Lethal endotoxic shock using alpha-galactosylceramide sensitization as a new experimental model of septic shock.
The effect of alpha-galactosylceramide (alpha-GalCer) on lipopolysaccharide (LPS)-mediated lethality was examined. Administration of LPS killed all mice pretreated with alpha-GalCer, but not untreated control mice. The lethal shock in alpha-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. alpha-GalCer sensitization was ineffective for the development of the systemic lethal shock in Valpha14-positive natural killer T cell-deficient mice. Sensitization with alpha-GalCer led to the circulation of a high level of interferon (IFN)-gamma and further augmented the production of tumor necrosis factor (TNF)-alpha in response to LPS. The lethal shock was abolished by the administration of anti-IFN-gamma or TNF-alpha antibody. Further, the lethal shock did not occur in TNF-alpha-deficient mice. Taken together, alpha-GalCer sensitization rendered mice very susceptible to LPS-mediated lethal shock, and IFN-gamma and TNF-alpha were found to play a critical role in the preparation and execution of the systemic lethal shock, respectively. The LPS-mediated lethal shock using alpha-GalCer sensitization might be useful for researchers employing experimental models of sepsis and septic shock.
Ito
Hiroyasu
H
Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan. hito@aichi-med-u.ac.jp
Koide
Naoki
N
Hassan
Ferdaus
F
Islam
Shamima
S
Tumurkhuu
Gantsetseg
G
Mori
Isamu
I
Yoshida
Tomoaki
T
Kakumu
Shinichi
S
Moriwaki
Hisataka
H
Yokochi
Takashi
T
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004731:Endotoxins / Q000633:toxicity*; D005699:Galactosylceramides / Q000494:pharmacology*; D007371:Interferon-gamma / Q000276:immunology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012772:Shock, Septic / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000276:immunology
D000276:Adjuvants, Immunologic; D019138:Antibodies, Blocking; D004731:Endotoxins; D005699:Galactosylceramides; D014409:Tumor Necrosis Factor-alpha; C493154:alpha-galactosylceramide; D007371:Interferon-gamma