To test the hypothesis that pretreatment with radiodetoxified endotoxin (RDE) may mitigate the deleterious effects of subsequent infection, in part by modifying leukocyte adhesion receptor expression, and to investigate the cellular mechanisms of endotoxin tolerance induced by RDE.
To assess the effect of RDE pretreatment on mortality from bacterial peritonitis, rats were implanted with an intraperitoneal, barium-fecal inoculum at intervals of 0,1, 3, and 5 days after RDE injection. Experiments were then conducted to test the effect on leukocyte adhesion receptor expression. Two groups of mice received saline solution, and one group, RDE. After 72 hours, one group received saline solution (saline/saline group), the others, lipopolysaccharide (LPS) (saline/LPS and RDE/LPS groups). Peripheral leukocytes were obtained 1 hour after injection and were analyzed for CD11b and CD18 expression by flow cytometry.
Laboratory animal study.
Survival rates were not improved in rats that were pretreated with RDE 0 and 24 hours before inoculum (0% and 7%, respectively). In rats that were pretreated 72 hours and 120 hours before inoculum, 47% (P<.01) and 60% (P<.01) survived, respectively. CD18 expression on polymorphonuclear leukocytes increased twofold in the RDE/LPS (mean±SEM, 300.3±32.9) and the saline/LPS (mean±SEM, 360.4±59.9) groups compared with controls (mean±SEM, 176.4±18.9) (P<.05). CD1 lb expression on polymorphonuclear leukocytes increased three-fold in the RDE/LPS (mean±SEM, 91.3±8.1) and the saline/LPS (mean±SEM, 89.8±11.4) groups compared with controls(mean±SEM,32.1 ±1.8) (P<.05). CD18 expression on monocytes decreased in the saline/LPS group (mean±SEM, 134.2±14.2) and was unchanged in the RDE/LPS group (mean±SEM, 200.2± 17.2) compared with controls (mean±SEM, 217.6±16.5) (P<.05). CD11b expression on monocytes decreased in the saline/LPS group (mean±SEM, 25.8±2.2) and was unchanged in the RDE/LPS group (mean±SEM, 36.4±0.9) compared with controls (mean±SEM, 39.7±3.9) (P<.05).
Radiodetoxified endotoxin reduces mortality rates from bacterial peritonitis when given at least 72 hours prior to a bacterial inoculum. Tolerance to subsequent LPS challenge is associated with an abrogation of the reduced peripheral monocyte CD11b and CD 18 expression observed in native LPS-stimulated mice but is not associated with changes in polymorphonuclear leukocyte CD 11b and CD 18 expression. The mechanism of the observed RDE-induced monocyte hyporesponsiveness to LPS and its possible protective effect is uncertain and requires further investigation.(Arch Surg. 1994;129:1153-1158)