ARDS in children indicating that pediatric ARDS (PARDS) also had the characteristic pathologic findings observed in adults (2–5). A newborn lung has approximately 50 million alveoli, increasing to between 300 and 800 million in the adult (6, 7). In a seemingly “opposite” fashion, the pulmonary vasculature begins as a duplicate network and develops into a single network. Pediatric studies suggest similarity in the pathophysiologic processes of ARDS in children and adults, but these studies have not investigated the nuances that may exist across the stages of lung development and may, therefore, impact the diagnosis, severity, and ultimately the best therapeutic strategies for ARDS with increasing age.

ARDS is a clinical syndrome of noncardiogenic pulmonary edema caused primarily by damage to the alveolar epithelial-endothelial permeability barrier. Breakdown of this permeability barrier results in increased movement of proteins and fluid across the lung epithelium/endothelium and accumulation of protein-rich inflammatory fluid in the normally fluid-free alveoli resulting in increased lung weight and loss of aerated lung tissue. This alteration in permeability and accumulation of fluid in the alveoli takes place in the setting of dysregulated inflammation, inappropriate activity of leukocytes and platelets, and uncontrolled activation of coagulation pathways. In addition, there is concurrent loss of surfactant and impairment of lymphatic drainage. Together, these physiological changes result in the clinical hallmarks of ARDS, which include hypoxemia, bilateral radiographic opacities, increased venous admixture, decreased functional residual capacity, increased physiologic deadspace, and decreased lung compliance. These changes may, in turn, result in the need to support work of breathing and gas exchange by mechanical ventilation, supplemental oxygen, and increased minute ventilation (8–10).

Both ARDS and PARDS are associated with many different underlying clinical conditions (pneumonia, sepsis, trauma, etc) (8, 11); although for PARDS, the most common underlying condition is respiratory infection rather than sepsis as observed for ARDS (12–14). Interestingly, viral infections are a much more common cause of ARDS in children than in adults and can be associated with histologically distinct patterns of injury consisting of a mix of bronchiolitis, acute interstitial pneumonia, and diffuse alveolar damage (15, 16). Although the general pathologic process of ARDS and PARDS in individuals with pneumonia, sepsis, or major trauma is similar, recent evidence indicates that there may also be important differences in the development and outcome of ARDS initiated by different clinical conditions.

It is also likely that there are subtle, yet significant differences between adults and children in the development and pathophysiology of ARDS as indicated by the differences in these two groups in response to treatment and in mortality rates (11, 13). These differences are likely greatly influenced by the substantial structural remodeling and growth of the lung parenchyma, as well as maturation of the immune system that occur in the developing child (17). However, very few studies have examined the potential differences in ARDS in children and adults. The pathobiology of ARDS has been primarily studied in adults and animal models using mature animals. Consequently, the following review will describe the current understanding of the mechanism of injury and resolution in ARDS using literature from animal models and human studies. However, particular attention will be given to studies related to the pathophysiology of PARDS and potential differences between children and adults.

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PULMONARY CIRCULATION AND THE EPITHELIAL-ENDOTHELIAL PERMEABILITY BARRIER

The alveolar epithelial/endothelial permeability barrier is comprised of alveolar epithelium, pulmonary capillary endothelium, and the intervening basement membranes. This barrier is absolutely essential for normal lung function due to its role in allowing gas exchange, while maintaining separation between the aqueous and gaseous compartments. A typical pair of fully developed human lungs contains about 500 million alveoli (6), producing ~50 m2 of surface area to serve the purpose of gas exchange. A thin layer of fluid, the so-called alveolar wall liquid (AWL), coats the inside surface of the alveolar epithelium and provides a liquid milieu for dispersal of surfactant molecules, which are important both in reducing surface tension and in preventing alveolar collapse (surfactant proteins [SP] B and C) and in host defense (SP-A and SP-D). The AWL also facilitates the transfer of gases between blood and alveolar air.

The lung parenchyma undergoes substantial structural remodeling and growth during childhood with maturation thought to be complete sometime in adolescence. At birth, there are less than 50 million alveoli and most of alveolarization occurs by 2 years of age (7). At 1 month, numerous short and blunt tissue ridges subdivide the peripheral airspaces into an increasing number of very shallow alveoli that contain a double capillary network with a central, highly cellular sheet of connective tissue. Over the next 6 months, there is reduction in the interstitial tissue mass in conjunction with a complex process of capillary remodeling, resulting in the adult structure with a single capillary network interwoven with connective tissue achieved by 18 months of age (7). Following this, the lung enters a period of alveolar growth that lasts at least through adolescence. The development and expansion of the lung parenchyma during childhood have never been fully considered in our understanding of the mechanisms of injury and of repair in PARDS. Evaluating the role of lung development and maturation more fully in future research is imperative to refine and improve the assessment, diagnosis, and treatment of PARDS.

Unique hemodynamic properties of the pulmonary circulation allow for formation of the AWL. Circulation in the lung functions at low hydrostatic pressure and blood flow occurs through two opposed sheet-like endothelial layers that account for the major drop in vascular pressure occurring across the alveolar capillary bed (18–20). In much of the capillary bed, microvascular pressure is lower than the filtration-opposing plasma protein osmotic pressure. However, vessels in the pulmonary circulation are leaky (permeable) in the extra-alveolar segment, particularly in the first generation of venules downstream from alveolar capillaries. Under physiological conditions, microvascular filtration and regulated transvascular flow of water, proteins, and small solutes occur across postcapillary venules. A major part of this filtrate flows into the lymphatic capillaries driven by the higher interstitial pressure at the septum than in the perilymphatic interstitium. A small part, however, flows across the alveolar septum by active chloride transport forming AWL (21–23). By this arrangement, fluid content of the alveolar septum is kept at a minimum, whereas sufficient fluid production occurs in the extra-alveolar vascular segments to account for lymph and AWL formation. Sodium-dependent vectorial transport across type II alveolar epithelial cells regulates the removal of excess alveolar fluid. Together, these characteristics of the epithelial-alveolar barrier and pulmonary circulation allow for formation of the AWL, which is essential for maintaining alveolar stability, facilitating gas exchange, and defending the lung against inhaled pathogens (24), while maintaining the air-filled, fluid-free, status of the alveoli (Fig. 1). At birth, the pulmonary vasculature is still immature with the presence of a double capillary network that with maturation becomes a single network. This restructuring of the pulmonary vasculature occurs from about 2 months to 2–3 years (7), at roughly the same time that the majority of alveolarization is occurring. Morphologically children’s lungs appear to be a smaller version of that of adults by about 3 years (7).

Figure 1

Figure 1

Given that the lungs of children are continuously developing between birth and adolescence, it seems likely that the degree of lung injury and the response to lung injury may vary with age in children and may be different than the response seen in adults. Some evidence supports this even now. Lung regeneration after pneumonectomy rarely occurs in adults, but it has been observed in children and, to a lesser degree, in adolescents (25–27). In addition, exposure to high oxygen during periods of lung growth in immature animals is associated with marked inhibition of pulmonary development, suggesting that PARDS may impact lung development in children (28).

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SYNOPSIS OF INCREASED PERMEABILITY PULMONARY EDEMA AND PATHOLOGY IN ARDS

Excessive entry of fluid into the alveoli from the pulmonary capillaries is called “pulmonary edema.” ARDS is characterized by increased permeability pulmonary edema as a result of loss of epithelial/endothelial barrier integrity and impaired alveolar fluid clearance. These changes result from either direct injury to the alveolar epithelium by inhaled toxins or pulmonary infection or they may occur after injury to the capillary endothelium as with sepsis or pancreatitis. As described above, most ARDS in children is a result of pulmonary infections, whereas sepsis is the commonest cause in adults (12–14). The wide variety of clinical entities that can lead to ARDS involve injury to the alveolar epithelium and capillary endothelium, generally via inflammation (as discussed below), resulting in increased permeability and formation of pulmonary edema. This results in characteristic changes in pulmonary mechanics and function, as well as interference with pulmonary gas exchange, which, when severe, may result in hypoxia and death. Concurrent with the loss of integrity of the alveolar-capillary barrier, solutes and large molecules such as albumin enter the alveolar space and result in the high protein content of the alveolar edema fluid in ARDS. In addition, significant concentrations of cytokines (e.g., interleukin [IL]-1, IL-8, and tumor necrosis factor-α [TNF-α]) and lipid mediators (e.g., leukotriene B4) are also present. In response to proinflammatory mediators, leukocytes (especially neutrophils) traffic into the pulmonary interstitium and alveoli (as described below) (Fig. 2). The presence of protein, fibrinogen, and fibrin-degradation products in the edema fluid contribute to surfactant degradation, resulting in large increases in surface tension. The fall in pulmonary compliance and alveolar instability eventually leads to areas of atelectasis. Increased surface tension also decreases the interstitial hydrostatic pressure and favors further fluid movement into the alveolus. As a further complication, loss of the epithelial barrier can lead to sepsis in patients with bacterial pneumonia. Because children less than 3 years old have fewer alveoli than adults and have not yet fully developed an adult’s pulmonary vasculature (as described above), it is likely that the development, pathophysiology, and outcome from ARDS in children may be different than that of adults. Although there have been many studies examining lung injury in neonates and neonatal animals, there are very few studies that specifically target infants and older children or juvenile animals.

Figure 2

Figure 2

On gross examination, the lungs of patients with ARDS appear edematous and heavy. The surface appears violaceous, and hemorrhagic fluid exudes from the cut pleural surface. Microscopically, there is cellular infiltration of the interalveolar septa and interstitium by inflammatory cells and erythrocytes, denuded regions of epithelium due to damage to alveolar type I (AT-I) epithelial cells, and ultimately a denuded alveolar barrier. Hyaline membranes (sheets of pink proteinaceous material composed of aggregated plasma proteins, fibrin, dysfunctional surfactant, and coagulated cellular debris) form in the absence of alveolar epithelium. Vascular obliteration by microthrombi and fibrocellular proliferation is also present (8). Fibrosis occurs in some cases. These pathologic hallmarks of ARDS in adults have also been observed in PARDS (2–5). Together, these pathologic changes ultimately result in the impaired lung physiology characteristic of ARDS, including decreased functional residual capacity, diminished compliance accompanied by increased work of breathing, increased deadspace and shunt fraction, and impaired gas exchange (8–10). Pulmonary function tests performed among children with PARDS confirm a decrease in compliance, forced vital capacity, and functional residual capacity (29, 30) along with an improvement in compliance with application of positive end-expiratory pressure (31).

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ALVEOLAR EPITHELIAL DYSFUNCTION IN ARDS

Under normal conditions, the lung epithelial barrier is much less permeable than the endothelial barrier. The normal alveolar epithelium is composed of two types of cells. Flat AT-I cells make up 90% of the alveolar surface area and are easily injured. Cuboidal AT-II cells make up the remaining 10% of the alveolar surface area and are more resistant to injury. The functions of AT-II cells include surfactant production, ion transport, and proliferation and differentiation to type I cells after injury (8). AT-I cells are responsible for maintaining lung architecture and appropriate fluid balance.

