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The role of RAGE in the pathogenesis of intestinal barrier dysfunction after hemorrhagic shock

Departments of ¹Surgery, ²Critical Care Medicine, and ³Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and ⁴Department of Surgery, College of Physicians and Surgeons of Columbia University, New York, New York

Submitted 2 February 2006 ; accepted in final form 1 May 2006

The receptor for advanced glycation end products (RAGE) has been implicated in the pathogenesis of numerous conditions associated with excessive inflammation. To determine whether RAGE-dependent signaling is important in the development of intestinal barrier dysfunction after hemorrhagic shock and resuscitation (HS/R), C57Bl/6, rage^–/–, or congenic rage^+/+ mice were subjected to HS/R (mean arterial pressure of 25 mmHg for 3 h) or a sham procedure. Twenty-four hours later, bacterial translocation to mesenteric lymph nodes and ileal mucosal permeability to FITC-labeled dextran were assessed. Additionally, samples of ileum were obtained for immunofluorescence microscopy, and plasma was collected for measuring IL-6 and IL-10 levels. HS/R in C57Bl/6 mice was associated with increased bacterial translocation, ileal mucosal hyperpermeability, and high circulating levels of IL-6. All of these effects were prevented when C57Bl/6 mice were treated with recombinant human soluble RAGE (sRAGE; the extracellular ligand-binding domain of RAGE). HS/R induced bacterial translocation, ileal mucosal hyperpermeability, and high plasma IL-6 levels in rage^+/+ but not rage^–/– mice. Circulating IL-10 levels were higher in rage^–/– compared with rage^+/+ mice. These results suggest that activation of RAGE-dependent signaling is a key factor leading to gut mucosal barrier dysfunction after HS/R.

translocation; HMGB1; sRAGE; s100b