Published online before print April 28, 2009
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* Departments of Medicine I and Clinical Chemistry, Medicine III, Anesthesiology and Institute of Neuropharmacology, University of Heidelberg, Heidelberg, Germany;
Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina, USA;
Department of Anatomy, Technical University of Dresden, Dresden, Germany;
|| Department of Medicine IV, University of Tübingen, Tübingen, Germany;
Biosistemi d.o.o., Zagreb, Croatia; and
¶ Department of Anesthesiology, University of Giessen and Marburg, Giessen, Germany
1. Correspondence: Department of Medicine I and Clinical Chemistry, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. E-mail: angelika.bierhaus{at}med.uni-heidelberg.de
ABSTRACT
HSA preparations for i.v. use are administered in critically ill patients. Although increasing intravascular osmotic pressure seems to be a pathophysiologically orientated treatment, clinical trials do not indicate a benefit for mortality in HSA-treated patients. Instead, there is evidence for inflammatory reactions upon infusion of different HSA batches. A neglected issue concerning the safety and quality of these therapeutics is processing-related post-transcriptional protein modifications, such as AGEs. We therefore tested the hypothesis that commercially available infusion solutions contain AGEs and studied whether these protein modifications influence outcome and inflammation in a murine model of sepsis induced by CLP. Screening of different HSA and Ig preparations in this study revealed an up to approximate tenfold difference in the amount of AGE modifications. Application of clinically relevant concentrations of CML-modified HSA in CLP led to increased inflammation and enhanced mortality in wild-type mice but not in mice lacking the RAGE. Lethality was paralleled by increased activation of the proinflammatory transcription factor NF-
B, NF-B-dependent gene expression, and infiltration of inflammatory cells in the peritoneal cavity. This study implies that infusion solutions containing a high load of the AGE-modified protein have the potential to activate RAGE/NF-B-mediated inflammatory reactions, causing increased mortality in experimental peritonitis.
Key Words: sepsis • fluid resuscitation • advanced glycation endproducts • RAGE • colloid
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