Increased levels of soluble receptor for advanced glycation end products (sRAGE) and high mobility group box 1 (HMGB1) are associated with death in patients with acute respiratory distress syndrome
Introduction
Acute respiratory distress syndrome (ARDS), the most severe form of acute lung injury, is a major cause of rapid-onset respiratory failure in critically ill patients, which could account for the high disability rate in these subjects [1], [2]. A variety of injurious insults could elicit diffuse alveolar damage, which is followed by alveolar edema and interstitial fibrosis [3]. Although the etiology of ARDS is multifactorial, uncontrolled inflammation has recently been considered to play a central role in the pathogenesis of this devastating disorder [4], [5].
There is a growing body of evidence that receptor for advanced glycation end products (RAGE) is mainly involved in inflammatory reactions in various disorders such as atherosclerotic cardiovascular disease, rheumatoid arthritis, and acute lung injury [6], [7], [8], [9]. Further, high mobility group box-1 (HMGB1), one of the ligands for RAGE, has been implicated as a putative danger signal in a variety of inflammatory conditions as well [10], [11], [12]. HMGB1–RAGE interaction promotes chemotaxis and maturation of immune cells, enhances the expression of adhesion molecules in endothelial cells, and stimulates the production of cytokines by various types of cells, thereby evoking local and systemic inflammation [10], [11], [12].
Recently, HMGB1 was found to be a late mediator of endotoxin-induced acute lung injury in mice [13], and serum levels of HMGB1 were increased in septic shock patients and positively associated with sepsis-related organ failure assessment score [14]. In addition, blockade of the HMGB1 and RAGE axis was reported to ameliorate acute pulmonary inflammatory responses after endotoxin instillation, including lung edema with neutrophil accumulation and increased production of cytokines [13], [14], [15], [16].
Moreover, soluble RAGE (sRAGE) has been identified in human plasma [17], [18], [19]. RAGE is expressed in alveolar type 1 cells and most abundant in the lung [20], [21]. In endotoxin-induced acute lung injury mouse models, sRAGE levels in bronchoalveolar lavage (BAL) fluid and serum were elevated and correlated with the severity of lung damage [20], [21]. These observations suggest that serum level of sRAGE is a biomarker of severity and clinical outcomes of ARDS subjects. Therefore, in this study, we examined whether sRAGE level was independently associated with the severity of lung injury and/or death in 20 ARDS patients with severe infection. We further examined which clinical parameters and inflammatory variables could be independent correlates of elevated sRAGE level in ARDS subjects.
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Patients and methods
Twenty ARDS patients with severe infection (12 males and 8 females, mean age; 64.6 years (pneumonia n = 12, pyelonephritis n = 2, peritonitis n = 2, pancreatitis n = 1, cholangitis n = 1, colitis n = 1, unknown origin n = 1) and 20 age-matched healthy volunteers (11 males and 9 females, mean age; 63.9 years) were included in this study. Research Ethics Committee of our hospital approved this study protocol, and informed consent was obtained from all the alert subjects or first-degree relatives of drowsy
Results
Table 1 shows the clinical and laboratory data of ARDS patients and age- and sex-matched healthy volunteers. Systolic BP (SBP) and diastolic BP (DBP) were significantly lower and heart rate was higher in ARDS patients than those in healthy volunteers (p < 0.01). Serum levels of KL-6, HMGB1, IL-6, HMGB1, sRAGE, and endotoxin were significantly elevated in ARDS patients compared with healthy volunteers. APACHE II score and lung injury score in ARDS subjects were 20.2 and 2.24, respectively. As
Discussion
In this study, we demonstrated for the first time that sRAGE and HMGB1 levels were correlated with each other and HMGB1 was a sole independent correlate of sRAGE in ARDS patients with severe infection. Furthermore, we found here that baseline sRAGE level was elevated in non-survivors compared with survivors and independently associated with death in patients with ARDS. The present study has extended the previous observation which showed that higher baseline sRAGE was associated with increased
Limitations
The present study was a cross-sectional one and, therefore, did not elucidate the causal relationship among serum levels of sRAGE, HMGB1, and 28-day mortality in patients with ARDS. Further, number of patients enrolled in the study was small and may not be adequate to provide statistically meaningful data. Longitudinal and/or interventional studies are helpful to clarify whether activation of HMGB1–RAGE axis is mechanistically linked to the progression of ARDS.
It would be interesting to
Acknowledgments
This work was supported in part by Grants of Collaboration with Venture Companies Project from the Ministry of Education, Culture, Sports, Science and Technology, Japan (S.Y.). The authors declare that they have no conflict of interest related to the publication of this article.
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