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

Mortality due to gram-negative septic shock remains high despite advances in medical care. Induction of endotoxin tolerance might be a new treatment strategy to prevent septic shock in the newborn. The present study was performed 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) in 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 lactacidemia and lower plasma TNF-alpha concentration in response to S.enteritidis LPS when compared to the newborn rats of saline-treated darns. Newborn rats of MPL-treated darns were more tolerant to TNF-alpha than those of saline-treated darns. MPL injection into pregnant rats did not increase plasma endotoxin concentration in the fetuses, suggesting no placental passage rook place, but it did increase plasma TNF-alpha concentration. We concluded that an injection of MPL into pregnant rats induced tolerance to LPS in their offspring, which might be due to TNF-alpha-induced TNF-alpha tolerance. Copyright (C) 2000 S. Karger AG, Basel.