American Journal of Respiratory and Critical Care Medicine

Rationale: Levels of the soluble form of the receptor for advanced glycation end-products (sRAGE) are elevated during acute respiratory distress syndrome (ARDS) and correlate with severity and prognosis. Alveolar fluid clearance (AFC) is necessary for the resolution of lung edema but is impaired in most patients with ARDS. No reliable marker of this process has been investigated to date.

Objectives: To verify whether sRAGE could predict AFC during ARDS.

Methods: Anesthetized CD-1 mice underwent orotracheal instillation of hydrochloric acid. At specified time points, lung injury was assessed by analysis of blood gases, alveolar permeability, lung histology, AFC, and plasma/bronchoalveolar fluid measurements of proinflammatory cytokines and sRAGE. Plasma sRAGE and AFC rates were also prospectively assessed in 30 patients with ARDS.

Measurements and Main Results: The rate of AFC was inversely correlated with sRAGE levels in the plasma and the bronchoalveolar fluid of acid-injured mice (Spearman’s ρ = −0.73 and −0.69, respectively; P < 10−3), and plasma sRAGE correlated with AFC in patients with ARDS (Spearman’s ρ = −0.59; P < 10−3). Similarly, sRAGE levels were significantly associated with lung injury severity, and decreased over time in mice, whereas AFC was restored and lung injury resolved.

Conclusions: Our results indicate that sRAGE levels could be a reliable predictor of impaired AFC during ARDS, and should stimulate further studies on the pathophysiologic implications of RAGE axis in the mechanisms leading to edema resolution.

Clinical trial registered with www.clinicaltrials.gov (NCT 00811629).

Scientific Knowledge on the Subject

Soluble receptor for advanced glycation end-products (sRAGE) is a marker of alveolar type I cell injury and correlates with severity and outcome in patients with acute respiratory distress syndrome. Efficient alveolar fluid clearance is a major determinant of lung injury resolution, but reliable biologic markers of such a process have been underinvestigated to date.

What This Study Adds to the Field

Elevated levels of sRAGE in plasma and bronchoalveolar fluid could predict alveolar fluid clearance and lung injury severity in a first replication of a translational mouse model of direct lung epithelial injury and an observational prospective study of patients with acute respiratory distress syndrome, thus reinforcing a role for sRAGE as a marker of lung injury and repair.

Acute respiratory distress syndrome (ARDS) is a major cause of acute respiratory failure and death in critically ill patients (1, 2). The reabsorption of pulmonary edema fluid from the alveolar space is necessary for the resolution of ARDS, and the magnitude of damage to the alveolar type (AT) I cell is a major determinant of the severity of ARDS (3). In addition, an intact alveolar epithelial barrier with preserved alveolar fluid clearance (AFC) is associated with better clinical outcomes in patients with ARDS (3). To date, few interventions have proved beneficial in ARDS (46) and pharmacologic approaches remain limited, with deceiving clinical translation (7, 8). Biomarkers reflecting alveolar epithelial function and injury may therefore be useful to run mechanistic explorations and ultimately develop innovative diagnostic and therapeutic approaches in patients with ARDS (9).

The soluble form of the receptor for advanced glycation end-products (sRAGE) is a recently described novel marker of AT I epithelial cell injury with both prognostic and pathogenic values in patients with ARDS (1012). A recent study suggests that alveolar sRAGE levels and AFC rates could be reliable markers of lung injury onset and resolution in a recent translational mouse model of direct epithelial lung injury (13). In addition, in an ex vivo model of isolated perfused human lungs declined for transplantation, the rate of AFC was inversely correlated with the level of sRAGE in alveolar fluid, but not with perfusate sRAGE levels (14). Apart from one recent study in mice, in which alveolar sRAGE correlated with AFC during the acute phase of acid-induced lung injury (15), sRAGE has not been comprehensively assessed as a marker of AFC in animal and clinical studies on ARDS.

We specifically designed an experimental and clinical study to prospectively determine if sRAGE levels are associated with AFC rate in the setting of ARDS. Partial results of this study have already been presented as an abstract and oral communication (16, 17).

