Ligands of the receptor for advanced glycation end products, including high-mobility group box 1, limit bacterial dissemination during Escherichia coli peritonitis

Objective: The receptor for advanced glycation end products mediates a variety of inflammatory responses. Soluble receptor for advanced glycation end products has been suggested to function as a decoy abrogating cellular activation. High-mobility group box 1 is a high-affinity binding ligand for the receptor for advanced glycation end products with cytokine activities and plays a role in sepsis. Design: Controlled, in vivo laboratory study. Setting: Research laboratory of a health sciences university. Subjects: C57BL/6 mice. Interventions: Peritonitis was induced by intraperitoneal injection of Escherichia coli. Mice received soluble receptor for advanced glycation end products or anti-high-mobility group box 1 immunoglobulin G, or the appropriate control treatment. Measurements and Main Results: Soluble receptor for advanced glycation end products-treated mice demonstrated an enhanced bacterial dissemination to liver and lungs, accompanied by increased hepatocellular injury and exaggerated systemic cytokine release, 20 hrs after intraperitoneal administration of Escherichia coli. Soluble receptor for advanced glycation end products administration in healthy, uninfected mice did not induce an immune response. Remarkably, lung inflammation was unaffected. Furthermore, high-mobility group box 1 release was enhanced during peritonitis and anti-high-mobility group box 1 treatment was associated with higher bacterial loads in liver and lungs. Conclusions: These data are the first to suggest that receptor for advanced glycation end products ligands, including high-mobility group box 1, limit bacterial dissemination during Gram-negative sepsis. (Crit Care Med 2010; 38: 1414 - 1422)