Prophylactic treatment of endotoxic shock with monophosphoryl lipid A in newborn rats

Mortality due to gram-negative septic shock remains high despite advances i n medical care. Induction of endotoxin tolerance might be a new treatment s trategy to prevent septic shock in the newborn. The present study was perfo rmed to show that an injection in pregnant rats of monophosphoryl lipid A ( MPL), a nontoxic derivative of lipopolysaccharide (LPS), induces tolerance to Salmonella enteritidis LPS and tumor necrosis factor alpha (TNF-alpha) i n their offspring. MPL at a dose of 2 mg/kg was injected into pregnant rats on the 19th day of gestation. Their 0-day-old offspring later received an intraperitoneal injection of S. enterifidis LPS or TNF-alpha. Newborn rats of MPL-treated dams exhibited a higher survival rate, absence of lactacidem ia and lower plasma TNF-alpha concentration in response to S.enteritidis LP S when compared to the newborn rats of saline-treated darns. Newborn rats o f MPL-treated darns were more tolerant to TNF-alpha than those of saline-tr eated darns. MPL injection into pregnant rats did not increase plasma endot oxin concentration in the fetuses, suggesting no placental passage rook pla ce, but it did increase plasma TNF-alpha concentration. We concluded that a n injection of MPL into pregnant rats induced tolerance to LPS in their off spring, which might be due to TNF-alpha-induced TNF-alpha tolerance. Copyri ght (C) 2000 S. Karger AG, Basel.