Additional details are provided in the online supplement.

Animal Studies

Our animal ethics committee approved protocols. CD-1 mice were anesthetized before orotracheal instillation of hydrochloric acid (13). After a recovery period under humidified oxygen, mice were transferred to stabulation.

Criteria for experimental ARDS were evaluated at baseline in injured and sham animals, and at specified time points (1, 2, and 4 d) after acid instillation in injured mice (13, 18). Mice were tracheotomized and ventilated for 30 minutes (tidal volume, 8–9 ml/kg; positive end-expiratory pressure, 6 cm H2O; respiratory rate, 160 breaths/min; FiO2, 1), before blood gas measurements. Intravenous human serum albumin was administered 1 hour before the animals were killed. The permeability index was calculated as the bronchoalveolar lavage (BAL) fluid-to-plasma human serum albumin ratio (19).

BAL was performed (13) and systemic blood was drawn from cardiac puncture. BAL and plasma IL-6, tumor necrosis factor-α, IL-17, keratinocyte-derived chemokine, macrophage inflammatory protein-2, sRAGE, and total proteins were measured. BAL cells were counted and differential cytology was performed. After the animals were killed, lungs were removed, fixed, and embedded, and slices were stained with hematoxylin and eosin. A standardized histology score was calculated (18).

In separate animals, AFC was determined using previous in situ models (13, 20, 21). A bovine serum albumin solution was instilled into the trachea; after 30-minute ventilation, proteins were measured in the instilled fluid to calculate AFC rate: percent AFC over 30 minutes = 100 × [1 − (initial/final total protein)]. In mice, the initial protein concentration was estimated by the protein concentration of the bovine serum albumin instillate. Animals were categorized into groups of maximal (≥14%/30 min) or submaximal (≥3%/30 min, <14%/30 min) AFC (3, 22).

Human Study

Our institutional review board approved protocols.

Arterial and alveolar samples for sRAGE and AFC measurements were obtained from 30 patients enrolled within 24 hours of ARDS onset (23) in a prospective observational study of soluble forms and ligands of RAGE in ARDS.

Baseline lung computed tomography (CT) scan was performed; nonfocal morphology was noted for diffuse or patchy patterns (24), according to the CT Scan ARDS Study Group criteria (25). Undiluted pulmonary edema fluid and plasma were collected simultaneously, at baseline (H0) and 4 hours later (H4). Edema fluid total proteins and baseline sRAGE were measured (22, 24). The AFC rate (in % per hour) was calculated: percent AFC = 100 × [1 − (initial (H0)/final (H4) total protein)] (26). Patients were categorized into three groups: (1) maximal (≥14%/h), (2) submaximal (≥3%/h, <14%/h), or (3) impaired AFC (<3%/h) (3, 22).

Statistical Analysis

Categorical data were expressed as numbers and percentages, and quantitative data as means and SD or medians and interquartile ranges as appropriate. Analyses were performed using Kruskal-Wallis with Bonferroni tests for pairwise comparisons between time points and sham controls. Spearman coefficient was used to test the correlations between sRAGE and continuous variables. Receiver operating characteristic curves were computed to determine which parameter distinguished better nonfocal from focal ARDS. Areas under the curve were calculated with 95% confidence intervals (CI). Analyses were performed using Prism 6 (Graphpad Software, La Jolla, CA). A P less than 0.05 (two-sided) was considered significant.

Study Patients

Thirty patients with criteria for ARDS were enrolled between February 2011 and January 2013. Main baseline characteristics and clinical outcomes are summarized in Table 1. Median ± SD PaO2/FiO2 ratio and tidal volume were 108 ± 41 mm Hg and 6.7 ± 0.9 ml/kg ideal body weight, respectively. Positive end-expiratory and inspiratory plateau pressures were 13.5 ± 3.3 and 27.9 ± 3.4 cm H2O, respectively. First plasma samples for the study were drawn a mean of 33 ± 39 hours after intubation. CT scan lung morphology was recorded at baseline in all patients, and ARDS was characterized with nonfocal morphology in 23 (77%) and focal loss of aeration in 7 (23%).

