title: The role of RAGE in the pathogenesis of intestinal barrier dysfunction after hemorrhagic shock.
abstract: 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.
authors.affiliation: Univ. of Pittsburgh School of Medicine, 616 Scaife Hall, 3550 Terrace St., Pittsburgh, PA 15213, USA.
authors.forename: Kathleen G
authors.initials: KG
authors.lastname: Raman
authors.forename: Penny L
authors.initials: PL
authors.lastname: Sappington
authors.forename: Runkuan
authors.initials: R
authors.lastname: Yang
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Levy
authors.forename: Jose M
authors.initials: JM
authors.lastname: Prince
authors.forename: Shiguang
authors.initials: S
authors.lastname: Liu
authors.forename: Simon K
authors.initials: SK
authors.lastname: Watkins
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Schmidt
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.forename: Mitchell P
authors.initials: MP
authors.lastname: Fink
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D015536:Down-Regulation; D020895:Enterocytes / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D017127:Glycation End Products, Advanced; D024243:HMGB1 Protein / Q000378:metabolism; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D007410:Intestinal Diseases / Q000150:complications* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D010100:Oxygen / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D012771:Shock, Hemorrhagic / Q000150:complications*; D015398:Signal Transduction
chemical_list: D017127:Glycation End Products, Advanced; D024243:HMGB1 Protein; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D010100:Oxygen