Sodium-dependent intracellular transport across the epithelium is a critical driving mechanism regulating the removal of excess alveolar fluid under normal (e.g., the perinatal lung) and pathologic conditions (e.g., pulmonary edema). In ARDS, vectorial transport of both sodium and chloride across the epithelium appears to be required for the absorption of fluid (32) and the ability to clear fluid rapidly is associated with improved outcome (33, 34). The rate of alveolar fluid clearance can be accelerated by cAMP agonists, including elevated endogenous levels of epinephrine or the exogenous administration of β2 adrenergic agonists (35, 36). However, the use of β adrenergic agonists has not proved efficacious in adults with ARDS (37). Several catecholamine-independent pathways, including glucocorticoids, keratinocyte growth factor (KGF) and thyroid hormone, also increase the rate of alveolar fluid clearance (38). Studies related to fluid clearance have been performed in adults, adult lungs, or animal models. Similar studies have not been performed in children or juvenile animals. However, as suggested by Smith et al (17), differences between children and adults are likely because factors that are involved in lung maturation, such as KGF, also appear to be involved in alveolar fluid clearance.

Paracellular permeability across the lung epithelium is primarily determined by the expression and regulation of transmembrane tight junction proteins. Tight junctions in the lung epithelium control paracellular permeability to solutes, proteins, and perhaps ions. The most important of these tight junction proteins appear to be in the claudin family. Claudin-4 is expressed at high levels in both AT-I and AT-II cells, and claudin-4 levels on lung histopathology are associated with intact alveolar fluid clearance in human lungs (39).

During ARDS, there is substantial damage to the lung epithelium. Such damage clearly compromises the lungs ability to maintain a permeability barrier and to remove excess alveolar fluid. The serum level of Krebs von den Lungen [KL]-6 (a glycoprotein present on type II pneumocytes) (40) is regarded as an index of alveolar epithelial cell damage and subsequent regeneration (41, 42) and elevation of serum KL-6 is associated with increased permeability of the alveolar—capillary barrier (43). KL-6 has been shown to be elevated in adults with ARDS (44). Similar studies have not been performed in children with PARDS although KL-6 is elevated in children with respiratory syncytial virus disease when compared with controls and the elevation is much more pronounced in those with severe disease with hypoxia and requiring mechanical ventilation (45). These findings underscore the importance of alveolar damage and impairment of alveolar capillary barrier in PARDS. The clinical significance of alveolar cell injury and loss of the permeability barrier is also highlighted by the association of elevated plasma levels of lung proteins such as SP-D and receptor for advanced glycation end products (RAGE), with clinical outcomes in adult patients with ARDS (46–49). Elevated plasma SP-D and RAGE levels have also been observed in children with bronchiolitis (50–52) and in children with lung injury after cardiac surgery (53).

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PULMONARY ENDOTHELIAL DYSFUNCTION IN ARDS

Endothelial cells (ECs) play a major role in the pathogenesis of ARDS. The pulmonary endothelium is a major component of the alveolar-capillary unit; it is therefore vulnerable to injury from noxious agents (mechanical, chemical, or cellular) that are either inhaled or delivered to the lung through the pulmonary circulation. Widespread vascular endothelial injury is thought to be the major mechanism for multiorgan dysfunction in sepsis and ARDS. Activated pulmonary endothelium 1) expresses leukocyte adhesion molecules, 2) produces cytokines, 3) induces changes in vascular integrity and tone, 4) becomes procoagulant, and 5) upregulates human leukocyte antigen molecules (54). If the proinflammatory process is ongoing, endothelial activation is followed by functional and, at a second stage, structural endothelial injury, which is an identifiable feature of ARDS in both children and adults. In humans with ARDS, the severity of vascular permeability is related to a four-point lung injury score as proposed by Murray et al (55) and to the number of neutrophils in bronchoalveolar lavage (BAL) fluid (56). Postmortem studies of adult patients who died of sepsis-related ARDS reveal patchy EC swelling and injury (57). In addition, there is excessive shedding of ECs and increased circulating ECs in sepsis and septic shock, suggesting widespread endothelial damage that likely includes the pulmonary endothelium (58). Thrombomodulin is an endothelial-bound protein, which is excessively shed as a result of endothelial injury resulting in elevated soluble thrombomodulin levels in plasma. Evidence for the involvement of the endothelium in PARDS is indicated by the association of increased levels of soluble thrombomodulin with mortality among children with indirect ARDS (59). This association between soluble thrombomodulin and mortality is also observed in adults with ARDS (60), underscoring the importance of endothelial injury in children and adults with ARDS.

Activity or elevated serum levels of other endothelial-specific proteins, including von Willebrand factor (vWF), angiotensin-converting enzyme (ACE), and tissue factor (TF) pathway inhibitor have been noted in children and adults with ARDS (61–64). Plasma vWF levels above 450 ng/mL have been shown to correlate with mortality in both pediatric (64) and adult (63) patients with ARDS. In addition, “protective” low tidal volumes appear to attenuate epithelial and endothelial injury (estimated by plasma vWF and permeability to albumin) in a rat model of acid-induced ARDS, supporting the role of endothelial injury in this pathophysiology (65).

A role for the endothelial permeability altering ACE/angiotensin system in ARDS has been suggested by several studies. The ACE D allele of the ACE insertion/deletion polymorphism is associated with higher enzyme activity and also appears to be related to patients’ susceptibility and outcome in several ARDS studies in adults, with the DD genotype being associated with worse prognosis (66, 67) (Table 1). Animal models indicate that angiotensin II induces pulmonary edema (68), and that ACE inhibition or angiotensin II receptor blockade ameliorates lung injury induced by oleic acid administration or exposure to ventilator-associated lung injury (69–71). In addition, angiotensin II has been implicated in the pathogenesis of the fibroproliferative response that follows lung injury, an effect also attenuated by ACE inhibition and angiotensin II receptor blockade, at least as described in animal studies (72). Blocking the deleterious effects of angiotensin II in the lung might offer protection against ARDS development and its sequelae. Vascular endothelial growth factor (VEGF) may be another important factor involved in the pathogenesis of noncardiogenic pulmonary edema. VEGF is decreased in lung fluid but is higher in the plasma of adult patients with ARDS (especially in subsequent nonsurvivors) compared with levels observed in patients at risk of ARDS or in controls (73–76). In addition, genetic variants in VEGF are associated with ARDS and ARDS severity (75, 77), again primarily in adult studies but with significant data in neonatal studies of hyaline membrane disease (78). Finally, angiopoietin-2, a protein involved in regulating permeability, may be involved in the development of ARDS as both plasma (79–83) and BAL levels (79) of angiopoietin-2 are elevated in adults with ARDS and genetic variants are associated with trauma-induced ARDS in adults (84). There is very little known about the role of angiopoietin in PARDS; however, we have recently reported that elevated plasma angiopoietin-2 levels are associated with mortality from PARDS and that an increase in angiopoietin-2 level from day 1 to day 3 after onset of PARDS is associated with a 13-fold increase in the odds of death among children with a history of cancer or bone marrow transplant (85).

TABLE 1

TABLE 1

The endothelial paracellular pathway, the major filtration route for the endothelium, contains protein assemblies that form tight junctions and adherens junctions (AJs). AJs are formed by the transmembrane proteins, cadherins: VE-cadherin in human and mouse lung endothelium (86–88) and E-cadherin in rat lung endothelium (89, 90). Weakening or loss of cadherin interactions at AJs or loss of cadherin from the endothelial junction accounts for the essential molecular defects underlying endothelial barrier failure. In ARDS, the failure of the endothelium to sieve proteins causes the vascular hyperpermeability and hyperfiltration underlying pulmonary edema. Lung microvascular hyperpermeability can also result from the formation of micrometer-scale endothelial gaps, a process mainly studied in cultured cells. On the basis of these studies, it has been suggested that a contractile mechanism similar to that of smooth muscle may exist in ECs (91). A central component of this hypothesis is that phosphorylation of myosin light-chain kinase causes actomyosin-based cell contraction, micrometer-scale gap formation, and hence barrier hyperpermeability. This hypothesis is supported by the results of adult studies that report an increased risk of sepsis-induced lung injury among individuals carrying specific genetic variants in the myosin light-chain kinase gene (92). However, these genetic variants were not associated with community-acquired pneumonia–induced ARDS in children or adults, suggesting that there may be differences in pathophysiology between different mechanisms of injury in both children and adults (93). Other contributors to vascular injury are mechanical stresses, such as vascular stretch resulting from lung overexpansion (94) or increased vascular pressure (95–97).

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INFLAMMATORY DYSFUNCTION AND ARDS

It is clear that the innate immune system and inflammation are integrally involved with the development of ARDS. Early histologic studies demonstrated the presence of neutrophils in the lungs of patients dying with ARDS (98, 99) and BAL fluid from patients with ARDS had elevated numbers of neutrophils (100–102), as well as elevated levels of reactive oxygen species (ROS) and proteases released from activated neutrophils (103). These initial pathologic findings were also documented in children and in animal models of ARDS developed after the initial description of the syndrome. During the past 20 years, animal models have been used extensively to characterize ARDS and have led to our current understanding of the molecular mechanisms underlying the observed histologic changes.

The trigger for the development of ARDS appears to be inflammation caused by the underlying clinical condition (pneumonia, sepsis, trauma, and transfusion) that results in the release of proinflammatory cytokines and injury to both the lung endothelium and epithelium (104–107). The result is loss of the epithelial-endothelial permeability barrier described above. Inflammation mediated by the innate immune system in response to infectious agents or tissue damage is triggered by the presence of pathogen-associated molecular patterns, such as lipopolysaccharide (LPS) found in molecules derived from pathogens and/or danger (or damage)-associated molecular patterns (DAMPs) (108–110). DAMPS are host-derived molecules elevated during cellular stress or damage and include specific extracellular matrix (ECM) components, heat shock proteins (HSPs), high-mobility group box 1 protein, nucleic acids, histones, and some immunomodulatory proteins such as β-defensins and SP-A (109). Pathogen-associated molecular patterns and DAMPs interact with Toll-like receptors and promote the inflammatory response via signaling through the MAP kinase pathway and the transcription factor, nuclear factor κB, resulting in the increased expression of inflammatory cytokines and chemokines (109, 110). If the initial insult is in the lung, this release of cytokines and chemokines triggers the movement of neutrophils into the lung as a part of a response by the host to either defend against infection or clear dying cells. However, this process is a part of a carefully orchestrated response by the host and, if this response is inadequately regulated, the process can also result in damage of the lung epithelium and endothelium that in turn can result in the development of ARDS.

ARDS is also observed in cases where the triggering inflammatory insult is not in the lung (nonpulmonary sepsis, trauma, and transfusion) and is considered to be “indirect,” as it does not originate in the lung itself. In such cases, systemic inflammation results in release of cytokines and activation of neutrophils in the bloodstream and lung damage is thought to occur via secondary accumulation of activated neutrophils in the lungs. Even under normal conditions transit time of neutrophils through the lungs is longer than that seen in other organs due to the need for neutrophils to change their shape as they pass through the small capillaries (103). In addition, experimental models indicate that activated neutrophils have reduced deformability (111–113). Together, these characteristics suggest that the lung endothelium and epithelium are particularly vulnerable to damage by inflammation triggered at nonpulmonary sites and that, once damaged, inflammation and cell death and changes in permeability will be propagated in the lung.