Table 1. Baseline Clinical Characteristics of Patients with ARDS (n = 30)

Male sex, n (%)16 (53)
Age, yr61 ± 15
Body mass index, kg/m225.9 ± 6.9
Sequential Organ Failure Assessment score10.9 ± 3.3
Acute Physiology and Chronic Health Evaluation II score25.5 ± 7.3
Coexisting conditions, n (%) 
 Atherosclerosis7 (23)
 Diabetes7 (23)
 Hypertension12 (40)
 Dyslipidemia6 (20)
 Current smoking6 (20)
 COPD4 (13)
 Asthma1 (3)
 Hematologic neoplasms8 (27)
 Chronic renal failure1 (3)
Cause of ARDS, n (%) 
 Sepsis27 (90)
 Pneumonia21 (70)
 Aspiration1 (3)
 Severe trauma1 (3)
Lung injury score3.3 ± 0.5
Baseline arterial level of sRAGE, pg/ml5,502 ± 2,994
Baseline alveolar level of sRAGE, pg/ml154,734 ± 217,417
Baseline AFC, %/h2.1 ± 8.9
 Maximal AFC (≥4%/h), n (%)2 (7)
 Submaximal AFC (≥3%/h, <14%/h), n (%)15 (50)
 Impaired AFC (<3%/h), n (%)13 (43)
Ventilator-free days7 ± 9
Survival on Day 28, n (%)18 (60)

Definition of abbreviations: AFC = alveolar fluid clearance; ARDS = acute respiratory distress syndrome; COPD = chronic obstructive pulmonary disease; sRAGE = soluble form of the receptor for advanced glycation end-products.

Data are expressed as mean ± SD, unless otherwise indicated. The body mass index is the weight in kilograms divided by the square of the height in meters. Lung injury (or Murray) score can range from 0 to 4, with higher values indicating more severe lung injury. Percentages may not exactly total 100% because of rounding.

Animal Model of Lung Injury

Alveolar-capillary barrier permeability, as assessed by BAL total protein concentration and the permeability index, showed a substantial increase at Days 1 and 2, with return to normal levels by Day 4 (Figures 1A and 1C) in injured animals, as compared with injured mice on Day 0 and with sham animals at the same time points. No difference was observed between sham animals at all time points; therefore, the results from sham and from Day 0 injured mice were mixed for analyses. Arterial oxygenation deteriorated by Day 1 after injury with gradual improvement by Day 4 (Figure 1B). Mean arterial oxygen tension (PaO2/FiO2 ratios) achieved clinical ARDS criteria on Days 1 and 2. Following acid instillation the number of total leukocytes in BAL fluid increased significantly (Figure 1D), and mononuclear cells remained predominant over time (∼90–92% of total leukocytes at all time points). Significant changes in both BAL (Figure 2) and plasma (Figure 3) levels of mouse neutrophil chemokines macrophage inflammatory protein-2 and keratinocyte-derived chemokine, and proinflammatory mediators tumor necrosis factor-α, IL-6, and IL-17 peaked on the first 2 days after injury.

Lung injury scores were significantly increased on Days 1 and 2 (Figure 4A), and acid aspiration caused substantial changes in lung architecture compared with sham mice and Day 0 injured animals (Figures 4B and 4C). Over the first 48 hours there were disrupted alveoli and the presence of fluid and hemorrhage within the alveolar space (Figures 4D and 4E). The alveolar walls were thickened with the presence of a neutrophilic and mononuclear infiltrate. On Day 4 lung neutrophil infiltration, alveolar structure, and debris were less intense, but there remained a cellular infiltrate (Figure 4F).

AFC rate (Figure 5A) showed a significant deterioration during the first 2 days after injury. The lungs regained the ability to clear fluid on Day 4. In parallel, BAL (Figure 5B) and plasma (Figure 5C) levels of sRAGE were significantly up-regulated at Days 1–2, and decreased near baseline by Day 4.

