TNF mediates a murine model of Addison's crisis.
TNF mediates a murine model of Addison's crisis.
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TNF 介导艾迪生危机的小鼠模型。
DOI：
10.1097/00024382-200115010-00005
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发表时间：
2001
期刊：
影响因子：
--
通讯作者：
Wright,TM
中科院分区：
文献类型：
--
作者：
Koniaris,LG;Wand,G;Wright,TM
——艾迪生危象是肾上腺皮质功能减退症最严重的并发症。为了阐明感染后这种疾病的机制，我们检查了 TNF 在艾迪生危象和艾迪生氏病（慢性糖皮质激素低下症）的去肾上腺小鼠模型中的作用。肾上腺切除术使脂多糖 (LPS) 致死作用的敏感性增加了 40 倍 (P<. 001)。发现对 LPS 的敏感性随着肾上腺功能不全的持续时间而增加（P<.02）。还证明了热灭活肺炎链球菌的致死率增强（P<0.02）。内毒素杀死的肾上腺切除小鼠的尸检显示出与其他小鼠在给予致死剂量的 LPS 或 TNF 时发现的相似的病理结果。肾上腺切除的TNF受体1a和1b双无效小鼠被证明对LPS的致死作用具有抵抗力(P<0.02)。发现用抗TNF而非对照抗血清进行预处理也可以预防LPS处理的野生型肾上腺切除小鼠的死亡（P<0.02）。对 TNF 引发艾迪生危象机制的研究表明，LPS 攻击后对 TNF 的敏感性增强（3 倍；P < 0.02），并且血清 TNF 浓度显着增加（约 5 倍；P < 0.001）。在TNF受体1a和1b缺陷的小鼠中检查TNF对肾上腺切除小鼠的长期存活的影响。注意到TNF受体1a或1b的缺陷在肾上腺切除术后相对于集落对照具有生存优势(P<0.02)。总之，LPS引起的艾迪生危象和慢性肾上腺功能不全都是TNF失调的疾病。根据这些数据，提出了针对肾上腺功能不全患者控制 TNF 的治疗策略。
mdash;: 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 endotoxinkilled 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 la and lb 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 la-and lb-deficient mice. Deficiencies in either the TNF-receptor la or lb 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.