In most cases, the presence of activated neutrophils is critical for the development of ARDS. Neutrophils migrate into the lung by crossing lung endothelium and epithelium. Movement across the endothelium has been studied in much more detail and appears to involve a complex process of selectin-mediated capture and rolling followed by adhesion to the endothelium through a chemokine-dependent activation of integrins (103, 114). Although neutrophils primarily use a paracellular route to traverse the endothelium, there is some evidence that they can also cross the endothelium transcellularly. Movement of neutrophils across the lung epithelium appears to occur only by a paracellular route and is a complex process involving integrins (115). The role of neutrophils is to protect the host by phagocytozing organisms and releasing antimicrobial agents such as ROS, proteases (serine and matrix metalloproteinases [MMPs]), and antimicrobial polypeptides although paradoxically such agents may also be involved in the lung injury observed in ARDS. Recent data also indicate that neutrophils release neutrophil extracellular traps, which are fibrillary networks composed of chromatin (DNA and histones), in addition to a number of antimicrobial proteins (116, 117). Experimental model systems indicate that under certain conditions neutrophil extracellular traps released by neutrophils may also cause damage to the lung (118, 119). MMPs released by neutrophils have also been implicated in lung injury observed in adult ARDS (120–124).

Other cell types also play a role in the inflammation observed in ARDS. Macrophages move into the lung and are stimulated to release inflammatory mediators. Resident alveolar macrophages may also be stimulated. ECs also play a role in the inflammatory response. Examination of pulmonary microvascular ECs from adult patients with ARDS demonstrates an up-regulation of TNF-RII receptors and a higher constitutive production of IL-6 and IL-8, suggesting that there is either a stronger pulmonary EC activation occurring during the ARDS process or that pulmonary ECs are inherently more reactive in subjects who subsequently develop ARDS (125). TNF-α induces IL-8 production by pulmonary ECs via the p38 mitogen-activated protein kinase pathway; the underlying mechanism is regulated by the EC redox status, suggesting that antioxidant therapy might be of value in ARDS treatment (126).

Although the role of inflammation in the development of ARDS is clear, exactly which inflammatory factors play a critical role in the development in patients is still being explored and may be different in children and adults. In adult patients with ARDS, both levels of IL-1β and its antagonist, IL-1 receptor antagonist (IL-1ra), in BAL fluid are correlated with severity and outcome, and the ratio of TNF to soluble TNF receptors (sTNFR) is related to the severity of ARDS (127). In addition, a relatively large multicenter trial demonstrated that sTNFR I and II were strongly associated with mortality and morbidity in adults, as measured by fewer nonpulmonary organ failure-free and ventilator-free days (128). Other inflammatory mediators associated with ARDS or outcome from ARDS in adult patients include IL-6 and IL-8 (129–132), decoy receptor 3 (a member of the TNF receptor superfamily) (133), pre–B-cell colony–enhancing factor (134), Clara cell secretory protein (135), HSP72 (136) and HSP60 (with ARDS in patients with severe trauma) (137). Interestingly, very recent data demonstrate that circulating histone levels are associated with respiratory failure and Sequential Organ Failure Assessment scores in adults with severe trauma (118). Consequently, a role for histones in ARDS has been proposed (118, 138). Several biomarkers related to inflammation (TNF-α, IL-10, and IL-8) are included in a group of seven biomarkers (others are RAGE, procollagen peptide III, brain natriuretic peptide, and angiopoietin-2) demonstrated to be associated with ARDS in adult trauma patients (81). In addition, lower levels of IL-6, IL-8, and sTNFR-1 have been shown to be associated with survival in adults with ARDS (130). The importance of the role of inflammation in ARDS is also supported by studies examining the association of genetic variants with either the development of ARDS or outcome from ARDS. Variants in the genes for the following inflammation-related genes have reproducibly shown association with development of ARDS and/or outcome from ARDS in adults: IL-1ra (139), IL-6, IL-8, IL-10, TNF-α, pre–B-cell colony–enhancing factor 1, VEGF, NFκB (77).

Very few studies examining the role of inflammatory molecules have been performed in children with ARDS. One small study demonstrated an association of elevated IL-6 serum levels with PARDS (140), whereas another demonstrated elevated plasma IL-8 in PARDS (141). In addition, soluble intercellular adhesion molecule-1 has been associated with increased risk of death and or prolonged duration of mechanical ventilation in PARDS (142). As observed in adults, MMP-8 and MMP-9 play key roles in the modulation of neutrophilic lung inflammation seen in children with ARDS. MMP-8 and MMP-9 are elevated in pooled lung secretions of children with ARDS (143) and higher levels of MMP-8 and active MMP-9 at 48 hours of disease onset are associated with a longer duration of mechanical ventilation and fewer ventilator-free days among pediatric patients with ARDS (144). Together, these results signify the pathogenic role of MMPs in PARDS and their potential roles as early biomarkers predictive of disease course and as potential therapeutic targets. To date, there has been only one small study in children examining the association of genetic variants in inflammatory genes with the development of PARDS. This showed the association of a genetic variant in the IL-1ra gene with ARDS in children with community-acquired pneumonia (145).

Although there is little doubt that inflammation and the immune system play an integral role in the development of PARDS, differences in immune responsiveness between adults and children are also likely to impact ARDS (17). Studies indicate that neonates have fewer neutrophils than adults, and that there is a decreased chemotactic response in polymorphonuclear cells of neonates that may persist until 1–2 years (17). In addition, neonatal polymorphonuclear cells and monocytes have lower cytokine release in response to LPS compared with adults (146–148). Differences in the response to LPS have also been reported in studies comparing the lungs of neonatal and adult mice (149). The studies described above, like most found in the literature, have compared responses in neonates with those of adults. There is a paucity of studies examining how the response of the immune system differs in its response to illness or infection across children of different ages and none examining the development or pathophysiology of PARDS throughout development. However, studies in healthy children indicate that substantial changes in lymphocyte subsets (150, 151) and cytokine response (152–154) occur during development. A few studies in animal models of ARDS compare the response of juvenile and adult animals. Interestingly, one study using a rat model indicated that older rats had a higher level of hemorrhagic shock-induced ARDS that peroxisome proliferator-activated receptor-N decreased with age and that a peroxisome proliferator-activated receptor-N ligand decreased inflammation in young, but not in old rats (155). In addition, Smith et al (156) demonstrated that the synergistic effect of mechanical ventilation and LPS on lung inflammation and permeability observed in adult mice was not found in juvenile mice. Microarray analysis demonstrated differences between juvenile and adult mice in gene expression triggered by mechanical ventilation and LPS. Another study comparing the response to LPS of neonatal and juvenile mice indicated that there are significant differences between these groups in the monocyte and T-cell response (157). That there may also be important differences between adults and children in the innate immune response to critical illness or injury is indicated by the difference in the rate of multiple organ failure between critically ill children and adults (154). In addition, in one study examining temporal cytokine profiles in both severely burned adults and children, the cytokine profiles differed significantly with adults appearing to exhibit a more hyperinflammatory state (158). Clearly, much additional research is needed to understand the development, outcome, and optimal treatment for children of different ages with PARDS.

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SURFACTANT DYSFUNCTION IN ARDS

Surfactant is required for normal lung function and contains four major proteins: SP-A, SP-B, SP-C, and SP-D. SP-A, SP-B, and SP-D are low in the BAL fluid of adults with ARDS, suggesting a loss of these proteins as a result of alveolar epithelial cell injury (159–162). Serum levels of these proteins have been shown to correlate with the extent of alveolar epithelial damage in children (141, 163) and adults (164–168). In addition, decreased phospholipid levels in BAL fluid (159), changes in phospholipid composition (169, 170), and a diminished ability of surfactant to lower surface tension (159, 171) have been reported in adults. Decreased phospholipid levels in BAL fluid and changes in phospholipid composition have also been reported in PARDS (141).

ROS released by neutrophils may also alter the biophysical properties of surfactant. Studies performed in vitro and in animal models indicate that oxidation of surfactant phospholipids and proteins decreases surfactant’s surface tension–lowering capabilities (172–174). Together, these observations suggest that the observed decreased ability of surfactant to lower surface tension in patients with ARDS is likely related to the observed changes in phospholipid composition, the loss of SP-B (which is integral to the ability of surfactant to lower surface tension), and possibly to oxidation of phospholipids and SPs. The loss in surfactant activity and resulting increased surface tension results in a fall in pulmonary compliance and alveolar instability, leading to areas of atelectasis. Interestingly, total phospholipid content of BAL appears to be highest in young children and decreases with age (175) although whether ARDS impacts surfactant function differently in children versus adults or in children of different ages has never been examined.

The importance of surfactant is also indicated by the association of lung injury with genetic variants of SP-B, a SP integral to the surface tension–lowering properties of surfactant. Several common polymorphisms within the SP-B gene have been reported to affect the level of SP-B (176, 177), and one of these sites, the SP-B +1580 polymorphism, has been reported to be associated with ARDS in adults (178–180). The SP-B +1580 polymorphism has also been associated with more severe lung injury in African American children with pneumonia (181). In addition, genetic variants in SP-A and SP-D have been reported to be associated with ARDS in adults with pneumonia (182).

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THROMBOSIS AND FIBRINOLYSIS DYSFUNCTION IN ARDS

Inflammation and coagulation are critical host responses to infection and injury and are involved in ARDS pathogenesis. The lung endothelium provides the surface that integrates inflammatory pathways of the innate immune system with the coagulation cascade (183). Clinical observations documented the presence of fibrin deposition as a marker of hemostasis in addition to intravascular clots and inflammatory markers in the lungs of patients with ARDS (184–186). Microthrombi and pulmonary vascular injury also occur early in ARDS (8). Thrombocytopenia is observed in adults with ARDS and is associated with mortality (187–190). A recent report indicates that thrombocytopenia is also associated with worse clinical outcomes including increased mortality and length of stay among children with ARDS (191), suggesting that platelets may play an important role in pathogenesis of ARDS in both children and adults.

It has been recognized that ECs orchestrate the immune and hemostatic response by shifting from their normal antithrombotic and anti-inflammatory phenotype to an “activated” state of endothelial “dysfunction” (192), characterized by prothrombotic and proadhesive properties. Key events in this transformation are the expression of adhesion molecules to leukocytes and platelets on the EC surface in addition to the expression of activators of the humoral clotting system, including TF (193) and vWF (62). The above processes are launched by a variety of stimuli, including hypoxia, cytokines, and chemokines, inflammatory mediators, and activated platelets and neutrophils. Intravascular thrombi may form on denuded vessel walls following EC desquamation via activation of the intrinsic coagulation pathway. They may also form by activation of the extrinsic pathway initiated by TF expression on EC and other cells, including macrophages. Cytokines such as IL-6 induce TF expression, whereas TNF-α blocks coagulation-inhibiting and fibrinolytic pathways (194). Initiation of the extrinsic coagulation pathway by TF leads to proteolytic cleavage of prothrombin and thrombin release, which has important downstream effects, including cleavage of fibrinogen to fibrin and platelet activation by binding to proteinase-activated receptors. Thrombin also acts on EC via proteinase-activated receptors and evokes several effects, including calcium release, EC contraction, and increased permeability (195, 196).

