Lethal endotoxic shock using |[alpha]|-galactosylceramide sensitization as a new experimental model of septic shock

摘要

The effect of -galactosylceramide (-GalCer) on lipopolysaccharide (LPS)-mediated lethality was examined. Administration of LPS killed all mice pretreated with -GalCer, but not untreated control mice. The lethal shock in -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. -GalCer sensitization was ineffective for the development of the systemic lethal shock in V14-positive natural killer T cell-deficient mice. Sensitization with -GalCer led to the circulation of a high level of interferon (IFN)- and further augmented the production of tumor necrosis factor (TNF)- in response to LPS. The lethal shock was abolished by the administration of anti-IFN- or TNF- antibody. Further, the lethal shock did not occur in TNF--deficient mice. Taken together, -GalCer sensitization rendered mice very susceptible to LPS-mediated lethal shock, and IFN- and TNF- were found to play a critical role in the preparation and execution of the systemic lethal shock, respectively. The LPS-mediated lethal shock using -GalCer sensitization might be useful for researchers employing experimental models of sepsis and septic shock.