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.