TNF MEDIATES A MURINE MODEL OF ADDISONʼS CRISIS
Abstract
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…
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Enhanced glucocorticoid secretion in critical illness is considered necessary to prevent defense mechanisms from overshooting with concomitant detrimental toxicity.
“Enhanced glucocorticoid secretion in critical illness is considered necessary to prevent defense mechanisms (eg, cytokine release) from overshooting with concomitant detrimental toxicity (142, 143).”
From Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline (2016) · cites this paper as [143]
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“Enhanced glucocorticoid secretion in critical illness is considered necessary to prevent defense mechanisms (eg, cytokine release) from overshooting with concomitant detrimental toxicity (142, 143).”
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- Authors
- Koniaris, L. G., Wand, G., & Wright, T. M.
- Affiliations
- Johns Hopkins University (US)
- University of Pittsburgh (US)
- Corresponding author
- Koniaris, Leonidas G.
- Venue
- Shock
- Published
- 2001-01
- Volume
- 15
- Issue
- 1
- Pages
- 29-34
- ISSN
- 1073-2322 (ISSN-L)
- OpenAlex
- W1970364949
- Cited by
- 16
- References
- 0
- Citations by year
- 2025: 1 · 2022: 2 · 2021: 1 · 2020: 1 · 2017: 1 · 2016: 1 · 2015: 1 · 2014: 2
- FWCI
- 0.69
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Shock (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5k12dk001298-10)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-01298)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- Addison's disease, adrenal insufficiency, TNF-α, adrenalectomy, anti-TNF therapy, hypoglycemia
- MeSH terms
- Addison Disease, Adrenalectomy, Animals, Disease Models, Animal, Endotoxins, Lipopolysaccharides, Male, Mice, Inbred Strains, Streptococcus pneumoniae, Tumor Necrosis Factor-alpha, Antigens, CD, Survival Rate, Receptors, Tumor Necrosis Factor, Receptors, Tumor Necrosis Factor, Type I, Receptors, Tumor Necrosis Factor, Type II, Mice
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