Submitted on February 2, 2006
Accepted on May 1, 2006
The role of RAGE in the pathogenesis of intestinal barrier dysfunction after hemorrhagic shock
Kathleen G Raman1, Penny L Sappington2, Runkuan Yang2, Ryan M Levy1, Jose M Prince1, Shiguang Liu2, Simon K. Watkins3, Ann Marie Schmidt4, Timothy R Billiar1, and Mitchell P Fink5*
1 Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
2 Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
3 Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
4 Department of Surgery, College of Physicians and Surgeons of Columbia University, New York, New York, United States
5 Departments of Surgery and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
* To whom correspondence should be addressed. E-mail: finkmp{at}upmc.edu.
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 mm Hg for 3 h) or a sham procedure. Twenty-four h later, bacterial translocation (BT) 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 BT, 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 sRAGE (the extracellular ligand-binding domain of RAGE). HS/R induced BT, ileal mucosal hyperpermeability and high plasma IL-6 levels in rage +/+ but not rage-/- mice. Circulating IL-10 levels were higher in rage-/- as compared to rage -/- mice. These results suggest that activation of RAGE-dependent signaling is a key factor leading to gut mucosal barrier dysfunction after HS/R.