Changes in the hemostatic balance favoring a procoagulant environment are observed in both the alveolar and the plasma compartments in adults with ARDS (197–201). This procoagulant environment appears to be due, in part, to elevated plasminogen activator inhibitor-1 (PAI-1), resulting in diminished fibrinolytic activity, lower levels of the anticoagulant protein C, and elevated TF. Fibrinolytic activity in BAL fluid from adults with ARDS is undetectable 3 days after the development of ARDS and is associated with increased PAI-1 activity (197). This increase in PAI-1 activity has been observed in a number of studies of adults with ARDS and adults at risk for ARDS (198, 199, 202); serum levels of PAI-1 return to near baseline in adults in the at-risk group, while staying persistently elevated in adults who develop ARDS (202). Adult (132, 203, 204) and pediatric (205) nonsurvivors of ARDS also have higher PAI-1 levels than survivors. The 4G allele of an insertion deletion polymorphism in the promoter region of the PAI-1 gene (4G/5G polymorphisms) that leads to increased transcription is associated with increased hospitalization and mortality among adults with pneumonia (206) and with mortality in patients with ARDS (207). Plasma levels of the anticoagulant protein C are decreased in adults with ARDS (208) and are associated with more nonpulmonary organ system dysfunction, a higher mortality (209, 210), and prolonged mechanical ventilation (210). Multivariable analysis comparing baseline protein C and PAI-1 plasma levels in adults with acute cardiogenic pulmonary edema relative to normal controls demonstrated that low protein C and high PAI-1 were strong, independent predictors of mortality, as well as ventilator and organ failure-free days; combined, these markers were synergistic in predicting mortality (204). TF, a potent stimulator of the extrinsic coagulation pathway, also appears to be elevated in the BAL fluid of adults with ARDS, and levels are more than 100-fold greater than in serum obtained simultaneously (211). Furthermore, it appears that alveolar epithelium can up-regulate TF in response to inflammatory stimuli (211). Taken together, these studies support the importance of the role of altered coagulation and fibrinolysis in ARDS and suggest that these alterations contribute to the pathogenesis of ARDS. No comparable studies exist in children. A deeper understanding of the role of coagulation and fibrinolysis in the pathogenesis of PARDS is imperative as many of the above described studies have been performed only in adults. Such studies may ultimately inform the development and the use of anticoagulant, profibrinolytic therapies such as heparinoids, antiplatelet agents, and activated protein C among selected groups of patients with specific biomarker or genetic profiles.

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RESOLUTION OF ARDS

Ideally, resolution of ARDS results in no long-lasting changes to underlying lung structure or function. Return of normal structure and function involves resolution of inflammation, repair of the lung epithelium and endothelium, and removal of fluid, without the generation of fibrotic tissue. Resolution of the underlying inflammatory process is required in order for the lung to regain its normal function. Studies over the past 15 years have indicated that ending an acute inflammatory event is an active, carefully orchestrated process that begins early in the inflammatory response (212). Although anti-inflammatory mediators are involved in limiting inflammation, there are also proresolution mediators that act to end inflammation and restore tissue homeostasis without causing immune suppression. Proresolution mediators include several classes of signaling molecules generated from polyunsaturated fatty acids: lipoxins, resolvins, and protectins. These agents appear to signal the recruitment of macrophages, the phagocytosis of apoptotic neutrophils, the secretion of anti-inflammatory molecules such as IL-10 and transforming growth factor (TGF)-β and, in some cases, increased chemokine scavenging from apoptotic neutrophils. There are very few studies on the role of proresolution mediators in resolution of ARDS; however, several recent studies in mouse models of ARDS indicate that resolvins can decrease lung injury and accelerate resolution (213, 214). Interestingly, there is some indication that resolvin E1 may signal for lung repair without being immunosuppressive; bacterial clearance and survival are improved in Escherichia coli–infected mice with acid-induced acute lung injury that are treated with resolvin E1 (214, 215).

Re-establishment of the permeability barrier in lung alveoli is required for resolution of ARDS. Very little is known about the repair of the lung endothelium and repair of the endothelial permeability barrier; however, platelets have been implicated recently in vascular repair and remodeling in extrapulmonary sites of vascular damage in mice (216, 217). In contrast, repair of the lung epithelium and re-establishment of its barrier function has been the subject of much research. Repair of the epithelium is a complex process that appears to involve epithelial cell spreading and migration, as well as proliferation and differentiation. During the early stages of epithelial repair, epithelial progenitor cells migrate along the underlying matrix that is, in turn, remodeled during the repair process. MMPs are up-regulated during the repair process and appear to be involved in facilitating migration and in the remodeling of the ECM (218). Studies in animal and tissue culture models indicate that migration and proliferation of the epithelial progenitor cells are regulated by a variety of soluble factors released in response to injury in the lung. These factors include members of the epidermal growth factor family (epidermal growth factor and TGF-α) and fibroblast growth factor family (hepatocyte growth factor, KGF, fibroblast growth factor-10). Interestingly TGF-α levels have also been reported to be elevated in BAL fluid in adult patients with ARDS (219).

Until very recently, it was thought that the AT-II cells were the progenitor epithelial cells responsible for repair of the alveolar epithelium (220). In experimental models, AT-II cells have been shown to migrate, proliferate, and differentiate into type I cells. However, recent studies in rodent models suggest that there may be other lung progenitor cells involved in repair of the lung epithelium, including Clara cells, integrin α6β4 alveolar epithelial cells, and Scgb1a1-expressing cells (221, 222). Interestingly, there is also evidence of a population of lung stem cells in human lungs that may be involved in repair of lung alveoli. These human lung stem cells were capable of differentiating into alveoli and pulmonary vessels in damaged mouse lungs (223). Additional studies will be required to determine whether these stem cells play a role in repair of lung injury in patients. Once the alveolar permeability barrier is re-established, removal of lung edema occurs via movement of water out of the airspaces through aquaporins (water channels) in AT-II cells, which is driven by the active transport of sodium and chloride through specific epithelial cell ion channels (eNAC and CFTR) (220, 224).

Resolution of lung injury also involves fibrocytes, fibroproliferation, and deposition of collagen. If there is excessive deposition of ECM, however, the normal architecture of the lung can be disrupted, resulting in loss of lung function. The control of this process is not well understood but appears to involve a number of factors including cytokines (such as IL-1β) and growth factors (such as TGF-β) (212, 224, 225). Experimental models indicate that a cell type with fibroblast-like morphology is responsible for the excessive production of ECM observed in the lung under certain conditions. The source of these cells remains unclear. Various studies have indicated that they arise from activation of stromal cells present in the lung (226), from bone marrow–derived fibrocytes (227), and from type II alveolar epithelial cells (228, 229). Studies indicate that higher levels of procollagen III are associated with increased mortality in patients with ARDS (230, 231), and recent studies have shown that the number of fibrocytes in BAL fluid is predictive of outcome from ARDS (232).

There are no studies related to repair or resolution of lung injury in children or juvenile animal models. However, it seems likely that the resolution of lung injury differs between adults and children and between children of different ages. If indeed there are specific lung stem cells, or even endothelial stem cells, involved in repair, it is possible that more are present in children than in adults and that younger children may have more than older children. In addition, because many of the same factors are involved in both lung development and resolution of lung injury, it is possible that children may recover more quickly from PARDS. Alternatively, PARDS and resolution of PARDS may impact the development of the immature lung.

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SUMMARY

Both the development and the resolution of ARDS are complex processes. ARDS is characterized by the loss of the permeability barrier in the lung with damage to both the lung epithelium and endothelium and the presence of protein-rich edema fluid. The trigger for ARDS appears to be a degree of inflammation (caused by the underlying clinical condition) precipitating sufficient damage to the lung to lead to a loss of the permeability barrier. Accompanying such changes are alterations to surfactant and changes in the hemostatic balance that favors a procoagulant state. Resolution of ARDS involves the migration of cells to the site of injury, deposition of ECM, and re-establishment of the epithelium and endothelium without the development of fibrosis. Most of the data, however, originate from adult studies with very few studies performed in children. Although much of what has been learned in adults is likely to be applicable to children, at least in part, differences in mortality rates and response to treatment together with changes occurring during development, particularly in the lungs and immune system, suggest that there may be subtle, yet important, differences between children and adults that impact the development of and outcomes from PARDS. Such differences in systems that play an integral role in PARDS suggest that studies in pediatric patients of various ages are necessary to better understand the development of PARDS, to identify risk, and to understand how to best treat children with PARDS.

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ACKNOWLEDGMENT

We acknowledge Martina Steurer-Muller, MD, MAS, for her assistance with drawing the figures.

