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 confer red a 40-fold increased sensitivity to the lethal effects of lipopolysachar ride (LPS) (P <.001). Enhanced sensitivity to LPS was found to increase wit h duration of adrenal insufficiency (P <.02). Enhanced lethality to heat-ki lled Streptococcus pneumonia was also demonstrated (P < 0.02). Necropsy of endotoxin-killed adrenalectomized mice demonstrated similar pathologic find ings to those found by others when the control mice were administered a let hal dose of either LPS or TNF. Adrenalectomized TNF receptor la and Ib doub le 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 < 0.0 01) following LPS challenge. The effect of TNF upon long-term survival in a drenalectomized mice was examined in TNF-receptor la- and Ib-deficient mice . Deficiencies in either the TNF-receptor la or Ib was noted to confer a su rvival advantage relative to colony controls following adrenalectomy (P< 0. 02). in summary, both LPS-induced Addison's crisis and chronic adrenal insu fficiency are disorders of TNF disregulation. Based upon these data, therap eutic strategies targeted at controlling TNF in adrenal insufficiency are s uggested.