Amelioration of endotoxin-induced sepsis in rats by membrane anchored lipid conjugates.

Objective: In the pathogenesis of septic shock, caused by either bacterial toxins or trauma, increased production of multiple proinflammatory mediators, such as phospholipase A 2 (PLAN, cytokines, and chemokines, is knownto be of major importance. The present study was undertaken to investigate the influence of a newly designed extracellular PLA 2 inhibitor (ExPLI) on synthesis of proinflammatory mediators and mortality rate in a rat sepsis model. Design: Prospective, randomized animal study. Setting: Experimental laboratory. Subjects: Male Wistar-rats weighing 200-300 g. Interventions: Mortality was induced by intraperitoneal bolus administration of lipopolysaccharide 15 mg/kg in 22 rats that were pretreated with NaCI or ExPLI (150 mg/kg). Furthermore, nine rats received a sublethal bolus of lipopolysaccharide (7.5 mg/kg) and nine rats received lipotechoic acid (8 mg/kg) simultaneously with or after ExPLI administration. Blood samples were collected from these rats, and cytokine concentrations were assessed by enzyme-linked immunosorbent assay. Lung and kidney were removed for RNA isolation and immunohistological analysis. Measurements and Main Results: ExPLI treatment significantly reduced lipopolysaccharide-induced mortality of rats (90.9 and 36.4%, p <.05). Up-regulation of tumor necrosis factor-a and interleukin-6 production in serum after endotoxin treatment was significantly inhibited when ExPLIs were administered at the time of or before sepsis induction by using lipopolysaccharide or lipotechoic acid (p <.01). Similarly, messenger RNA expression of secreted PLA 2 -IIA, interleukin-1, or inducible nitric oxide synthase and the expression of intercellular adhesion molecule-1 were significantly down-regulated in lung and kidney of ExPLI-treated rats, as demonstrated by RNase protection assay, reverse transcription-polymerase chain reaction, or immunohistochemistry. Conclusions: ExPLIs may be considered as potentially effective compounds to prevent the production of inflammatory mediators and to improve mortality rate in septic patients.