Division of Research, Department of Surgery, University of Cincinnati, Cincinnati, Ohio.
Department of Molecular Biology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Shock. 2019 Mar;51(3):356-363. doi: 10.1097/SHK.0000000000001146.
During sepsis, the early innate response and inflammatory cytokine cascade are associated with activation of the coagulation cascade. Acute hypercoagulability can contribute to lethal sequela of vascular thrombosis, tissue ischemia, and organ failure. We investigated if amitriptyline (AMIT), an antidepressant drug with a number of anti-inflammatory effects, could ameliorate sepsis in a murine model of sepsis-cecal ligation and puncture (CLP). We hypothesized that AMIT treatment would reduce inflammation and mitigate sepsis-induced coagulopathy. Coagulation was measured using thromboelastometry and ferric chloride-induced carotid artery thrombosis. Our findings demonstrate a dynamic early hypercoagulability, followed by delayed hypocoagulability in septic mice. However, septic mice treated with AMIT were unaffected by these coagulation changes and exhibited a coagulation profile similar to sham mice. TNFα was markedly elevated in septic mice, but decreased in AMIT-treated mice. Exogenous administration of recombinant TNFα in naive mice recapitulated the acute sepsis-induced hypercoagulability profile. After sepsis and endotoxemia, peritoneal macrophages were the predominant source of TNFα expression. AMIT treatment significantly decreased macrophage TNFα expression and blunted M1 polarization. Altogether, during polymicrobial sepsis, AMIT treatment suppressed macrophage TNFα expression and the M1 phenotype, mitigating an initial hypercoagulable state, and protecting septic mice from delayed hypocoagulability. We propose that AMIT treatment is a promising therapeutic approach in the treatment of sepsis-associated coagulopathy and prevention of acute thromboembolic events or delayed bleeding complications.
在脓毒症中，早期固有免疫反应和炎症细胞因子级联反应与凝血级联反应的激活有关。急性高凝状态可导致血管血栓形成、组织缺血和器官衰竭的致死性后果。我们研究了阿米替林（AMIT）是否可以改善脓毒症-盲肠结扎和穿刺（CLP）的小鼠模型中的脓毒症。我们假设 AMIT 治疗可以减轻炎症并减轻脓毒症引起的凝血功能障碍。使用血栓弹性描记术和三氯化铁诱导颈动脉血栓形成来测量凝血。我们的研究结果表明，脓毒症小鼠表现出早期的高凝状态，随后出现延迟性低凝状态。然而，接受 AMIT 治疗的脓毒症小鼠不受这些凝血变化的影响，其凝血谱与假手术小鼠相似。TNFα 在脓毒症小鼠中明显升高，但在 AMIT 治疗的小鼠中降低。在无TNFα 的小鼠中给予重组 TNFα 可重现急性脓毒症引起的高凝状态。在脓毒症和内毒素血症后，腹膜巨噬细胞是 TNFα 表达的主要来源。AMIT 治疗显著降低了巨噬细胞 TNFα 的表达并减弱了 M1 极化。总之，在多微生物脓毒症中，AMIT 治疗抑制了巨噬细胞 TNFα 的表达和 M1 表型，减轻了初始高凝状态，并保护脓毒症小鼠免受延迟性低凝状态的影响。我们提出，AMIT 治疗是治疗脓毒症相关凝血功能障碍和预防急性血栓栓塞事件或延迟性出血并发症的有前途的治疗方法。
