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. enteritidis 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 dams. Newborn rats of MPL-treated dams were more tolerant to TNF-alpha 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-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.
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The Ronald McDonald Children's Hospital at Loyola, Loyola University of Chicago, Maywood, IL 60153, USA. jmurask@luc.edu
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D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000818:Animals; D000831:Animals, Newborn / Q000097:blood; D004731:Endotoxins / Q000097:blood; D005260:Female; D005312:Fetal Blood; D016753:Interleukin-10 / Q000097:blood; D019344:Lactic Acid / Q000097:blood; D008050:Lipid A / Q000031:analogs & derivatives* / Q000627:therapeutic use; D008431:Maternal-Fetal Exchange; D011247:Pregnancy; D011315:Preventive Medicine / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000401:mortality / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D000276:Adjuvants, Immunologic; D004731:Endotoxins; D008050:Lipid A; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D019344:Lactic Acid; C048436:monophosphoryl lipid A