Amitriptyline Reduces Inflammation and Mortality in a Murine Model of Sepsis.
Amitriptyline Reduces Inflammation and Mortality in a Murine Model of Sepsis.
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DOI：
10.33594/000000040
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发表时间：
2019-01-01
期刊：
影响因子：
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通讯作者：
Caldwell, Charles C
中科院分区：
文献类型：
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作者：
Xia, Brent T;Beckmann, Nadine;Caldwell, Charles C
背景/目的：在脓毒症期间，未经控制的促炎反应可能对宿主有害。方法：采用盲肠结扎穿孔和内毒素血症两种脓毒症模型。测量耳温，并用细胞计数珠法测定细胞因子。肺组织学检查和支气管肺泡灌洗液蛋白测定。用流式细胞仪分析细胞在腹膜中的积聚，以及细胞因子的产生和p38的磷酸化。结果：我们的研究结果表明，经AT处理的脓毒症小鼠存活率提高，肺水肿得到保护。AT治疗可显著降低脓毒症小鼠血清KC和单核细胞趋化蛋白-1水平，减少中性粒细胞和单核细胞在腹膜中的聚集。经AT治疗后，脓毒症小鼠的腹膜IL-10水平升高。IL-10对脓毒症小鼠的直接治疗概括了AT的作用。内毒素血症小鼠在给予AT后也表现出IL-10的产生增加，腹膜巨噬细胞被鉴定为AT影响的IL-10的产生。体外用AT处理这些细胞后，p38磷酸化和IL-10生成增加，而神经酰胺和p38抑制作用相反。结论：AT治疗可提高脓毒症患者的存活率，提高IL-10水平，减轻炎症反应。我们得出结论，AT是一种很有前途的治疗方法，可以缓解感染性休克时的炎症反应。
BACKGROUND/AIMS: During sepsis, an unchecked pro-inflammatory response can be detrimental to the host. We investigated the potential protective effect of amitriptyline (AT).METHODS: We used two murine models of sepsis: Cecal ligation and puncture and endotoxemia following LPS challenge. Aural temperatures were taken and cytokines quantified by cytometric bead assay. Lung injury was determined histologically and by protein determination in bronchoalveolar lavage fluid. Cell accumulation in the peritoneum was analyzed by flow cytometry, as well as cytokine production and p38-phosphorylation. Neutrophil chemotaxis was evaluated using an in vitro transwell assay.RESULTS: Our findings demonstrate that AT-treated septic mice have improved survival and are protected from pulmonary edema. Treatment with AT significantly decreased serum levels of KC and monocyte chemoattractant protein-1, as well as the accumulation of neutrophils and monocytes in the peritoneum of septic mice. Peritoneal IL-10 levels in septic mice were increased upon AT treatment. Direct treatment of septic mice with IL-10 recapitulated the effects of AT. Endotoxemic mice also exhibited enhanced IL-10 production upon AT-administration and peritoneal macrophages were identified as the ATinfluenced producers of IL-10. Treatment of these cells with AT in vitro resulted in increased p38-phosphorylation and IL-10 generation, whereas ceramide and p38 inhibition had the opposite effect.CONCLUSION: Altogether, AT treatment improved survival, increased IL-10 levels, and mitigated a pro-inflammatory response during sepsis. We conclude that AT is a promising therapeutic to temper inflammation during septic shock.