Inhibition of the RAGE products increases survival in experimental models of severe sepsis and systemic infection.
BACKGROUND
The receptor for advanced glycation end products (RAGE), a multi-ligand member of the immunoglobulin superfamily, contributes to acute and chronic disease processes, including sepsis.


METHODS
We studied the possible therapeutic role of RAGE inhibition in the cecal ligation and puncture (CLP) model of polymicrobial sepsis and a model of systemic listeriosis using mice genetically deficient in RAGE expression or mice injected with a rat anti-murine RAGE monoclonal antibody.


RESULTS
The 7-day survival rates after CLP were 80% for RAGE-/- mice (n = 15) (P < 0.01 versus wild-type), 69% for RAGE+/- mice (n = 23), and 37% for wild-type mice (n = 27). Survival benefits were evident in BALB/c mice given anti-RAGE antibody (n = 15 per group) over serum-treated control animals (P < 0.05). Moreover, delayed treatment with anti-RAGE antibody up to 24 hours after CLP resulted in a significant survival benefit compared with control mice. There was no significant increase in tissue colony counts from enteric Gram-negative or Gram-positive bacteria in animals treated with anti-RAGE antibody. RAGE-/-, RAGE+/-, and anti-RAGE antibody-treated animals were resistant to lethality from Listeria monocytogenes by almost two orders of magnitude compared with wild-type mice.


CONCLUSIONS
Further studies are warranted to determine the clinical utility of anti-RAGE antibody as a novel treatment for sepsis.
Division of Infectious Diseases, Memorial Hospital of Rhode Island, 111 Brewster St, Pawtucket, RI 02860, USA.
Emily C
EC
Lutterloh
Steven M
SM
Opal
Debra D
DD
Pittman
James C
JC
Keith
Xiang-Yang
XY
Tan
Brian M
BM
Clancy
Helen
H
Palmer
Kim
K
Milarski
Ying
Y
Sun
John E
JE
Palardy
Nicholas A
NA
Parejo
Noubar
N
Kessimian
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D004195:Disease Models, Animal; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D008088:Listeriosis / Q000378:metabolism* / Q000401:mortality / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D018805:Sepsis / Q000235:genetics / Q000401:mortality* / Q000628:therapy*; D015996:Survival Rate; D018746:Systemic Inflammatory Response Syndrome / Q000378:metabolism / Q000401:mortality / Q000628:therapy
D000911:Antibodies, Monoclonal; D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic