Inhibition of the RAGE products increases survival in experimental models of severe sepsis and systemic infection - PubMed (original) (raw)

Comparative Study

doi: 10.1186/cc6184.

Steven M Opal, Debra D Pittman, James C Keith Jr, Xiang-Yang Tan, Brian M Clancy, Helen Palmer, Kim Milarski, Ying Sun, John E Palardy, Nicholas A Parejo, Noubar Kessimian

Affiliations

Comparative Study

Inhibition of the RAGE products increases survival in experimental models of severe sepsis and systemic infection

Emily C Lutterloh et al. Crit Care. 2007.

Abstract

Introduction: 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.

Conclusion: Further studies are warranted to determine the clinical utility of anti-RAGE antibody as a novel treatment for sepsis.

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Figures

Figure 1

Figure 1

Modulation of receptor for advanced glycation end products (RAGE) protects mice from the effects of cecal ligation and puncture (CLP). Kaplan-Meier survival analysis following CLP comparing wild-type RAGE+/+ 129SvEvBrd mice (n = 15), RAGE-/- mice (n = 15), RAGE+/- mice (n = 23), and anti-RAGE monoclonal antibody-treated (15 mg/kg intravenously 30 to 60 minutes before CLP) wild-type mice (n = 15). P < 0.001 for each group in comparison with the wild-type CLP control group. Sham surgery-treated wild-type 129SvEvBrd mice (n = 5) were used as an additional control group. WT, wild-type.

Figure 2

Figure 2

Receptor for advanced glycation end products (RAGE) protein expression in lung tissue from individual RAGE-/- (lanes 1 to 3), RAGE+/- (lanes 4 to 6), and RAGE+/+ (lanes 7 to 9) animals. Actin was used to demonstrate equal loading.

Figure 3

Figure 3

Lethality from cecal ligation and puncture (CLP) is decreased in BALB/c mice administered an anti-RAGE monoclonal antibody (mAb). The Kaplan-Meier survival analysis following CLP compares anti-RAGE mAb-treated animals given 7.5 mg/kg (n = 15) or 15 mg/kg (n = 15) intravenously 30 to 60 minutes before CLP with serum control animals (n = 15). The group given 15 mg/kg had a significantly greater survival than the group given 7.5 mg/kg (P < 0.05) or serum control (P < 0.001). RAGE, receptor for advanced glycation end products.

Figure 4

Figure 4

Delayed administration of the anti-RAGE antibody is protective in cecal ligation and puncture (CLP). The Kaplan-Meier survival analysis following CLP in BALB/c mice compares delayed anti-RAGE monoclonal antibody (mAb) treatment given at various time intervals after CLP with serum control. Each group had a significantly greater survival than the control group (P < 0.01), except for the 36-hour delayed treatment group (P = 0.12). RAGE, receptor for advanced glycation end products.

Figure 5

Figure 5

Inhibition or deletion of receptor for advanced glycation end products (RAGE) does not disrupt the host mechanism for clearance of Listeria monocytogenes. Quantitative levels of L. monocytogenes in organ samples (liver and spleen, n = 10 per group) 48 hours after an intraperitoneal injection of 104 colony-forming units (CFU) per animal (P < 0.001 anti-tumor necrosis factor [TNF] monoclonal antibody [mAb] group versus all other groups).

Figure 6

Figure 6

Interferon-gamma levels following intraperitoneal challenge with 104 colony-forming units (CFU) of Listeria monocytogenes are shown (n = 10 for each group). P < 0.05 for anti-tumor necrosis factor (TNF) monoclonal antibody (mAb) group and RAGE-/- group, both versus control group. RAGE, receptor for advanced glycation end products.

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