Immune Mechanisms Underlying Susceptibility to Endotoxin Shock in Aged Hosts: Implication in Age-Augmented Generalized Shwartzman Reaction
Immune Mechanisms Underlying Susceptibility to Endotoxin Shock in Aged Hosts: Implication in Age-Augmented Generalized Shwartzman Reaction
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DOI：
10.3390/ijms20133260
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发表时间：
2019-07
影响因子：
5.6
通讯作者：
M. Kinoshita;M. Nakashima;H. Nakashima;S. Seki
中科院分区：
文献类型：
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作者：
M. Kinoshita;M. Nakashima;H. Nakashima;S. Seki
近几十年来，许多国家的老年人口迅速增加。这类患者易患革兰氏阴性脓毒性休克，即内毒素休克。尽管最近医疗保健取得了进展，但内毒素休克的死亡率仍然很高。广泛性Shwartzman反应是公认的实验性内毒素休克。老年小鼠同样易受全身性Shwartzman反应的影响，并显示死亡率增加，伴有肿瘤坏死因子（TNF）的产生增加。与鼠模型中的发现一致，体外Shwartzman反应样应答在人外周血单核细胞中也呈年龄依赖性增强，如通过增强的TNF产生所评估的。有趣的是，年龄依赖性增加的先天性淋巴细胞与T细胞受体的中间表达，如CD8+CD122+T细胞在小鼠和CD57+T细胞在人类，可能与巨噬细胞和诱导老年人的Shwartzman反应的加剧。然而，小鼠中的内毒素耐受性，类似于广义Shwartzman反应的镜像现象，大大减少了巨噬细胞的TNF产生，同时强烈激活了它们在感染中的杀菌活性。重要的是，这种效应可以在老年小鼠中诱导。安全诱导内毒素耐受可能是治疗老年患者难治性感染性休克的一种潜在策略。
In recent decades, the elderly population has been rapidly increasing in many countries. Such patients are susceptible to Gram-negative septic shock, namely endotoxin shock. Mortality due to endotoxin shock remains high despite recent advances in medical care. The generalized Shwartzman reaction is well recognized as an experimental endotoxin shock. Aged mice are similarly susceptible to the generalized Shwartzman reaction and show an increased mortality accompanied by the enhanced production of tumor necrosis factor (TNF). Consistent with the findings in the murine model, the in vitro Shwartzman reaction-like response is also age-dependently augmented in human peripheral blood mononuclear cells, as assessed by enhanced TNF production. Interestingly, age-dependently increased innate lymphocytes with T cell receptor-that intermediate expression, such as that of CD8+CD122+T cells in mice and CD57+T cells in humans, may collaborate with macrophages and induce the exacerbation of the Shwartzman reaction in elderly individuals. However, endotoxin tolerance in mice, which resembles a mirror phenomenon of the generalized Shwartzman reaction, drastically reduces the TNF production of macrophages while strongly activating their bactericidal activity in infection. Importantly, this effect can be induced in aged mice. The safe induction of endotoxin tolerance may be a potential therapeutic strategy for refractory septic shock in elderly patients.