Neutralization of receptor for advanced glycation end-products and high mobility group box-1 attenuates septic diaphragm dysfunction in rats with peritonitis

Objectives: To determine the relationship between intra-abdominal sepsis-induced high mobility group-box 1 and diaphragm contractile performance and to determine the inhibitory effects of antibodies for high mobility group-box I and receptor for advanced glycation end-products on septic peritonitis-induced diaphragmatic dysfunction, lipid peroxidation, and intracellular signal transduction in the rat diaphragm. In animal models of sepsis, production of reactive oxygen species has been shown to elicit diaphragmatic dysfunction. Extracellularly released high mobility group-box 1 can bind to cell surface receptors, such as receptor for advanced glycation end-products, eliciting inflammatory responses that lead to the development of sepsis. Design: Prospective laboratory study. Setting: University laboratory. Subjects: Wistar rats (n = 186). Interventions: Intra-abdominal sepsis was induced, using cecal ligation and perforation. In experiment 1, serum and diaphragm homogenates were obtained from sham-operated rats and from cecal ligation and perforation rats at 4-hr intervals postoperatively. In experiment 2, anti-high mobility group-box 1 and anti-receptor for advanced glycation end-products antibodies were administered 4 firs and 8 hrs after cecal ligation and perforation to determine their effects on cecal ligation and perforation-induced diaphragm dysfunction, reactive oxygen species-related variables, and intracellular signal transduction. Measurements and Main Results: In experiment 1, cecal ligation and perforation induced serum and diaphragmatic high mobility group-box 1 within 8 firs postoperatively with a decline in diaphragmatic force generation at 12 firs after cecal ligation and perforation. In experiment 2, anti-receptor for advanced glycation end-products and anti-high mobility group-box 1 antibodies significantly attenuated cecal ligation and perforation-induced diaphragmatic dysfunction in a dose-related manner. Diaphragmatic malondialdehyde concentration and phosphorylation level of extracellular signal-regulated kinase 1/2 in the groups treated with these antibodies were significantly lower than those in the nontreated group. Anti-receptor for advanced glycation end-products antibody down-regulated high mobility group-box 1 expression in the diaphragm during sepsis. Conclusions: Cecal ligation and perforation induces high mobility group-box 1 in the diaphragm and increases serum high mobility group-box 1 level as a late-phase mediator, decreasing contractile performance by high mobility group-box 1 receptor for advanced glycation end-products interaction-mediated reactive oxygen species production. These findings suggested an important role of receptor for advanced glycation end-products-high mobility group-box 1 interaction in diaphragmatic dysfunction induced by lipid peroxidation in rats with intra-abdominal sepsis. (Crit Care Med 2009; 37:2619-2624)