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