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REFERENCES

1. Ashbaugh DG, Bigelow DB, Petty TL, et al. Acute respiratory distress in adults. Lancet. 1967;2:319–323
2. Effmann EL, Merten DF, Kirks DR, et al. Adult respiratory distress syndrome in children. Radiology. 1985;157:69–74
3. Katz R. Adult respiratory distress syndrome in children. Clin Chest Med. 1987;8:635–639
4. Nussbaum E. Adult-type respiratory distress syndrome in children. Experience with seven cases. Clin Pediatr (Phila). 1983;22:401–406
5. Pfenninger J, Gerber A, Tschäppeler H, et al. Adult respiratory distress syndrome in children. J Pediatr. 1982;101:352–357
6. Ochs M, Nyengaard JR, Jung A, et al. The number of alveoli in the human lung. Am J Respir Crit Care Med. 2004;169:120–124
7. Burri PH. Structural aspects of postnatal lung development—alveolar formation and growth. Biol Neonate. 2006;89:313–322
8. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000;342:1334–1349
9. Ranieri VM, Rubenfeld GD, Thompson BT, et al.ARDS Definition Task Force. ARDS Definition Task Force. Acute respiratory distress syndrome: The Berlin Definition. JAMA. 2012;307:2526–2533
10. Fein A, Grossman RF, Jones JG, et al. The value of edema fluid protein measurement in patients with pulmonary edema. Am J Med. 1979;67:32–38
11. Flori HR, Glidden DV, Rutherford GW, et al. Pediatric acute lung injury: Prospective evaluation of risk factors associated with mortality. Am J Respir Crit Care Med. 2005;171:995–1001
12. Rubenfeld GD, Caldwell E, Peabody E, et al. Incidence and outcomes of acute lung injury. N Engl J Med. 2005;353:1685–1693
13. Zimmerman JJ, Akhtar SR, Caldwell E, et al. Incidence and outcomes of pediatric acute lung injury. Pediatrics. 2009;124:87–95
14. Santschi M, Jouvet P, Leclerc F, et al.PALIVE Investigators; Pediatric Acute Lung Injury and Sepsis Investigators Network (PALISI); European Society of Pediatric and Neonatal Intensive Care (ESPNIC). Acute lung injury in children: Therapeutic practice and feasibility of international clinical trials. Pediatr Crit Care Med. 2010;11:681–689
15. Walker TA, Khurana S, Tilden SJ. Viral respiratory infections. Pediatr Clin North Am. 1994;41:1365–1381
16. Newth CJ. Time course of severe respiratory syncytial virus infection in mechanically ventilated infants. Acta Paediatr. 2000;89:893–895
17. Smith LS, Zimmerman JJ, Martin TR. Mechanisms of acute respiratory distress syndrome in children and adults: A review and suggestions for future research. Pediatr Crit Care Med. 2013;14:631–643
18. Bhattacharya J, Nakahara K, Staub NC. Effect of edema on pulmonary blood flow in the isolated perfused dog lung lobe. J Appl Physiol Respir Environ Exerc Physiol. 1980;48:444–449
19. Bhattacharya S, Glucksberg MR, Bhattacharya J. Measurement of lung microvascular pressure in the intact anesthetized rabbit by the micropuncture technique. Circ Res. 1989;64:167–172
20. Haworth ST, Rickaby DA, Linehan JH, et al. Subpleural pulmonary microvascular pressures in the dog lung. J Appl Physiol (1985). 1995;79:615–622
21. Bhattacharya J. Hydraulic conductivity of lung venules determined by split-drop technique. J Appl Physiol (1985). 1988;64:2562–2567
22. Qiao RL, Bhattacharya J. Segmental barrier properties of the pulmonary microvascular bed. J Appl Physiol (1985). 1991;71:2152–2159
23. Lai-Fook SJ. Perivascular interstitial fluid pressure measured by micropipettes in isolated dog lung. J Appl Physiol Respir Environ Exerc Physiol. 1982;52:9–15
24. Bhattacharya J, Matthay MA. Regulation and repair of the alveolar-capillary barrier in acute lung injury. Annu Rev Physiol. 2013;75:593–615
25. Cagle PT, Thurlbeck WM. Postpneumonectomy compensatory lung growth. Am Rev Respir Dis. 1988;138:1314–1326
26. Nakajima C, Kijimoto C, Yokoyama Y, et al. Longitudinal follow-up of pulmonary function after lobectomy in childhood—factors affecting lung growth. Pediatr Surg Int. 1998;13:341–345
27. Fernandez LG, Isbell JM, Jones DR, et al. Compensatory Lung Growth After Pneumonectomy, Topics in Thoracic Surgery. Cardoso P (Ed). InTech 2012 Available at: http://www.intechopen.com/books/topics-in-thoracic-surgery/compensatory-lung-growth-after-pneumonectomy. Accessed April 13, 2015
28. Bartlett D Jr. Postnatal growth of the mammalian lung: Influence of low and high oxygen tensions. Respir Physiol. 1970;9:58–64
29. Newth CJ, Stretton M, Deakers TW, et al. Assessment of pulmonary function in the early phase of ARDS in pediatric patients. Pediatr Pulmonol. 1997;23:169–175
30. Hammer J, Numa A, Newth CJ. Total lung capacity by N2 washout from high and low lung volumes in ventilated infants and children. Am J Respir Crit Care Med. 1998;158:526–531
31. Sivan Y, Deakers TW, Newth CJ. Effect of positive end-expiratory pressure on respiratory compliance in children with acute respiratory failure. Pediatr Pulmonol. 1991;11:103–107
32. Matthay MA, Zemans RL. The acute respiratory distress syndrome: Pathogenesis and treatment. Annu Rev Pathol. 2011;6:147–163
33. Matthay MA. Alveolar fluid clearance in patients with ARDS: Does it make a difference? Chest. 2002;122:340S–343S
34. Sartori C, Matthay MA. Alveolar epithelial fluid transport in acute lung injury: New insights. Eur Respir J. 2002;20:1299–1313
35. Matthay MA, Fukuda N, Frank J, et al. Alveolar epithelial barrier. Role in lung fluid balance in clinical lung injury. Clin Chest Med. 2000;21:477–490
36. Sakuma T, Gu X, Wang Z, et al. Stimulation of alveolar epithelial fluid clearance in human lungs by exogenous epinephrine. Crit Care Med. 2006;34:676–681
37. Matthay MA, Brower RG, Carson S, et al.National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Randomized, placebo-controlled clinical trial of an aerosolized beta(2)-agonist for treatment of acute lung injury. Am J Respir Crit Care Med. 2011;184:561–568
38. Matthay MA, Clerici C, Saumon G. Invited review: Active fluid clearance from the distal air spaces of the lung. J Appl Physiol (1985). 2002;93:1533–1541
39. Rokkam D, Lafemina MJ, Lee JW, et al. Claudin-4 levels are associated with intact alveolar fluid clearance in human lungs. Am J Pathol. 2011;179:1081–1087
40. Sun AP, Ohtsuki Y, Fujita J, et al. KL-6, a human MUC1 mucin, is expressed early in premature lung. Respir Med. 2003;97:964–969
41. Kohno N, Awaya Y, Oyama T, et al. KL-6, a mucin-like glycoprotein, in bronchoalveolar lavage fluid from patients with interstitial lung disease. Am Rev Respir Dis. 1993;148:637–642
42. Kuwano K, Maeyama T, Inoshima I, et al. Increased circulating levels of soluble Fas ligand are correlated with disease activity in patients with fibrosing lung diseases. Respirology. 2002;7:15–21
43. Inoue Y, Barker E, Daniloff E, et al. Pulmonary epithelial cell injury and alveolar-capillary permeability in berylliosis. Am J Respir Crit Care Med. 1997;156:109–115
44. Sato H, Callister ME, Mumby S, et al. KL-6 levels are elevated in plasma from patients with acute respiratory distress syndrome. Eur Respir J. 2004;23:142–145
45. Kawasaki Y, Aoyagi Y, Abe Y, et al. Serum KL-6 levels as a biomarker of lung injury in respiratory syncytial virus bronchiolitis. J Med Virol. 2009;81:2104–2108
46. Guo WA, Knight PR, Raghavendran K. The receptor for advanced glycation end products and acute lung injury/acute respiratory distress syndrome. Intensive Care Med. 2012;38:1588–1598
47. Calfee CS, Ware LB, Eisner MD, et al.NHLBI ARDS Network. Plasma receptor for advanced glycation end products and clinical outcomes in acute lung injury. Thorax. 2008;63:1083–1089
48. Determann RM, Royakkers AA, Haitsma JJ, et al. Plasma levels of surfactant protein D and KL-6 for evaluation of lung injury in critically ill mechanically ventilated patients. BMC Pulm Med. 2010;10:6
49. Eisner MD, Parsons P, Matthay MA, et al.Acute Respiratory Distress Syndrome Network. Plasma surfactant protein levels and clinical outcomes in patients with acute lung injury. Thorax. 2003;58:983–988
50. Kawasaki Y, Endo K, Suyama K, et al. Serum SP-D levels as a biomarker of lung injury in respiratory syncytial virus bronchiolitis. Pediatr Pulmonol. 2011;46:18–22
51. Chu MA, Lee EJ, Park HJ, Lee KH, Kim WT, Chung HL.. Increased serum surfactant protein-D in the infants with acute respiratory syncytial virus bronchiolitis. Allergy Asthma Respir Dis. 2013;1:p. 235–240
52. Mosbah AA, Abdellatif NA, Sorour EI, et al. Serum SP-D levels as a biomarker of lung injury in children suffering of bronchopneumonia. J Egypt Soc Parasitol. 2012;42:25–32
53. Liu X, Chen Q, Shi S, et al. Plasma sRAGE enables prediction of acute lung injury after cardiac surgery in children. Crit Care. 2012;16:R91
54. Wort SJ, Evans TW. The role of the endothelium in modulating vascular control in sepsis and related conditions. Br Med Bull. 1999;55:30–48
55. Murray JF, Matthay MA, Luce JM, et al. An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis. 1988;138:720–723
56. Sinclair DG, Braude S, Haslam PL, et al. Pulmonary endothelial permeability in patients with severe lung injury. Clinical correlates and natural history. Chest. 1994;106:535–539
57. Meyrick B. Pathology of the adult respiratory distress syndrome. Crit Care Clin. 1986;2:405–428
58. Mutunga M, Fulton B, Bullock R, et al. Circulating endothelial cells in patients with septic shock. Am J Respir Crit Care Med. 2001;163:195–200
59. Orwoll B, Spicer A, Khemani RG, et al. O-080 elevated soluble thrombomodulin is associated with increased mortality among children with indirect acute respiratory distress syndrome (ARDS). Arch Dis Child. 2014;99(suppl 2):A56
60. Sapru A, Calfee CS, Liu KD, et al. The NHLBI ARDS Network. Plasma soluble thrombomodulin levels are associated with mortality in the acute respiratorydistress syndrome. Intensive Care Med. 2015
61. Orfanos SE, Armaganidis A, Glynos C, et al. Pulmonary capillary endothelium-bound angiotensin-converting enzyme activity in acute lung injury. Circulation. 2000;102:2011–2018
62. Sabharwal AK, Bajaj SP, Ameri A, et al. Tissue factor pathway inhibitor and von Willebrand factor antigen levels in adult respiratory distress syndrome and in a primate model of sepsis. Am J Respir Crit Care Med. 1995;151:758–767
63. Ware LB, Eisner MD, Thompson BT, et al. Significance of von Willebrand factor in septic and nonseptic patients with acute lung injury. Am J Respir Crit Care Med. 2004;170:766–772
64. Flori HR, Ware LB, Milet M, et al. Early elevation of plasma von Willebrand factor antigen in pediatric acute lung injury is associated with an increased risk of death and prolonged mechanical ventilation. Pediatr Crit Care Med. 2007;8:96–101
65. Frank JA, Gutierrez JA, Jones KD, et al. Low tidal volume reduces epithelial and endothelial injury in acid-injured rat lungs. Am J Respir Crit Care Med. 2002;165:242–249
66. Adamzik M, Frey U, Sixt S, et al. ACE I/D but not AGT (-6)A/G polymorphism is a risk factor for mortality in ARDS. Eur Respir J. 2007;29:482–488
67. Marshall RP, Webb S, Bellingan GJ, et al. Angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome. Am J Respir Crit Care Med. 2002;166:646–650
68. Yamamoto T, Wang L, Shimakura K, et al. Angiotensin II-induced pulmonary edema in a rabbit model. Jpn J Pharmacol. 1997;73:33–40
69. He X, Han B, Mura M, et al. Angiotensin-converting enzyme inhibitor captopril prevents oleic acid-induced severe acute lung injury in rats. Shock. 2007;28:106–111
70. Jerng JS, Hsu YC, Wu HD, et al. Role of the renin-angiotensin system in ventilator-induced lung injury: An in vivo study in a rat model. Thorax. 2007;62:527–535
71. Yao S, Feng D, Wu Q, et al. Losartan attenuates ventilator-induced lung injury. J Surg Res. 2008;145:25–32
72. Marshall RP, Gohlke P, Chambers RC, et al. Angiotensin II and the fibroproliferative response to acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2004;286:L156–L164
73. Koh H, Tasaka S, Hasegawa N, et al. Vascular endothelial growth factor in epithelial lining fluid of patients with acute respiratory distress syndrome. Respirology. 2008;13:281–284
74. Medford AR, Millar AB. Vascular endothelial growth factor (VEGF) in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS): Paradox or paradigm? Thorax. 2006;61:621–626
75. Medford AR, Godinho SI, Keen LJ, et al. Relationship between vascular endothelial growth factor + 936 genotype and plasma/epithelial lining fluid vascular endothelial growth factor protein levels in patients with and at risk for ARDS. Chest. 2009;136:457–464
76. Thickett DR, Armstrong L, Christie SJ, et al. Vascular endothelial growth factor may contribute to increased vascular permeability in acute respiratory distress syndrome. Am J Respir Crit Care Med. 2001;164:1601–1605
77. Gao L, Barnes KC. Recent advances in genetic predisposition to clinical acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2009;296:L713–L725
78. Levesque BM, Kalish LA, Winston AB, et al. Low urine vascular endothelial growth factor levels are associated with mechanical ventilation, bronchopulmonary dysplasia and retinopathy of prematurity. Neonatology. 2013;104:56–64
79. Bhandari V, Choo-Wing R, Lee CG, et al. Hyperoxia causes angiopoietin 2-mediated acute lung injury and necrotic cell death. Nat Med. 2006;12:1286–1293
80. Gallagher DC, Parikh SM, Balonov K, et al. Circulating angiopoietin 2 correlates with mortality in a surgical population with acute lung injury/adult respiratory distress syndrome. Shock. 2008;29:656–661
81. Fremont RD, Koyama T, Calfee CS, et al. Acute lung injury in patients with traumatic injuries: Utility of a panel of biomarkers for diagnosis and pathogenesis. J Trauma. 2010;68:1121–1127
82. Calfee CS, Gallagher D, Abbott J, et al.NHLBI ARDS Network. Plasma angiopoietin-2 in clinical acute lung injury: Prognostic and pathogenetic significance. Crit Care Med. 2012;40:1731–1737
