INDUCTION OF ENDOTOXIN TOLERANCE WITH MONOPHOSPHORYL LIPID-A IN PERITONITIS - IMPORTANCE OF LOCALIZED THERAPY

Endotoxin is a principle mediator of septic shock during peritonitis. induction of endotoxin tolerance with monophosphoryl lipid A (MPL), a nontoxic derivative of lipid A, improves survival from peritonitis. Th e induction of tolerance with intravenous versus intraperitoneally adm inistration of MPL before peritonitis was compared. Mice were pretreat ed with varying doses of MPL (intravenously) and MPL (intraperitoneall y) 48 hours before peritonitis was induced by cecal ligation and perfo ration. Survival was determined at 72 hours, and serum and peritoneal levels of tumor necrosis factor-alpha (TNF-1 alpha) and interleukin-1 alpha (lL-1 alpha) were assayed at 24 hours. Survival was 0% in contro l animals, 20% in MPL (100 mu g intravenously) animals, and 70% in MPL (100 mu g intraperitoneally) animals (p < 0.05 versus control, MPL [i ntravenously]). Cytokine release was compared in control animals and a nimals receiving MPL 100 mu g (intraperitoneally) or MPL 100 mu g (int ravenously). In MPL (intraperitoneally)-treated animals, serum and per itoneal TNF-alpha levels, 160 +/- 7 pg/ml and 204 +/- 25 pg/ml, were s ignificantly lower than those in control animals, 429 +/- 34 pg/ml and 642 +/- 108 pg/ml, and MPL (intravenously)-treated animals, 302 +/- 6 8 pg/ml and 495 +/- 97 pg/ml, (p < 0.05). Similarly, lL-1 alpha levels were significantly lower in MPL (intraperitoneally)-treated animals t han in control animals. Because the development of tolerance appears t o be a cytokine-mediated process, a subsequent experiment compared per itoneal and serum TNF-alpha and IL-1 alpha levels at 2 hours after MPL (intraperitoneally) or MPL (intravenously). Peritoneal TNF-alpha and IL-1 alpha release was greatest after MPL (intraperitoneally); serum l evels were greatest after MPL (intravenously). These data suggest that the induction of endotoxin tolerance in peritonitis is most effective when site-specific therapy Is used. This may be related to enhanced i nduction of tolerance in peritoneal macrophages with intraperitoneal t herapy.