Targeting inflammation in traumatic injury: entering a new era.
Targeting inflammation in traumatic injury: entering a new era.
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针对创伤性损伤中的炎症：进入新时代。
DOI：
10.1007/s00134-023-07152-2
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发表时间：
2023
影响因子：
38.9
通讯作者：
Bailly,Sebastien
中科院分区：
文献类型：
--
作者：
Billiar,TimothyR;Hunt,BeverleyJ;Bailly,Sebastien
创伤通常被称为“无声的大流行病”，在近代历史上，创伤一直是儿童和成年男性死亡和慢性发病的最常见原因，直到中年[1]。随着人类年龄的增长，非传染性疾病占主导地位，但创伤仍然是死亡的重要原因。在创伤性事件之后，通常健康的人突然进入急性危重病状态。早期死亡通常是由于创伤性脑损伤和/或出血引起的失血性休克。在存活的患者中，创伤和出血以及创伤诱导的凝血病（TIC）[2]的影响可导致全身炎症反应综合征（SIRS）。人类转录组学显示，循环白细胞表现出“基因组风暴”，血浆多组学揭示了损伤后早期细胞成分大量释放到循环中[3-5]。这种释放包括损伤相关分子模式（DAMP）分子，这些分子通过与免疫细胞和其他细胞上的模式识别受体相互作用而引发炎症[6]。随后促炎介质的产生以及补体和凝血级联的激活，当过度时，可导致早期多器官功能障碍（MODS），其平均在创伤事件后约2-3天达到峰值[7]。靶向早期炎症反应以减少MODS的潜在益处及其下游后果，已经成为20多年来激烈研究和辩论的领域。这一概念得到了临床前研究的支持，这些研究表明，在啮齿动物出血性休克后靶向促炎介质（例如，白细胞介素（IL）6和8）或受体后信号传导（例如，伯顿酪氨酸激酶9）可显著降低早期器官损伤。然而，基于许多针对脓毒症免疫反应的失败试验，另一种导致MODS的急性SIRS的常见原因[10]，许多重症监护医生可能会警告不要依赖啮齿动物模型的数据来指导人体试验。相反，那些从事基础创伤研究的人经常指出创伤的独特特征，例如对创伤和休克后非感染性炎症反应的发病时间和独特性质的精确了解，作为考虑创伤抗炎剂的理由。根据这期《重症监护医学》的一篇文章[11]，关于是否以及如何针对创伤后炎症反应的争论可能会发生实质性变化。Shepherd及其同事报告了TOP-ART试验的结果，该试验测试了抗疟疾药物青蒿琥酯在严重创伤患者48小时内减少MODS的安全性和有效性。青蒿琥酯被认为是一种很好的试验药物，因为它在严重疟疾患者中有令人印象深刻的安全记录，其已知的抗炎特性，并且因为青蒿琥酯在大鼠出血性休克的良好校准模型中显著减少了早期器官损伤[12]。研究者计划周密并执行了试验设计，包括针对高MODS队列（成人大出血方案患者）的入组标准，知情同意，使用平行组两阶段给药方案在损伤后4小时内给药，以及频繁的给药后采样以确认足够的药物水平。重要的是，药物监测委员会每15名患者后监测严重不良事件。由于青蒿琥酯组静脉血栓栓塞事件的发生率较高（3.3%），90名患者被随机分配到青蒿琥酯组或安慰剂组，而不是计划的105名患者，因此试验提前结束。
Trauma is often referred to as the “Silent Pandemic”, and in recent history has been the most common cause of death and chronic morbidity in children and adult men until mid-life [1]. As humans age, non-communicable diseases are predominant but trauma remains a significant cause of death. Following a traumatic event, otherwise typically healthy people abruptly enter a state of acute critical illness. Early mortality is most often due to traumatic brain injury and/or bleeding causing haemorrhagic shock. In patients who survive, the effects of trauma and bleeding and trauma-induced coagulopathy (TIC)[2], can lead to a systemic inflammatory response syndrome (SIRS). Human transcriptomics show that circulating leukocytes manifest a “genomic storm” and plasma multiomics reveal a massive release of cellular constituents into the circulation early after injury [3–5]. This release includes damage-associated molecular patterns (DAMP) molecules that initiate inflammation by interacting with pattern recognition receptors on immune and other cells [6]. The ensuing production of pro-inflammatory mediators and activation of complement and coagulation cascades, when excessive, can lead to early multiple organ dysfunction (MODS), which peaks on average about 2–3 days after the traumatic event [7]. The potential benefit of targeting the early inflammatory response to reduce MODS, and hence its downstream consequences, has been an area of intense research and debate for over 2 decades. This concept has been supported by pre-clinical research showing that targeting pro-inflammatory mediators (eg, interleukin (IL) 6 and 8) or post-receptor signaling (eg, Burton’s tyrosine kinase, 9) after haemorrhagic shock in rodents dramatically reduces early organ injury. However, based on the many failed trials targeting the immune response in sepsis, another common cause of acute SIRS leading to MODS [10], many intensivists would likely caution against relying on data from rodent models to guide trials in humans. Conversely, those working in basic trauma research frequently point to the unique characteristics of trauma, such as the precise knowledge of the time of onset and the unique nature of the non-infectious inflammatory response after trauma and shock as a reason to consider anti-inflammatory agents in trauma. Based on an article in this issue of Intensive Care Medicine [11], the debate on whether and how to target the inflammatory response following trauma is likely to substantially shift. Shepherd and co-workers report the results of the TOP-ART trial that tested the safety and effectiveness of the anti-malarial, artesunate, to reduce MODS at 48 h in severely injured trauma patients. Artesunate was reasoned to be a good agent for the trial because of its impressive safety record in patients with severe malaria, its known anti-inflammatory properties, and because artesunate significantly reduced early organ damage in a well-calibrated model of hemorrhagic shock in rats [12]. The investigators are to be applauded for the well-planned and executed trial design that included, enrollment criteria targeting a high MODS cohort (adult massive hemorrhage protocol patients), informed consent, drug administration within 4 h of injury using a parallel group two-stage dosing regimen, and frequent post-dosing sampling to confirm adequate drug levels. Importantly, serious adverse events were monitored after every 15 patients by a Drug Monitoring Committee. The trial was ended early after 90 patients had been randomized to artesunate or placebo instead of the planned 105 patients due to a higher incidence of venous thromboembolic events in the artesunate group (3 …
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DOI：
10.1073/pnas.96.22.12905
发表时间：
1999-10-26
影响因子：
11.1
作者：
Mihalek, RM;Banerjee, PK;Homanics, GE
通讯作者：
Homanics, GE
神经活性类固醇在经期癫痫大鼠模型中增强抗惊厥活性。
影响因子：
5.6
作者：
Reddy,DS;Rogawski,MA
通讯作者：
Rogawski,MA
开发基于神经类固醇的新型精神药物。
影响因子：
--
作者：
D Samba Reddy;Shrinivas K. Kulkarni
通讯作者：
Shrinivas K. Kulkarni
影响因子：
3.6
作者：
Aouad, M.;Petit-Demouliere, N.;Poisbeau, P.
通讯作者：
Poisbeau, P.
内源性神经类固醇的临床潜力。
影响因子：
1.8
作者：
D. Reddy
通讯作者：
D. Reddy