Adenosine monophosphate-activated protein kinase activation protects against sepsis-induced organ injury and inflammation.
Adenosine monophosphate-activated protein kinase activation protects against sepsis-induced organ injury and inflammation.
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DOI：
10.1016/j.jss.2014.10.009
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发表时间：
2015-03
影响因子：
2.2
通讯作者：
Gomez, Hernando
中科院分区：
文献类型：
--
作者：
Escobar, Daniel A.;Botero-Quintero, Ana M.;Kautza, Benjamin C.;Luciano, Jason;Loughran, Patricia;Darwiche, Sophie;Rosengart, Matthew R.;Zuckerbraun, Brian S.;Gomez, Hernando
脓毒症的死亡率最常归因于多器官衰竭的发展。在脓毒症中，炎症介导的内皮激活（定义为内皮细胞的促炎和促凝状态）与疾病的严重程度相关。因此，本研究的目的是检验AMPK活化限制炎症和内皮活化以保护免于脓毒症中的器官损伤的假设。5-氨基咪唑-4-甲酰胺核糖核苷酸（AICAR）是AMP类似物，已被用于上调AMPK的活性。化合物C是抑制AMPK活性的细胞可渗透的吡唑并嘧啶化合物。野生型小鼠经历CLP或假手术。将小鼠随机分配至媒介物、AICAR或化合物C。小鼠肾内皮细胞用于体外实验。通过血清胱抑素C、BUN、肌酐和ALT测定肾功能和肝功能。ELISA法检测血清细胞因子水平。用伊文思蓝染色和电子显微镜测定微血管损伤。免疫组化法检测p-AMPK、LC 3和ICAM的蛋白水平。LC 3水平用作自噬体形成的量度。AICAR在体内和体外降低了CLP诱导的肝和肾损伤，并使细胞因子升高最小化。CLP增加肾脏和肝脏AMPK磷酸化和自噬信号传导，如LC 3所确定。用化合物C抑制AMPK防止CLP诱导的自噬并加剧组织损伤。此外，CLP导致内皮损伤，如通过电子显微镜和伊文思蓝染料外渗所确定的，AICAR限制了这种损伤。此外，AICAR在体内和体外限制CLP和LPS诱导的ICAM上调，并在体外降低LPS诱导的中性粒细胞粘附。在该模型中，AMPK的激活具有保护作用，AICAR通过减少炎性细胞因子和内皮激活来最大限度地减少器官损伤。这些数据表明AMPK信号影响脓毒症或LPS诱导的内皮活化和器官损伤。
Mortality in sepsis is most often attributed to the development of multiple organ failure. In sepsis, inflammation-mediated endothelial activation, defined as a proinflammatory and procoagulant state of the endothelial cells, has been associated with severity of disease. Thus, the objective of this study was to test the hypothesis that AMPK activation limits inflammation and endothelium activation to protect against organ injury in sepsis. 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR), which is an AMP analogue, has been used to upregulate activity of AMPK. Compound C is a cell-permeable pyrrazolopyrimidine compound that inhibits AMPK activity. Wild-type mice underwent CLP or Sham surgery. Mice were randomized to vehicle, AICAR, or Compound C. Mouse kidney endothelial cells were used for in vitro experiments. Renal and liver function, were determined by serum Cystatin C, BUN, creatinine, and ALT. Serum cytokines were measured by ELISA. Microvascular injury was determined using Evan’s blue dye and electron microscopy. Immunohistochemistry was used to measure protein levels of p-AMPK, LC3, and ICAM. LC3 levels were used as a measure of autophagosome formation. AICAR decreased liver, and kidney injury induced by CLP and minimized cytokine elevation, in vivo and in vitro. CLP increased renal and hepatic phosphorylation of AMPK and autophagic signaling as determined by LC3. Inhibition of AMPK with Compound C prevented CLP-induced autophagy and exacerbated tissue injury. Additionally, CLP led to endothelial injury as determined by electron microscopy and Evan’s blue dye extravasation, and AICAR limited this injury. Furthermore, AICAR limited CLP and LPS induced upregulation of ICAM in vivo and in vitro, and decreased LPS induced neutrophil adhesion in vitro. In this model, activation of AMPK was protective and AICAR minimized organ injury by decreasing inflammatory cytokines and endothelial activation. These data suggest that AMPK signaling influences sepsis or LPS induced endothelial activation and organ injury.
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DOI：
10.4049/jimmunol.1102975
发表时间：
2013-04-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Guo L;Stripay JL;Zhang X;Collage RD;Hulver M;Carchman EH;Howell GM;Zuckerbraun BS;Lee JS;Rosengart MR
通讯作者：
Rosengart MR
影响因子：
5
作者：
Gross, ER;Nithipatikom, K;Gross, GJ
通讯作者：
Gross, GJ
影响因子：
4.4
作者：
Nath, N;Giri, S;Singh, I
通讯作者：
Singh, I
影响因子：
4.3
作者：
Carre, Jane E.;Singer, Mervyn
通讯作者：
Singer, Mervyn
影响因子：
4.8
作者：
Carchman, Evie H.;Whelan, Sean;Zuckerbraun, Brian S.
通讯作者：
Zuckerbraun, Brian S.