The hydroxylase inhibitor dimethyloxallyl glycine attenuates endotoxic shock via alternative activation of macrophages and IL-10 production by B1 cells.
The hydroxylase inhibitor dimethyloxallyl glycine attenuates endotoxic shock via alternative activation of macrophages and IL-10 production by B1 cells.
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羟化酶抑制剂二甲氧亚甘氨酸通过巨噬细胞的替代激活和B1细胞产生的IL-10产生来减轻内毒性休克。
DOI：
10.1097/shk.0b013e318225ad7e
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发表时间：
2011-09
期刊：
影响因子：
--
通讯作者：
Fallon PG
中科院分区：
文献类型：
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作者：
Hams E;Saunders SP;Cummins EP;O'Connor A;Tambuwala MT;Gallagher WM;Byrne A;Campos-Torres A;Moynagh PM;Jobin C;Taylor CT;Fallon PG
局部组织缺氧是感染和炎症的特征，通过抑制氧敏感羟化酶导致转录因子HIF-1α和NF-κB上调。先前的研究已经证明了羟化酶抑制剂二甲基氧烯丙基甘氨酸（DMOG）通过调节HIF-1和NF-κB的活性在炎症条件（包括实验性结肠炎）中的有益作用。我们已经在体内证明，DMOG预处理减弱了全身LPS诱导的NF-κB通路的激活。此外，用DMOG治疗的小鼠在LPS诱导的休克中的存活率显著增加。相反，在多微生物败血症模型中，DMOG加重了疾病的严重程度。DMOG处理小鼠可促进腹腔内巨噬细胞的M2极化，导致促炎细胞因子（如TNFα）下调。此外，体内DMOG处理上调IL-10表达，特别是在腹膜B-1细胞群中。本研究证明了羟化酶抑制在体内的细胞类型的特定作用，并提供了深入了解DMOG在内毒素休克模型中传达的保护机制。
Localized tissue hypoxia is a feature of infection and inflammation, resulting in the upregulation of the transcription factors HIF-1α and NF-κB via inhibition of oxygen sensing hydroxylase enzymes. Previous studies have demonstrated a beneficial role for the hydroxylase inhibitor dimethyloxallyl glycine (DMOG) in inflammatory conditions, including experimental colitis, by regulating the activity of HIF-1 and NF-κB. We have demonstrated in vivo that pre-treatment with DMOG attenuates systemic LPS-induced activation of the NF-κB pathway. Furthermore, mice treated with DMOG had significantly increased survival in LPS-induced shock. Conversely, in models of polymicrobial sepsis, DMOG exacerbates disease severity. DMOG treatment of mice promotes M2 polarization in macrophages within the peritoneal cavity, resulting in the downregulation of pro-inflammatory cytokines such as TNFα. In addition, in vivo DMOG treatment upregulates IL-10 expression, specifically in the peritoneal B-1 cell population. This study demonstrates cell type specific roles for hydroxylase inhibition in vivo and provides insight into the mechanism underlying the protection conveyed by DMOG in models of endotoxic shock.