83. Agrawal A, Matthay MA, Kangelaris KN, et al. Plasma angiopoietin-2 predicts the onset of acute lung injury in critically ill patients. Am J Respir Crit Care Med. 2013;187:736–742
84. Meyer NJ, Li M, Feng R, et al. ANGPT2 genetic variant is associated with trauma-associated acute lung injury and altered plasma angiopoietin-2 isoform ratio. Am J Respir Crit Care Med. 2011;183:1344–1353
85. Zinter M, Spicer A, Orwoll B, AlKhouli A, Sapru A. Increasing Ang-2 Levels Are Associated With Mortality in Pediatric Cancer and Stem Cell Transplant Patients With ARDS.4107.58 2015 San Diego Pediatric Academic Societies Annual meeting
86. Lim MJ, Chiang ET, Hechtman HB, et al. Inflammation-induced subcellular redistribution of VE-cadherin, actin, and gamma-catenin in cultured human lung microvessel endothelial cells. Microvasc Res. 2001;62:366–382
87. Lampugnani MG, Zanetti A, Breviario F, et al. VE-cadherin regulates endothelial actin activating Rac and increasing membrane association of Tiam. Mol Biol Cell. 2002;13:1175–1189
88. Herwig MC, Müller KM, Müller AM. Endothelial VE-cadherin expression in human lungs. Pathol Res Pract. 2008;204:725–730
89. Quadri SK, Bhattacharjee M, Parthasarathi K, et al. Endothelial barrier strengthening by activation of focal adhesion kinase. J Biol Chem. 2003;278:13342–13349
90. Parker JC, Stevens T, Randall J, et al. Hydraulic conductance of pulmonary microvascular and macrovascular endothelial cell monolayers. Am J Physiol Lung Cell Mol Physiol. 2006;291:L30–L37
91. Wysolmerski RB, Lagunoff D. Involvement of myosin light-chain kinase in endothelial cell retraction. Proc Natl Acad Sci U S A. 1990;87:16–20
92. Gao L, Grant A, Halder I, et al. Novel polymorphisms in the myosin light chain kinase gene confer risk for acute lung injury. Am J Respir Cell Mol Biol. 2006;34:487–495
93. Russell R, Quasney MW, Halligan N, et al. Genetic variation in MYLK and lung injury in children and adults with community-acquired pneumonia. Pediatr Crit Care Med. 2010;11:731–736
94. Bhattacharya S, Sen N, Yiming MT, et al. High tidal volume ventilation induces proinflammatory signaling in rat lung endothelium. Am J Respir Cell Mol Biol. 2003;28:218–224
95. Tsukimoto K, Mathieu-Costello O, Prediletto R, et al. Ultrastructural appearances of pulmonary capillaries at high transmural pressures. J Appl Physiol (1985). 1991;71:573–582
96. West JB, Tsukimoto K, Mathieu-Costello O, et al. Stress failure in pulmonary capillaries. J Appl Physiol (1985). 1991;70:1731–1742
97. Kuebler WM, Ying X, Singh B, et al. Pressure is proinflammatory in lung venular capillaries. J Clin Invest. 1999;104:495–502
98. Bachofen M, Weibel ER. Alterations of the gas exchange apparatus in adult respiratory insufficiency associated with septicemia. Am Rev Respir Dis. 1977;116:589–615
99. Bachofen M, Weibel ER. Structural alterations of lung parenchyma in the adult respiratory distress syndrome. Clin Chest Med. 1982;3:35–56
100. Matthay MA, Eschenbacher WL, Goetzl EJ. Elevated concentrations of leukotriene D4 in pulmonary edema fluid of patients with the adult respiratory distress syndrome. J Clin Immunol. 1984;4:479–483
101. Parsons PE, Fowler AA, Hyers TM, et al. Chemotactic activity in bronchoalveolar lavage fluid from patients with adult respiratory distress syndrome. Am Rev Respir Dis. 1985;132:490–493
102. Steinberg KP, Milberg JA, Martin TR, et al. Evolution of bronchoalveolar cell populations in the adult respiratory distress syndrome. Am J Respir Crit Care Med. 1994;150:113–122
103. Grommes J, Soehnlein O. Contribution of neutrophils to acute lung injury. Mol Med. 2011;17:293–307
104. Bernard GR, Artigas A, Brigham KL, et al. The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med. 1994;149:818–824
105. Pittet JF, Mackersie RC, Martin TR, et al. Biological markers of acute lung injury: Prognostic and pathogenic significance AM J Respir Crit Care Med. 1999;155:1187–1205
106. Flori H, Francois-Pittet J. Biological markers of acute lung injury: Prognostic and pathogenetic significance. New Horiz. 1999;7:287–311
107. Matthay MA. Function of the alveolar epithelial barrier under pathologic conditions. Chest. 1994;105:67S–74S
108. Kovach MA, Standiford TJ. Toll like receptors in diseases of the lung. Int Immunopharmacol. 2011;11:1399–1406
109. Tolle LB, Standiford TJ. Danger-associated molecular patterns (DAMPs) in acute lung injury. J Pathol. 2013;229:145–156
110. Xiang M, Fan J. Pattern recognition receptor-dependent mechanisms of acute lung injury. Mol Med. 2010;16:69–82
111. Doerschuk CM. Mechanisms of leukocyte sequestration in inflamed lungs. Microcirculation. 2001;8:71–88
112. Drost EM, MacNee W. Potential role of IL-8, platelet-activating factor and TNF-alpha in the sequestration of neutrophils in the lung: Effects on neutrophil deformability, adhesion receptor expression, and chemotaxis. Eur J Immunol. 2002;32:393–403
113. Worthen GS, Schwab B III, Elson EL, et al. Mechanics of stimulated neutrophils: Cell stiffening induces retention in capillaries. Science. 1989;245:183–186
114. Ley K, Laudanna C, Cybulsky MI, et al. Getting to the site of inflammation: The leukocyte adhesion cascade updated. Nat Rev Immunol. 2007;7:678–689
115. Zemans RL, Colgan SP, Downey GP. Transepithelial migration of neutrophils: Mechanisms and implications for acute lung injury. Am J Respir Cell Mol Biol. 2009;40:519–535
116. Mantovani A, Cassatella MA, Costantini C, et al. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol. 2011;11:519–531
117. Papayannopoulos V, Zychlinsky A. NETs: A new strategy for using old weapons. Trends Immunol. 2009;30:513–521
118. Abrams ST, Zhang N, Manson J, et al. Circulating histones are mediators of trauma-associated lung injury. Am J Respir Crit Care Med. 2013;187:160–169
119. Fuchs TA, Brill A, Duerschmied D, et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A. 2010;107:15880–15885
120. Lanchou J, Corbel M, Tanguy M, et al. Imbalance between matrix metalloproteinases (MMP-9 and MMP-2) and tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) in acute respiratory distress syndrome patients. Crit Care Med. 2003;31:536–542
121. Torii K, Iida K, Miyazaki Y, et al. Higher concentrations of matrix metalloproteinases in bronchoalveolar lavage fluid of patients with adult respiratory distress syndrome. Am J Respir Crit Care Med. 1997;155:43–46
122. Ricou B, Nicod L, Lacraz S, et al. Matrix metalloproteinases and TIMP in acute respiratory distress syndrome. Am J Respir Crit Care Med. 1996;154:346–352
123. Pugin J, Verghese G, Widmer MC, et al. The alveolar space is the site of intense inflammatory and profibrotic reactions in the early phase of acute respiratory distress syndrome. Crit Care Med. 1999;27:304–312
124. Fligiel SE, Standiford T, Fligiel HM, et al. Matrix metalloproteinases and matrix metalloproteinase inhibitors in acute lung injury. Hum Pathol. 2006;37:422–430
125. Grau GE, Mili N, Lou JN, et al. Phenotypic and functional analysis of pulmonary microvascular endothelial cells from patients with acute respiratory distress syndrome. Lab Invest. 1996;74:761–770
126. Hashimoto S, Gon Y, Matsumoto K, et al. N-acetylcysteine attenuates TNF-alpha-induced p38 MAP kinase activation and p38 MAP kinase-mediated IL-8 production by human pulmonary vascular endothelial cells. Br J Pharmacol. 2001;132:270–276
127. Park WY, Goodman RB, Steinberg KP, et al. Cytokine balance in the lungs of patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 2001;164:1896–1903
128. Parsons PE, Matthay MA, Ware LB, et al.National Heart, Lung, Blood Institute Acute Respiratory Distress Syndrome Clinical Trials Network. Elevated plasma levels of soluble TNF receptors are associated with morbidity and mortality in patients with acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2005;288:L426–L431
129. Takala A, Jousela I, Takkunen O, et al. A prospective study of inflammation markers in patients at risk of indirect acute lung injury. Shock. 2002;17:252–257
130. Parsons PE, Eisner MD, Thompson BT, et al.NHLBI Acute Respiratory Distress Syndrome Clinical Trials Network. Lower tidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury. Crit Care Med. 2005;33:1–6; discussion 230
131. Liu KD, Glidden DV, Eisner MD, et al.National Heart, Lung, and Blood Institute ARDS Network Clinical Trials Group. Predictive and pathogenetic value of plasma biomarkers for acute kidney injury in patients with acute lung injury. Crit Care Med. 2007;35:2755–2761
132. McClintock D, Zhuo H, Wickersham N, et al. Biomarkers of inflammation, coagulation and fibrinolysis predict mortality in acute lung injury. Crit Care. 2008;12:R41
133. Chen CY, Yang KY, Chen MY, et al. Decoy receptor 3 levels in peripheral blood predict outcomes of acute respiratory distress syndrome. Am J Respir Crit Care Med. 2009;180:751–760
134. Ye SQ, Simon BA, Maloney JP, et al. Pre-B-cell colony-enhancing factor as a potential novel biomarker in acute lung injury. Am J Respir Crit Care Med. 2005;171:361–370
135. Kropski JA, Fremont RD, Calfee CS, et al. Clara cell protein (CC16), a marker of lung epithelial injury, is decreased in plasma and pulmonary edema fluid from patients with acute lung injury. Chest. 2009;135:1440–1447
136. Ganter MT, Ware LB, Howard M, et al. Extracellular heat shock protein 72 is a marker of the stress protein response in acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2006;291:L354–L361
137. Pespeni M, Mackersie RC, Lee H, et al. Serum levels of Hsp60 correlate with the development of acute lung injury after trauma. J Surg Res. 2005;126:41–47
138. Zhang H, Villar J, Slutsky AS. Circulating histones: A novel target in acute respiratory distress syndrome? Am J Respir Crit Care Med. 2013;187:118–120
139. Meyer NJ, Feng R, Li M, et al. IL1RN coding variant is associated with lower risk of acute respiratory distress syndrome and increased plasma IL-1 receptor antagonist. Am J Respir Crit Care Med. 2013;187:950–959
140. Dobyns EL, Eells PL, Griebel JL, et al. Elevated plasma endothelin-1 and cytokine levels in children with severe acute respiratory distress syndrome. J Pediatr. 1999;135:246–249
141. Todd DA, Marsh MJ, George A, et al. Surfactant phospholipids, surfactant proteins, and inflammatory markers during acute lung injury in children. Pediatr Crit Care Med. 2010;11:82–91
142. Flori HR, Ware LB, Glidden D, et al. Early elevation of plasma soluble intercellular adhesion molecule-1 in pediatric acute lung injury identifies patients at increased risk of death and prolonged mechanical ventilation. Pediatr Crit Care Med. 2003;4:315–321
143. Kong MY, Gaggar A, Li Y, et al. Matrix metalloproteinase activity in pediatric acute lung injury. Int J Med Sci. 2009;6:9–17
144. Kong MY, Li Y, Oster R, et al. Early elevation of matrix metalloproteinase-8 and -9 in pediatric ARDS is associated with an increased risk of prolonged mechanical ventilation. PLoS One. 2011;6:e22596
145. Patwari PP, O’Cain P, Goodman DM, et al. Interleukin-1 receptor antagonist intron 2 variable number of tandem repeats polymorphism and respiratory failure in children with community-acquired pneumonia. Pediatr Crit Care Med. 2008;9:553–559
146. Bortolussi R, Howlett S, Rajaraman K, et al. Deficient priming activity of newborn cord blood-derived polymorphonuclear neutrophilic granulocytes with lipopolysaccharide and tumor necrosis factor-alpha triggered with formyl-methionyl-leucyl-phenylalanine. Pediatr Res. 1993;34:243–248
147. Lee SM, Suen Y, Chang L, et al. Decreased interleukin-12 (IL-12) from activated cord versus adult peripheral blood mononuclear cells and upregulation of interferon-gamma, natural killer, and lymphokine-activated killer activity by IL-12 in cord blood mononuclear cells. Blood. 1996;88:945–954
148. Peters AM, Bertram P, Gahr M, et al. Reduced secretion of interleukin-1 and tumor necrosis factor-alpha by neonatal monocytes. Biol Neonate. 1993;63:157–162
149. Alvira CM, Abate A, Yang G, et al. Nuclear factor-kappaB activation in neonatal mouse lung protects against lipopolysaccharide-induced inflammation. Am J Respir Crit Care Med. 2007;175:805–815
150. Shearer WT, Rosenblatt HM, Gelman RS, et al.Pediatric AIDS Clinical Trials Group. Lymphocyte subsets in healthy children from birth through 18 years of age: The Pediatric AIDS Clinical Trials Group P1009 study. J Allergy Clin Immunol. 2003;112:973–980
151. Shahabuddin S, Al-Ayed I, Gad El-Rab MO, et al. Age-related changes in blood lymphocyte subsets of Saudi Arabian healthy children. Clin Diagn Lab Immunol. 1998;5:632–635
152. Härtel C, Adam N, Strunk T, et al. Cytokine responses correlate differentially with age in infancy and early childhood. Clin Exp Immunol. 2005;142:446–453
153. Upham JW, Lee PT, Holt BJ, et al. Development of interleukin-12-producing capacity throughout childhood. Infect Immun. 2002;70:6583–6588
154. Wood JH, Partrick DA, Johnston RB Jr. The inflammatory response to injury in children. Curr Opin Pediatr. 2010;22:315–320
155. Zingarelli B, Hake PW, O’Connor M, et al. Lung injury after hemorrhage is age dependent: Role of peroxisome proliferator-activated receptor gamma. Crit Care Med. 2009;37:1978–1987
156. Smith LS, Gharib SA, Frevert CW, et al. Effects of age on the synergistic interactions between lipopolysaccharide and mechanical ventilation in mice. Am J Respir Cell Mol Biol. 2010;43:475–486
157. McGrath-Morrow SA, Lee S, Gibbs K, et al. Immune response to intrapharyngeal LPS in neonatal and juvenile mice. Am J Respir Cell Mol Biol. 2015;52:323–331
158. Finnerty CC, Jeschke MG, Herndon DN, et al.Investigators of the Inflammation and the Host Response Glue Grant. Temporal cytokine profiles in severely burned patients: A comparison of adults and children. Mol Med. 2008;14:553–560
159. Gregory TJ, Longmore WJ, Moxley MA, et al. Surfactant chemical composition and biophysical activity in acute respiratory distress syndrome. J Clin Invest. 1991;88:1976–1981
