A glutamine synthetase inhibitor increases survival and decreases cytokine response in a mouse model of acute liver failure
A glutamine synthetase inhibitor increases survival and decreases cytokine response in a mouse model of acute liver failure
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DOI：
10.1111/j.1478-3231.2011.02553.x
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发表时间：
2011-09-01
影响因子：
6.7
通讯作者：
Brusilow, William S. A.
中科院分区：
文献类型：
--
作者：
Jambekar, Amruta A.;Palma, Elena;Brusilow, William S. A.
背景资料：急性肝衰竭（ALF）可以通过给予大肠杆菌脂多糖（LPS）和D-半乳糖胺（D-GalN）在小鼠中诱导，其诱导涉及肿瘤坏死因子（TNF）-α产生和肝细胞特异性转录阻断的炎症反应。在这些条件下，TNF-α与肝细胞上其同源受体的结合最终导致其凋亡。目的：作为确定治疗这种疾病模型的药物的努力的一部分，我们研究了谷氨酰胺合成酶抑制剂甲硫氨酸亚砜亚胺（MSO）是否可以发挥保护作用，因为它可以有效抑制与高氨血症相关的脑肿胀。研究方法：在腹腔注射LPS/D-GalN之前，在用MSO处理的小鼠中测量小鼠存活率、谷氨酰胺合成酶活性、肝细胞凋亡和炎性细胞因子的诱导。还在炎性细胞和肝细胞上评估了MSO对活力和TNF-α释放的影响。结果如下：我们已经发现，在用LPS/D-GalN处理的小鼠中，MSO（i）显著增加动物存活率;（ii）显著降低谷氨酰胺合成酶活性，而不抑制其另一个靶点γ-谷氨酰半胱氨酸合成酶;（iii）抑制细胞因子结合上游肝细胞中死亡受体介导的凋亡;（iv）强烈降低总体炎性细胞因子应答，包括体内和离体TNF-α诱导以及干扰素-γ水平和信号传导的显著降低。结论：这些结果表明，MSO靶谷氨酰胺合成酶是细胞因子对内毒素反应的早期步骤所必需的，并且其药理学抑制可用于治疗炎症。
Background: Acute liver failure (ALF) can be induced in mice by administering Escherichia coli lipopolysaccharide (LPS) and D-galactosamine (D-GalN), which induce an inflammatory response involving tumour necrosis factor (TNF)-alpha production and a hepatocyte-specific transcriptional block. Under these conditions, binding of TNF-alpha to its cognate receptor on hepatocytes eventually leads to their apoptosis. Aims: As part of an effort to identify drugs to treat this disease model, we have investigated whether the glutamine synthetase inhibitor methionine sulfoximine (MSO) could play a protective role, given its effectiveness in the inhibition of brain swelling associated with hyperammonaemia. Methods: Mouse survival, glutamine synthetase activity, hepatocyte apoptosis and induction of inflammatory cytokines were measured in mice treated with MSO before an intraperitoneal injection of LPS/D-GalN. The effect of MSO on viability and on TNF-alpha release was also assessed on inflammatory and liver cells. Results: We have found that, in mice treated with LPS/D-GalN, MSO (i) drastically increases animal survival; (ii) sharply reduces glutamine synthetase activity, without inhibiting its other target, gamma-glutamyl cysteine synthetase; (iii) inhibits death receptor-mediated apoptosis in hepatocytes upstream to cytokine binding; (iv) strongly reduces the overall inflammatory cytokine response, including a significant decrease in TNF-alpha induction in vivo and ex vivo, and in the interferon-gamma level and signalling. Conclusions: These results demonstrate that the MSO target glutamine synthetase is required for the early steps of the cytokine response to endotoxins, and that its pharmacological inhibition may be exploited to treat inflammation.