Elevated Levels of sRAGE Correlate with Impaired AFC

When analyzed as a continuous variable, both plasma (Figure 5D) and BAL (Figure 5E) sRAGE baseline levels were inversely correlated with AFC in acid-injured animals (Spearman’s ρ = −0.73 [95% CI, −0.88 to −0.45] and −0.69 [95% CI, −0.86 to −0.38], respectively; P < 10−3 for both). After correction by murine albumin measurement, AFC remained correlated with plasma and BAL sRAGE levels (Spearman’s ρ = −0.73 [95% CI, −0.88 to −0.4; P < 10−4] and −0.54 [95% CI, −0.78 to −0.15; P = 0.008], respectively). In lung-injured mice, AFC was also moderately, but significantly, correlated with histologic lung injury score, PaO2/FiO2 ratio, permeability index, and plasma IL-6, but not with other markers (see Table E1 in the online supplement).

In patients with ARDS, baseline plasma sRAGE levels correlated with net AFC rates (Spearman’s ρ = −0.6 [95% CI, −0.79 to −0.29]; P = 0.0004) (Figure 6A). A total of 13 patients (43%) had impaired AFC, 15 patients (50%) had submaximal AFC, and two patients (7%) had maximal AFC (Figure 6B). Baseline plasma sRAGE levels increased significantly with decreasing AFC rates (P = 0.005). Alveolar sRAGE and lung injury score (Murray score) also correlated with AFC rates in patients with ARDS (Spearman’s ρ = −0.8 [95% CI, −0.91 to −0.63], P < 0.0001; and −0.5 [95% CI, −0.75 to −0.19], P = 0.03, respectively). Correlations between AFC and other clinical or biologic markers of lung injury did not reach significance (see Table E1).

Levels of sRAGE Are Associated with Lung Injury Severity

In acid-injured animals, plasma and BAL sRAGE levels were significantly correlated with PaO2/FiO2 ratio, histologic lung injury score, and permeability index (see Figure E1).

The ability of baseline plasma sRAGE levels from patients with ARDS to inform on CT scan lung morphology was determined. The area under the receiver operating characteristic curve when plasma sRAGE was used to differentiate the presence from absence of nonfocal loss of aeration was 0.75 (95% CI, 0.52–0.98; P = 0.04) for a cut-off value of 3,029 pg/ml, with a sensitivity of 88% (95% CI, 67–97) and a specificity of 71% (95% CI, 29–96) (see Figure E2A). Median plasma sRAGE levels were significantly higher in patients with nonfocal (6,234 pg/ml [3,607–7,420]) than in those with focal lung damage (2,550 pg/ml [2,323–6,368]) (P = 0.02) (see Figure E2B). The correlation between plasma sRAGE and lung injury severity, as assessed by PaO2/FiO2 ratio and Murray lung injury score, was also significant in patients with ARDS (see Figure E3).

Baseline plasma sRAGE levels were higher in patients with severe ARDS (6,399 pg/ml [4,654–8,656]; n = 17) than in those with moderate ARDS (2,846 pg/ml [2,498–4,156]; n = 13; P = 0.0001), but baseline BAL sRAGE levels were not statistically different (53,829 pg/ml [13,873–275,929] in patients with severe ARDS vs. 17,478 pg/ml [4,134–325,516] in those with moderate ARDS; P = 0.4) (see Figure E4). In addition, net AFC rates were lower in patients with severe ARDS (0.8%/h [0–5.5]) than in those with moderate ARDS (5%/h [2.4–11.3]), but this difference did not reach significance (P = 0.06). Day-28 survivors (n = 18) had lower baseline plasma and alveolar sRAGE levels but higher AFC rates than nonsurvivors (n = 12) (see Figure E5).

Our main goal was to determine whether levels of sRAGE would serve as a marker of AFC in the setting of ARDS. In both a clinical study of patients with ARDS and an experimental model of acid-induced lung injury in mice, alveolar and plasma levels of sRAGE significantly correlated with AFC rate. sRAGE was also a marker of lung injury severity over time in mice, as alveolar-capillary barrier permeability, arterial oxygenation impairment, lung injury scores, and the extent of human lung damage on CT scan were all associated with sRAGE levels.

