TNF mediates a murine model of Addison's crisis.
Addison's crisis is the most serious complication of adrenal insufficiency. To elucidate the mechanism of this disorder following infection, the role of TNF in adrenalectomized murine models of Addison's crisis and Addison's disease (chronic hypoglucocorticoidism) were examined. Adrenalectomy conferred a 40-fold increased sensitivity to the lethal effects of lipopolysacharride (LPS) (P < .001). Enhanced sensitivity to LPS was found to increase with duration of adrenal insufficiency (P < .02). Enhanced lethality to heat-killed Streptococcus pneumonia was also demonstrated (P < 0.02). Necropsy of endotoxin-killed adrenalectomized mice demonstrated similar pathologic findings to those found by others when the control mice were administered a lethal dose of either LPS or TNF. Adrenalectomized TNF receptor Ia and Ib double null mice were demonstrated to be resistant to the lethal effects of LPS (P < 0.02). Pretreatment with anti-TNF, but not control antisera, was found to prevent death in LPS-treated wild-type adrenalectomized mice as well (P < 0.02). Studies into the mechanism by which TNF was precipitating Addison's crisis demonstrated enhanced sensitivity to TNF (3-fold; P < 0.02), and a marked increase in serum TNF concentration (approximately 5-fold; P < 0.001) following LPS challenge. The effect of TNF upon long-term survival in adrenalectomized mice was examined in TNF-receptor Ia- and Ib-deficient mice. Deficiencies in either the TNF-receptor Ia or Ib was noted to confer a survival advantage relative to colony controls following adrenalectomy (P < 0.02). In summary, both LPS-induced Addison's crisis and chronic adrenal insufficiency are disorders of TNF disregulation. Based upon these data, therapeutic strategies targeted at controlling TNF in adrenal insufficiency are suggested.
Koniaris
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Department of Molecular Biology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Wand
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Wright
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D000224:Addison Disease / Q000378:metabolism / Q000401:mortality / Q000503:physiopathology*; D000315:Adrenalectomy / Q000009:adverse effects; D000818:Animals; D015703:Antigens, CD; D004195:Disease Models, Animal; D004731:Endotoxins; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D013296:Streptococcus pneumoniae; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
D015703:Antigens, CD; D004731:Endotoxins; D008070:Lipopolysaccharides; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha