Lethal endotoxic shock using α-galactosylceramide sensitization as a new experimental model of septic shock

Abstract

The effect of α-galactosylceramide (α-GalCer) on lipopolysaccharide (LPS)-mediated lethality was examined. Administration of LPS killed all mice pretreated with α-GalCer, but not untreated control mice. The lethal shock in α-GalCer-sensitized mice was accompanied by severe pulmonary lesions with marked infiltration of inflammatory cells and massive cell death. On the other hand, hepatic lesions were focal and mild. A number of cells in pulmonary and hepatic lesions underwent apoptotic cell death. α-GalCer sensitization was ineffective for the development of the systemic lethal shock in Vα14-positive natural killer T cell-deficient mice. Sensitization with α-GalCer led to the circulation of a high level of interferon (IFN)-γ and further augmented the production of tumor necrosis factor (TNF)-α in response to LPS. The lethal shock was abolished by the administration of anti-IFN-γ or TNF-α antibody. Further, the lethal shock did not occur in TNF-α-deficient mice. Taken together, α-GalCer sensitization rendered mice very susceptible to LPS-mediated lethal shock, and IFN-γ and TNF-α were found to play a critical role in the preparation and execution of the systemic lethal shock, respectively. The LPS-mediated lethal shock using α-GalCer sensitization might be useful for researchers employing experimental models of sepsis and septic shock. © 2006 USCAP, Inc All rights reserved.