In our study, plasma levels of sRAGE were associated in both patients with ARDS and lung-injured animals with impaired AFC. In a prior study by Briot and colleagues (14) in isolated perfused human lungs, airspace sRAGE levels were inversely correlated with the rate of AFC, supporting the theory that sRAGE is a relevant marker of alveolar epithelial injury. In a recently published mouse model of acid-induced lung injury reproducing several features of the pathophysiology of ARDS, alveolar levels of sRAGE were elevated on Days 1 and 2 and seemed to correlate with a decrease in AFC on the same days (13), although this correlation was demonstrated for alveolar sRAGE only during the acute phase of acid-lung injury in mice (15). Measurement of AFC has not been routinely performed in small-animal ARDS studies, but it adds insight into the function of the alveolar epithelium. Moreover, a decrease in AFC is characteristic of human ARDS (3, 22).

We aimed at replicating the translational model of direct epithelial lung injury published by Patel and colleagues, a model of both the onset of lung injury and its resolution (13). The acid aspiration model has been described as potentially the most translatable model of direct ARDS, because there is a clear clinical correlate (27). To date, it has been poorly used because of a narrow dosing window between no injury and overwhelming injury leading to high mortality (28). In our study, we reproduced this mouse model of ARDS that replicates several features of ARDS, and plasma measurements of proinflammatory mediators and sRAGE were included. There was a marked increase in proinflammatory cytokines at Days 1 and 2 in hydrochloric acid–treated mice, as previously reported (13), and alveolar IL-17 (expressed by a distinct type of T cells, T helper 17 cells, and certain other lymphocytes) was still significantly increased on Day 4. This novel finding could suggest an underinvestigated role for the IL-17–T helper 17 cell pathway during ARDS resolution and stimulate further research (29, 30). The report of sRAGE plasma levels in lung-injured mice is rather novel (31) and further supports the value of sRAGE as a surrogate marker of lung injury severity in general (1012), and of AFC in particular, in both the experimental and clinical settings of ARDS. Because of the evidence that alveolar epithelial type I cells transport sodium and contribute to AFC (32, 33), a marker of AT I cell injury could reflect intact AFC.

Our results, combined with those from others, support sRAGE as a marker of epithelial injury and barrier dysfunction clinically; they also provide prospective validation of previously published research in experimental ARDS and in patients following lung transplantation (10, 34). These data also support the hypothesis that a marker of alveolar epithelial injury could have predictive value in the assessment of lung dysfunction and recovery during ARDS (8, 13). Our study was not designed to provide insights on the precise molecular mechanisms through which RAGE axis activation could modulate transepithelial fluid clearance, and on the effects of RAGE modulation on AFC. Although RAGE has the striking capacity to induce cellular attachment and spreading (35, 36) and to enhance the adherence of epithelial cells to the collagen-coated surfaces (37), the role of RAGE in the alveolar epithelial cell proliferation/differentiation and the regulation of the expression or function of epithelial membrane channels (e.g., Na+-K+-ATPase, sodium channels, aquaporins) remains underinvestigated (38). More importantly, whether the modulation of RAGE axis could lead to enhanced AFC has not been explored to date.

Our findings, along with those from others, reinforce the role of sRAGE as a biomarker of epithelial function during ARDS. Its diagnostic and prognostic values have been reported, and its correlation with severity is established in ARDS (1012). The availability of the measurement of plasma biomarker sRAGE could be of particular interest to assess response to therapy during ARDS, in preclinical studies (39), and ultimately in patients (40). The impact of mechanical ventilation settings on sRAGE levels has been reported in patients with ARDS, with prognostic values in those receiving higher tidal volumes (11), and the effects of various strategies including alveolar recruitment strategy and lung imaging–based mechanical ventilation settings are under investigation by our team. Our results support plasma sRAGE as a marker of AFC during ARDS, and could be useful to better tailor respiratory interventions to the individual patients with ARDS. Nevertheless, whether patients with the most impaired AFC and with diffuse ARDS might better respond to alveolar recruitment than others is uncertain (24, 41). In this perspective, the availability of biomarkers should at least stimulate further research on assessing biomarker-guided respiratory settings (24, 41).