160. Günther A, Schmidt R, Feustel A, et al. Surfactant subtype conversion is related to loss of surfactant apoprotein B and surface activity in large surfactant aggregates. Experimental and clinical studies. Am J Respir Crit Care Med. 1999;159:244–251
161. Greene KE, Wright JR, Steinberg KP, et al. Serial changes in surfactant-associated proteins in lung and serum before and after onset of ARDS. Am J Respir Crit Care Med. 1999;160:1843–1850
162. Cheng IW, Ware LB, Greene KE, et al. Prognostic value of surfactant proteins A and D in patients with acute lung injury. Crit Care Med. 2003;31:20–27
163. LeVine AM, Lotze A, Stanley S, et al. Surfactant content in children with inflammatory lung disease. Crit Care Med. 1996;24:1062–1067
164. Doyle IR, Bersten AD, Nicholas TE. Surfactant proteins-A and -B are elevated in plasma of patients with acute respiratory failure. Am J Respir Crit Care Med. 1997;156:1217–1229
165. Doyle IR, Nicholas TE, Bersten AD. Serum surfactant protein-A levels in patients with acute cardiogenic pulmonary edema and adult respiratory distress syndrome. Am J Respir Crit Care Med. 1995;152:307–317
166. Greene KE, King TE Jr, Kuroki Y, et al. Serum surfactant proteins-A and -D as biomarkers in idiopathic pulmonary fibrosis. Eur Respir J. 2002;19:439–446
167. Honda Y, Kuroki Y, Matsuura E, et al. Pulmonary surfactant protein D in sera and bronchoalveolar lavage fluids. Am J Respir Crit Care Med. 1995;152:1860–1866
168. Veldhuizen RA, McCaig LA, Akino T, et al. Pulmonary surfactant subfractions in patients with the acute respiratory distress syndrome. Am J Respir Crit Care Med. 1995;152:1867–1871
169. Günther A, Siebert C, Schmidt R, et al. Surfactant alterations in severe pneumonia, acute respiratory distress syndrome, and cardiogenic lung edema. Am J Respir Crit Care Med. 1996;153:176–184
170. Schmidt R, Meier U, Yabut-Perez M, et al. Alteration of fatty acid profiles in different pulmonary surfactant phospholipids in acute respiratory distress syndrome and severe pneumonia. Am J Respir Crit Care Med. 2001;163:95–100
171. Pison U, B[Latin Small Letter o with Caron]ck J, Pietschmann S, et al.Robertson B, Taeusch HW The adult respiratory distress syndrome: Pathophysiological concepts related to the pulmonary surfactant system. Surfactant Therapy for Lung Disease. 1995 New York Marcel Dekker:167–197
172. Manzanares D, Rodriguez-Capote K, Liu S, et al. Modification of tryptophan and methionine residues is implicated in the oxidative inactivation of surfactant protein B. Biochemistry. 2007;46:5604–5615
173. Rodríguez-Capote K, Manzanares D, Haines T, et al. Reactive oxygen species inactivation of surfactant involves structural and functional alterations to surfactant proteins SP-B and SP-C. Biophys J. 2006;90:2808–2821
174. Zenri H, Rodriquez-Capote K, McCaig L, et al. Hyperoxia exposure impairs surfactant function and metabolism. Crit Care Med. 2004;32:1155–1160
175. Ratjen F, Rehn B, Costabel U, et al. Age-dependency of surfactant phospholipids and surfactant protein A in bronchoalveolar lavage fluid of children without bronchopulmonary disease. Eur Respir J. 1996;9:328–333
176. Steagall WK, Lin JP, Moss J. The C/A(-18) polymorphism in the surfactant protein B gene influences transcription and protein levels of surfactant protein B. Am J Physiol Lung Cell Mol Physiol. 2007;292:L448–L453
177. Lin Z, Thomas NJ, Wang Y, et al. Deletions within a CA-repeat-rich region of intron 4 of the human SP-B gene affect mRNA splicing. Biochem J. 2005;389:403–412
178. Lin Z, Pearson C, Chinchilli V, et al. Polymorphisms of human SP-A, SP-B, and SP-D genes: Association of SP-B Thr131Ile with ARDS. Clin Genet. 2000;58:181–191
    179. Max MP, Pison U, Floros J. Frequency of SP-B and SP-A1 gene polymorphisms in the acute respiratory distress syndrome (ARDS). Appl Cardiopulm Physiol. 1996;6:111–118
      180. Quasney MW, Waterer GW, Dahmer MK, et al. Association between surfactant protein B + 1580 polymorphism and the risk of respiratory failure in adults with community-acquired pneumonia. Crit Care Med. 2004;32:1115–1119
        181. Dahmer MK, O’cain P, Patwari PP, et al. The influence of genetic variation in surfactant protein B on severe lung injury in African American children. Crit Care Med. 2011;39:1138–1144
        182. García-Laorden MI, Rodríguez de Castro F, Solé-Violán J, et al. Influence of genetic variability at the surfactant proteins A and D in community-acquired pneumonia: A prospective, observational, genetic study. Crit Care. 2011;15:R57
        183. Levi M, ten Cate H, van der Poll T. Endothelium: Interface between coagulation and inflammation. Crit Care Med. 2002;30:S220–S224
        184. Fuchs-Buder T, de Moerloose P, Ricou B, et al. Time course of procoagulant activity and D dimer in bronchoalveolar fluid of patients at risk for or with acute respiratory distress syndrome. Am J Respir Crit Care Med. 1996;153:163–167
        185. Quinn DA, Carvalho AC, Geller E, et al. 99mTc-fibrinogen scanning in adult respiratory distress syndrome. Am Rev Respir Dis. 1987;135:100–106
        186. Tomashefski JF Jr, Davies P, Boggis C, et al. The pulmonary vascular lesions of the adult respiratory distress syndrome. Am J Pathol. 1983;112:112–126
        187. Bozza FA, Shah AM, Weyrich AS, et al. Amicus or adversary: Platelets in lung biology, acute injury, and inflammation. Am J Respir Cell Mol Biol. 2009;40:123–134
        188. Bone RC, Balk R, Slotman G, et al. Adult respiratory distress syndrome. Sequence and importance of development of multiple organ failure. The Prostaglandin E1 Study Group. Chest. 1992;101:320–326
        189. Bone RC, Francis PB, Pierce AK. Intravascular coagulation associated with the adult respiratory distress syndrome. Am J Med. 1976;61:585–589
        190. Mandal RV, Mark EJ, Kradin RL. Megakaryocytes and platelet homeostasis in diffuse alveolar damage. Exp Mol Pathol. 2007;83:327–331
        191. Orwoll B, Spicer A, AlKhouli A, Zinter M, Sapru A. Thrombocytopenia at the onset of pediatric acute respiratory distress syndrome (ARDS) is associated with increased mortality. 2015 San Diego Pediatric Academic Societies Annual meeting
        192. Félétou M, Vanhoutte PM. Endothelial dysfunction: A multifaceted disorder (The Wiggers Award Lecture). Am J Physiol Heart Circ Physiol. 2006;291:H985–1002
        193. Scarpati EM, Sadler JE. Regulation of endothelial cell coagulant properties. Modulation of tissue factor, plasminogen activator inhibitors, and thrombomodulin by phorbol 12-myristate 13-acetate and tumor necrosis factor. J Biol Chem. 1989;264:20705–20713
        194. Schultz MJ, Haitsma JJ, Zhang H, et al. Pulmonary coagulopathy as a new target in therapeutic studies of acute lung injury or pneumonia—a review. Crit Care Med. 2006;34:871–877
        195. Su X, Camerer E, Hamilton JR, et al. Protease-activated receptor-2 activation induces acute lung inflammation by neuropeptide-dependent mechanisms. J Immunol. 2005;175:2598–2605
        196. Ahmmed GU, Malik AB. Functional role of TRPC channels in the regulation of endothelial permeability. Pflugers Arch. 2005;451:131–142
        197. Idell S, Koenig KB, Fair DS, et al. Serial abnormalities of fibrin turnover in evolving adult respiratory distress syndrome. Am J Physiol. 1991;261:L240–L248
        198. Prabhakaran P, Ware LB, White KE, et al. Elevated levels of plasminogen activator inhibitor-1 in pulmonary edema fluid are associated with mortality in acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2003;285:L20–L28
        199. El Solh AA, Bhora M, Pineda L, et al. Alveolar plasminogen activator inhibitor-1 predicts ARDS in aspiration pneumonitis. Intensive Care Med. 2006;32:110–115
        200. Günther A, Mosavi P, Heinemann S, et al. Alveolar fibrin formation caused by enhanced procoagulant and depressed fibrinolytic capacities in severe pneumonia. Comparison with the acute respiratory distress syndrome. Am J Respir Crit Care Med. 2000;161:454–462
        201. Moalli R, Doyle JM, Tahhan HR, et al. Fibrinolysis in critically ill patients. Am Rev Respir Dis. 1989;140:287–293
        202. Gando S, Nanzaki S, Morimoto Y, et al. Systemic activation of tissue-factor dependent coagulation pathway in evolving acute respiratory distress syndrome in patients with trauma and sepsis. J Trauma. 1999;47:719–723
        203. Groeneveld AB, Kindt I, Raijmakers PG, et al. Systemic coagulation and fibrinolysis in patients with or at risk for the adult respiratory distress syndrome. Thromb Haemost. 1997;78:1444–1449
        204. Ware LB, Matthay MA, Parsons PE, et al.National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Clinical Trials Network. Pathogenetic and prognostic significance of altered coagulation and fibrinolysis in acute lung injury/acute respiratory distress syndrome. Crit Care Med. 2007;35:1821–1828
        205. Sapru A, Curley MA, Brady S, et al. Elevated PAI-1 is associated with poor clinical outcomes in pediatric patients with acute lung injury. Intensive Care Med. 2010;36:157–163
        206. Sapru A, Hansen H, Ajayi T, et al. 4G/5G polymorphism of plasminogen activator inhibitor-1 gene is associated with mortality in intensive care unit patients with severe pneumonia. Anesthesiology. 2009;110:1086–1091
        207. Tsangaris I, Tsantes A, Bonovas S, et al. The impact of the PAI-1 4G/5G polymorphism on the outcome of patients with ALI/ARDS. Thromb Res. 2009;123:832–836
        208. Sheth SB, Carvalho AC. Protein S and C alterations in acutely ill patients. Am J Hematol. 1991;36:14–19
        209. Lorente JA, García-Frade LJ, Landín L, et al. Time course of hemostatic abnormalities in sepsis and its relation to outcome. Chest. 1993;103:1536–1542
        210. Ware LB, Fang X, Matthay MA. Protein C and thrombomodulin in human acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2003;285:L514–L521
        211. Bastarache JA, Wang L, Geiser T, et al. The alveolar epithelium can initiate the extrinsic coagulation cascade through expression of tissue factor. Thorax. 2007;62:608–616
        212. Ariel A, Timor O. Hanging in the balance: Endogenous anti-inflammatory mechanisms in tissue repair and fibrosis. J Pathol. 2013;229:250–263
        213. Eickmeier O, Seki H, Haworth O, et al. Aspirin-triggered resolvin D1 reduces mucosal inflammation and promotes resolution in a murine model of acute lung injury. Mucosal Immunol. 2013;6:256–266
        214. Seki H, Fukunaga K, Arita M, et al. The anti-inflammatory and proresolving mediator resolvin E1 protects mice from bacterial pneumonia and acute lung injury. J Immunol. 2010;184:836–843
        215. Uddin M, Levy BD. Resolvins: Natural agonists for resolution of pulmonary inflammation. Prog Lipid Res. 2011;50:75–88
        216. Zarbock A, Ley K. The role of platelets in acute lung injury (ALI). Front Biosci (Landmark Ed). 2009;14:150–158
        217. Weyrich AS, Zimmerman GA. Platelets in lung biology. Annu Rev Physiol. 2013;75:569–591
        218. Crosby LM, Waters CM. Epithelial repair mechanisms in the lung. Am J Physiol Lung Cell Mol Physiol. 2010;298:L715–L731
        219. Madtes DK, Rubenfeld G, Klima LD, et al. Elevated transforming growth factor-alpha levels in bronchoalveolar lavage fluid of patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 1998;158:424–430
        220. Matthay MA, Ware LB, Zimmerman GA. The acute respiratory distress syndrome. J Clin Invest. 2012;122:2731–2740
        221. Chapman HA, Li X, Alexander JP, et al. Integrin α6β4 identifies an adult distal lung epithelial population with regenerative potential in mice. J Clin Invest. 2011;121:2855–2862
        222. Zheng D, Limmon GV, Yin L, et al. Regeneration of alveolar type I and II cells from Scgb1a1-expressing cells following severe pulmonary damage induced by bleomycin and influenza. PLoS One. 2012;7:e48451
        223. Kajstura J, Rota M, Hall SR, et al. Evidence for human lung stem cells. N Engl J Med. 2011;364:1795–1806
        224. Ware LB. Pathophysiology of acute lung injury and the acute respiratory distress syndrome. Semin Respir Crit Care Med. 2006;27:337–349
        225. Fahy RJ, Lichtenberger F, McKeegan CB, et al. The acute respiratory distress syndrome: A role for transforming growth factor-beta 1. Am J Respir Cell Mol Biol. 2003;28:499–503
        226. Rock JR, Barkauskas CE, Cronce MJ, et al. Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition. Proc Natl Acad Sci U S A. 2011;108:E1475–E1483
        227. Hashimoto N, Jin H, Liu T, et al. Bone marrow-derived progenitor cells in pulmonary fibrosis. J Clin Invest. 2004;113:243–252
        228. Tanjore H, Xu XC, Polosukhin VV, et al. Contribution of epithelial-derived fibroblasts to bleomycin-induced lung fibrosis. Am J Respir Crit Care Med. 2009;180:657–665
        229. Willis BC, duBois RM, Borok Z. Epithelial origin of myofibroblasts during fibrosis in the lung. Proc Am Thorac Soc. 2006;3:377–382
        230. Chesnutt AN, Matthay MA, Tibayan FA, et al. Early detection of type III procollagen peptide in acute lung injury. Pathogenetic and prognostic significance. Am J Respir Crit Care Med. 1997;156:840–845
        231. Clark JG, Milberg JA, Steinberg KP, et al. Type III procollagen peptide in the adult respiratory distress syndrome. Association of increased peptide levels in bronchoalveolar lavage fluid with increased risk for death. Ann Intern Med. 1995;122:17–23
        232. Quesnel C, Piednoir P, Gelly J, et al. Alveolar fibrocyte percentage is an independent predictor of poor outcome in patients with acute lung injury. Crit Care Med. 2012;40:21–28
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        APPENDIX 1. Pediatric Acute Lung Injury Consensus Conference Group

