Prophylactic Treatment of Endotoxic Shock with Monophosphoryl Lipid A in Newborn Rats

Abstract

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.

Alkaline phosphatase for treatment of sepsis-induced acute kidney injury: a prospective randomized double-blind placebo-controlled trial

“…Local AP concentrations reflect the host defense against endotoxin in the kidney [9], and during ischemia enzyme levels are markedly depleted, associated with the development of AKI [10]. Apart from local effects in the kidney, AP may attenuate the innate immune response, as dephosphorylation of endotoxin abolishes its biological activity and induces tolerance to subsequent endotoxin exposure [11]. In animal models of sepsis, AP administration attenuates the inflammatory response and reduces mortality [12,13].…”

Protection Against an Escherichia Coli-Induced Sepsis by Alkaline Phosphatase in Mice

“…Chemical removal of one of these phosphate groups, resulting in the conversion of LPS to monophosphoryl lipid A (MPLA), abolished the toxicity of LPS (5). This MPLA has shown to have protective effects against experimental septic shock in animals (5,6) and to induce tolerance to endotoxin in humans (7).…”

The Toll-Like Receptor 4 Agonist Monophosphoryl Lipid A Augments Innate Host Resistance to Systemic Bacterial Infection

“…However, few studies have examined the effects of LPS treatment on the host response to live bacterial infections. Recent studies from our laboratory, and others, have demonstrated that mice primed with LPS have improved resistance to bacterial infections (23,39,40). However, the clinical applicability of LPS as a therapeutic or prophylactic agent is precluded by toxicity and a narrow therapeutic index in humans.…”

“…The attenuated toxicity of MPLA is associated with reduced induction of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-␣), interleukin-1␤ (IL-1␤), and gamma interferon (IFN-␥) during initial exposure (13,29). MPLA retains significant immunomodulatory activity and prior treatment with MPLA increases survival after otherwise lethal exposure to LPS in animal models (2,16,39). However, the effect of MPLA on the innate response to clinically relevant models of bacterial infection has not been determined.…”