Bench to bedside: HMGB1 - A novel proinflammatory cytokine and potential therapeutic target for septic patients in the emergency department
Bench to bedside: HMGB1 - A novel proinflammatory cytokine and potential therapeutic target for septic patients in the emergency department
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DOI：
10.1197/j.aem.2004.03.011
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发表时间：
2004-08-01
影响因子：
4.4
通讯作者：
Wang, HC
中科院分区：
文献类型：
--
作者：
Sama, AE;D'Amore, J;Wang, HC
压倒性的革兰氏阴性细菌感染和危及生命的全身炎症是危重急诊患者普遍存在的问题。目前，这些患者的治疗主要是支持性的，重点是抗生素、液体、血流动力学和通气支持以及强化监测。唯一经美国食品和药物管理局批准用于治疗脓毒症的药物是活化蛋白 C，其用途主要集中在重症监护病房。因此，该主题仍然是急诊医学研究的活跃探索领域。在脓毒症和炎症期间，先天免疫细胞会释放过量的促炎细胞因子，例如肿瘤坏死因子 (TNF) 和白介素-1β。如果尽早提供，抗 TNF 抗体可以成为感染性休克实验模型的有效疗法。抗 TNF 抗体已开发用于临床治疗类风湿性关节炎和克罗恩病。然而，脓毒症的抗 TNF 治疗在临床上很难实现，这可能是因为 TNF 的早期释放和血清中的短暂出现造成了狭窄的治疗窗。另一种策略是识别临床上更容易接近的“晚期”介质。高迁移率族蛋白 1 (HMGB1) 是一种以前仅被称为核转录因子的蛋白质，现在被认为是脓毒症的晚期介质。针对致命性全身炎症的晚期介质代表了一种新方法，可以扩大治疗窗口并产生抑制炎症级联有害影响的新策略。在此，作者回顾了导致 HMGB1 作为全身炎症晚期介质的发现的研究，并讨论了 HMGB1 作为急诊科脓毒症患者治疗靶点的可能性。
Overwhelming gram-negative bacterial infection and life-threatening systemic inflammation are widespread problems in critically ill emergency department patients. Currently, the treatment of these patients is largely supportive, focusing on antibiotics, fluids, hemodynamic and ventilatory support, and intensive monitoring. The only Food and Drug Administration-approved pharmaceutical agent for the treatment of sepsis is activated protein C, with its use largely relegated to the intensive care unit. The subject thus remains an active area of exploration for emergency medicine research. During sepsis and inflammation, innate immune cells release excessive amounts of proinflammatory cytokines such as tumor necrosis factor (TNF) and interleukin-1beta. If delivered early enough, anti-TNF antibodies can be an effective therapy in experimental models of septic shock. Anti-TNF antibodies have been developed for clinical use in rheumatoid arthritis and Crohn's disease. However, anti-TNF treatment for sepsis has been difficult to achieve in the clinical setting, perhaps because TNF's early release and transient appearance in the serum create a narrow therapeutic window. An alternative strategy would be to identify "late" mediators that may be clinically more accessible. High mobility group box 1 (HMGB1), a protein previously known only as a nuclear transcription factor, is now implicated as a late mediator of sepsis. Targeting late mediators of lethal systemic inflammation represents a novel approach that may widen the therapeutic window and lead to new strategies for inhibiting the deleterious effects of the inflammatory cascade. Here the authors review the studies that led to the discovery of HMGB1 as a late mediator of systemic inflammation and discuss the possibility of HMGB1 as a therapeutic target for septic patients in the emergency department.