        Organizing Committee: Philippe Jouvet, University of Montreal, Canada; Neal J. Thomas, Pennsylvania State University; Douglas F. Willson, Medical College of Virginia.

        Section 1, Definition, incidence, and epidemiology: Simon Erickson, Princess Margaret Hospital for Children, Australia; Robinder Khemani, University of Southern California; Lincoln Smith, University of Washington; Jerry Zimmerman, University of Washington.

        Section 2, Pathophysiology, co-morbidities and severity: Mary Dahmer, University of Michigan; Heidi Flori, Children’s Hospital & Research Center Oakland; Michael Quasney, University of Michigan; Anil Sapru, University of California San Francisco.

        Section 3, Ventilatory support: Ira M. Cheifetz, Duke University; Peter C. Rimensberger, University Hospital of Geneva, Switzerland.

        Section 4, Pulmonary specific ancillary treatment: Martin Kneyber, University Medical Center Groningen, Netherlands; Robert F. Tamburro, Pennsylvania State University.

        Section 5, Nonpulmonary treatment: Martha A. Q. Curley, University of Pennsylvania; Vinay Nadkarni, University of Pennsylvania; Stacey Valentine, Harvard University.

        Section 6, Monitoring: Guillaume Emeriaud, University of Montreal, Canada; Christopher Newth, University of Southern California.

        Section 7, Noninvasive support and ventilation: Christopher L. Carroll, University of Connecticut; Sandrine Essouri, Université Pierre et Marie Curie, France.

        Section 8, Extra-corporeal support: Heidi Dalton, University of Arizona; Duncan Macrae, Royal Brompton Hospital, England.

        Section 9, Morbidity and long-term outcomes: Yolanda Lopez, Cruces University Hospital, Spain; Michael Quasney, University of Michigan; Miriam Santschi, Université de Sherbrooke, Canada; R. Scott Watson, University of Pittsburgh.

        Literature Search Methodology: Melania Bembea, Johns Hopkins University.

        Keywords:

        acute lung injury; acute respiratory distress syndrome; pediatrics; pathobiology

        ©2015The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies