Chest
Volume 135, Issue 2, February 2009, Pages 269-275
Journal home page for Chest

Original Research
Critical Care Medicine
Elevated Levels of the Receptor for Advanced Glycation End Products, a Marker of Alveolar Epithelial Type I Cell Injury, Predict Impaired Alveolar Fluid Clearance in Isolated Perfused Human Lungs

https://doi.org/10.1378/chest.08-0919Get rights and content

Background

Although alveolar epithelial injury is a major determinant of outcome in patients with acute lung injury, there is no reliable biological marker of alveolar epithelial injury. The primary objective was to determine whether elevated levels of the receptor for advanced glycation end products (RAGE), a marker of alveolar epithelial injury, reflect impaired alveolar fluid clearance (AFC) in an ex vivo perfused human lung preparation. A second objective was to determine whether levels of a marker of endothelial injury, von Willebrand factor antigen (vWF:Ag), are associated with impaired AFC.

Methods

Human lungs (N = 30) declined for transplantation by the California Transplant Donor Network were perfused at a constant pulmonary artery pressure of 12 mm Hg. Following rewarming to 36°C, the lungs were inflated with a continuous positive airway pressure of 10 cm H2O. RAGE and vWF:Ag levels and AFC rates were then measured.

Results

The rate of AFC was inversely correlated with RAGE levels in the alveolar fluid (p < 0.005). Similarly, the concentration of RAGE in the alveolar fluid was significantly higher in lungs with submaximal AFC, defined in a prespecified analysis as ≤ 14%/h, when compared with lungs with preserved AFC (median 0.82 vs 0.43 μg/mL; p < 0.05). In contrast, vWF:Ag levels did not correlate with the rate of AFC.

Conclusions

RAGE may be a useful biological marker of alveolar epithelial injury and impaired AFC in donor lungs prior to transplant and perhaps in patients with acute lung injury.

Section snippets

Ex Vivo Human Lung Preparation

Lungs from brain-dead organ donors used for this study were rejected for transplantation by the Northern California Transplant Donor Network according to international criteria for human lung donors.10 The demographic data and the reasons for rejections were collected and analyzed. The lungs were prepared as previously described.9 Briefly, after consent from family was obtained, lungs from donors were removed en bloc, inflated, and transported on ice to the laboratory. The lungs were not

Demographic Data and Procurement Times

The demographic data and procurement times for the 30 lungs used in this study are summarized in Table 1. All patients died from catastrophic CNS events, including intracranial hemorrhage and anoxic brain injury. Lungs were rejected for transplantation for a variety of reasons, most commonly due to concern for suspicion of pulmonary edema, infection, or airway inflammation. The mean rewarming time (4° to 36°C) with perfusion was 53 ± 2 min.

AFC Rates, Hemodynamic Data, and Gas Tensions

Consistent with our previous studies, the mean AFC rate

Discussion

Clinical criteria used to evaluate donor lungs prior to transplantation may not be adequate as many lungs rejected for transplant appear to have normal alveolar epithelial function.1 Biological markers of lung endothelial and alveolar epithelial injury may have clinical value in determining the severity of alveolar barrier injury in potential transplant donor lungs or in patients with ALI. Prior studies have shown a relationship between elevated levels of vWF:Ag and poor clinical outcomes in

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  • Cited by (0)

    This study was supported by National Heart, Lung, and Blood Institute HL51856 and HL088263 (Dr. Matthay), HL88440 (Dr. Frank), and Egide-Programme Lavoisier (Ministère Français des Affaires Etrangères) [Dr. Briot]. Dr. Calfee is supported by a National Heart, Lung, and Blood Institute K23 award (HL090833).

    The authors have no conflicts of interest to disclose.

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).

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