Overexpression of human SOD1 improves survival of mice susceptible to endotoxic shock.
Overexpression of human SOD1 improves survival of mice susceptible to endotoxic shock.
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DOI：
10.2147/jir.s32073
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发表时间：
2012
影响因子：
4.5
通讯作者：
Zhang M
中科院分区：
文献类型：
--
作者：
Charchaflieh J;Labaze GI;Li P;Van Remmen H;Lee H;Stutz H;Richardson A;Emanuel A;Zhang M
抗氧化酶铜锌超氧化物歧化酶（SOD 1）对内毒素休克的保护作用尚未在动物模型中得到证实。我们使用小鼠模型来研究SOD 1的过表达是否对内毒素休克具有保护作用，以及SOD 1的遗传背景是否影响其有效的保护作用和对内毒素休克的易感性。将过表达人SOD 1的转基因（tg）小鼠和对照小鼠基于其遗传背景分为四组：（1）具有混合遗传背景的tg小鼠（tg-JAX）;（2）tg-JAX品系的野生型（WT）同窝小鼠（WT-JAX）;（3）具有C57 BL/6 J背景的tg小鼠（tg-TX）;（4）tg-TX品系的WT同窝小鼠（WT-TX）。使用聚丙烯酰胺活性凝胶确认tg和对照小鼠的肠、心脏和肝脏中的SOD 1活性。腹腔注射脂多糖诱导内毒素休克。使用Kaplan-Meier生存曲线分析120小时内的生存率（平均值，95%置信区间）。人SOD 1酶活性在两种tg菌株（tg-JAX和tg-TX）的肠、心脏和肝脏中显著高于其WT同窝仔（分别为WT-JAX和WT-TX）。有趣的是，tg-JAX小鼠中的内源性SOD 1活性与其WT同窝小鼠（WT-JAX）相比降低，但在tg-TX小鼠中未观察到这种异常变化。tg-JAX组与WT-JAX组内毒素休克后存活时间无差异（P > 0.05）。而tg-TX组小鼠的生存时间是WT-TX组的2倍以上（P < 0.05）。另外，WT-JAX小鼠的存活时间显著长于WT-TX小鼠（P < 0.05）。内源性SOD 1活性的异常降低可能掩盖了tg小鼠（tg-JAX）中SOD 1过表达的作用。具有C57 BL/6 J背景的小鼠（tg-TX）比具有混合遗传背景的小鼠（tg-JAX）更易发生内毒素休克。SOD 1的过表达仅在具有C57 BL/6 J背景（tg-TX）的小鼠中具有保护性。
Protective effects of the antioxidant enzyme Cu-Zn superoxide dismutase (SOD1) against endotoxic shock have not been demonstrated in animal models. We used a murine model to investigate whether overexpression of SOD1 protects against endotoxic shock, and whether the genetic background of SOD1 affects its effective protective effects and susceptibility to endotoxic shock. Transgenic (tg) mice overexpressing human SOD1 and control mice were divided into four groups based on their genetic background: (1) tg mice with mixed genetic background (tg-JAX); (2) wild-type (WT) littermates of tg-JAX strain (WT-JAX); (3) tg mice with C57BL/6J background (tg-TX); (4) WT littermates of tg-TX strain (WT-TX). Activity of SOD1 in the intestine, heart, and liver of tg and control mice was confirmed using a polyacrylamide activity gel. Endotoxic shock was induced by intraperitoneal injection of lipopolysaccharide. Survival rates over 120 hours (mean, 95% confidence interval) were analyzed using Kaplan–Meier survival curves. Human SOD1 enzymatic activities were significantly higher in the intestine, heart, and liver of both tg strains (tg-JAX and tg-TX) compared with their WT littermates (WT-JAX and WT-TX, respectively). Interestingly, the endogenous SOD1 activities in tg-JAX mice were decreased compared with their WT littermates (WT-JAX), but such aberrant changes were not observed in tg-TX mice. There was no difference in the survival time between tg-JAX and WT-JAX groups after endotoxic shock (P > 0.05). However, the survival time in the tg-TX group was more than twofold longer than that in the WT-TX group (P < 0.05). In addition, WT-JAX mice survived significantly longer than WT-TX mice (P < 0.05). Aberrant decrease of endogenous SOD1 activities may have overshadowed the effect of overexpression of SOD1 in tg mice (tg-JAX). Mice with C57BL/6J background (tg-TX) are more susceptible to lipopolysaccharide-induced endotoxic shock than those with mixed genetic background (tg-JAX). Overexpression of SOD1 is protective only in mice with C57BL/6J background (tg-TX).