Our study has some potential limitations. First, we have not withdrawn a reference alveolar fluid sample immediately after bovine albumin instillation for AFC measurement in mice, as previously reported, to be as representative of alveolar content as possible (13). However, we chose to use another published procedure in which the instilled albumin concentration serves as reference (20, 42), but we measured mouse albumin in the final alveolar sample to demonstrate that an increase in total protein concentration (which is what should happen if AFC is occurring) is not caused by leakage of mouse plasma proteins into the bronchoalveolar space.

Second, although we could replicate most recommended features of ARDS in our experimental model, we did not find an increase in the absolute number of neutrophils in BAL fluid from hydrochloric acid–treated mice (13, 18). In our study, lung-injured mice had increased total alveolar leukocytes, higher lung injury scores, and higher concentrations of proinflammatory cytokines in BAL, suggesting that we were able to observe an inflammatory response in both the lung and the systemic circulation (18). Moreover, we believe that the lack of alveolar neutrophilia should not call into question our main findings, because it is frequently not possible to observe every single feature of lung injury in experimental models of ARDS (18). However, our findings could be consistent with a growing body of evidence supporting a role for monocytes in ARDS (43). Because they may also reflect frequent differences between the findings from mice and human studies (44), we chose a priori to also validate in the clinical setting our findings in mice on the association between sRAGE levels and AFC. Also, we limited our evaluation in animals at Day 4 after injury and did not assess later time points (13). The exploration of this later resolution period in such a model is promising to investigate the pathologic processes focusing on resolution and repair (45). Finally, as with any biomarker study, a derivation cohort always demonstrates better biomarker test characteristics than a validation cohort. Validating our results in an independent cohort of patients remains therefore necessary.

In conclusion, in both a translational mouse model of direct lung epithelial injury and a prospective observational study of patients with ARDS, both plasma and alveolar sRAGE levels were associated with AFC and lung injury severity. Our findings should prompt further studies on the pathophysiologic implications of RAGE axis in the mechanisms leading to alveolar epithelial fluid clearance.

The authors thank the nurses of the intensive care unit at Estaing University Hospital, and the technicians and staff from the Department of Medical Biochemistry and Molecular Biology, Estaing University Hospital, CHU Clermont-Ferrand, and from the Université d’Auvergne in Clermont-Ferrand, France.

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Correspondence and requests for reprints should be addressed to Matthieu Jabaudon, M.D., M.Sc., Department of Anesthesiology, Critical Care and Perioperative Medicine, Intensive Care Unit, Estaing University Hospital, Clermont-Ferrand, France. E-mail:

Supported by grants from the Auvergne Regional Council (“Programme Nouveau Chercheur de la Région Auvergne” 2013), the French Agence Nationale de la Recherche and the Direction Générale de l’Offre de Soins (“Programme de Recherche Translationnelle en Santé” ANR-13-PRTS-0010), and from Clermont-Ferrand University Hospital (“Appel d’Offre Interne 2010”, CHU Clermont-Ferrand).

Author Contributions: M.J. takes responsibility for the content of the manuscript, and was involved in the conception, hypothesis delineation, and design of the study; acquisition and analysis of the data; writing the article; and its revision prior to submission. R.B. was involved in the hypothesis delineation and design of the study, acquisition and analysis of the data, writing the article, and its revision prior to submission. L.R., J.A., and P.D. were involved in the design of the study, acquisition and analysis of the data, and the revision of the article prior to submission. G.C. was involved in the design of the study and acquisition and analysis of the data. D.B., M.F., and G.M. were involved in the acquisition and analysis of the data and the revision of the article prior to submission. B.P. was involved in the hypothesis delineation and design of the study, analysis of the data, writing the article, and its revision prior to submission. V.S. and J.-M.C. were involved in the conception, hypothesis delineation, and design of the study; analysis of the data; writing the article; and its revision prior to submission.

This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org

Originally Published in Press as DOI: 10.1164/rccm.201501-0020OC on May 1, 2015

Author disclosures are available with the text of this article at www.atsjournals.org.

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