The role of RAGE in the pathogenesis of intestinal barrier dysfunction after hemorrhagic shock.
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.
Raman
Kathleen G
KG
Univ. of Pittsburgh School of Medicine, 616 Scaife Hall, 3550 Terrace St., Pittsburgh, PA 15213, USA.
Sappington
Penny L
PL
Yang
Runkuan
R
Levy
Ryan M
RM
Prince
Jose M
JM
Liu
Shiguang
S
Watkins
Simon K
SK
Schmidt
Ann Marie
AM
Billiar
Timothy R
TR
Fink
Mitchell P
MP
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
D017127:Glycation End Products, Advanced; D024243:HMGB1 Protein; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D010100:Oxygen