The newborn has high mortality in septic shock. Induction of endotoxin tolerance may prevent endotoxic shock in the newborn. The present study showed that a small dose of Salmonella enteritidis lipopolysaccharide (S. ent. LPS), Rc mutant Escherichia coli lipopolysaccharide (J5 LPS), or tumor necrosis factor-alpha (TNF-alpha) given to pregnant rats on the 19th day of gestation induced endotoxin tolerance in their 0-day-old offspring. S. ent. LPS or J5 LPS injected into pregnant rats increased plasma endotoxin-like activity in dams, although not in their fetuses, and increased plasma TNF-alpha concentration in both dams and their fetuses. The endotoxin-tolerant newborn rats were also resistant to TNF-alpha. In those newborn rats, an LPS injection increased plasma TNF-alpha concentration and liver TNF-alpha mRNA abundance. These experiments showed that the endotoxin tolerance could be due to TNF-alpha tolerance. In conclusion, prenatal treatment of dams with a small dose of S. ent. LPS, J5 LPS, or TNF-alpha was beneficial in preventing endotoxic shock in the newborn.

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-α) 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. enteritidis LPS or TNF-α. Newborn rats of MPL-treated dams exhibited a higher survival rate, absence of lactacidemia and lower plasma TNF-α concentration in response to S. enteritidis LPS when compared to the newborn rats of saline-treated dams. Newborn rats of MPL-treated dams were more tolerant to TNF-α than those of saline-treated dams. MPL injection into pregnant rats did not increase plasma endotoxin concentration in the fetuses, suggesting no placental passage took place, but it did increase plasma TNF-α concentration. We concluded that an injection of MPL into pregnant rats induced tolerance to LPS in their offspring, which might be due to TNF-α-induced TNF-α tolerance.