Blocking interleukin-18: a tumor necrosis factor-alpha lesson already learned.
Blocking interleukin-18: a tumor necrosis factor-alpha lesson already learned.
复制标题
阻断白细胞介素 18：肿瘤坏死因子 α 的教训。
DOI：
10.1097/01.ccm.0000080490.82918.5f
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发表时间：
2003
影响因子：
8.8
通讯作者：
Moldawer,LyleL
中科院分区：
文献类型：
--
作者：
Efron,PhilipA;Moldawer,LyleL
Remick博士的优雅研究为败血症复杂综合征的谜题增添了另一个部分。他的实验报告在这一问题的重症监护医学（1）已经证明了内源性产生的白细胞介素（IL）-18在保护小鼠免于败血症死亡的重要性，在一个明确的小鼠模型盲肠结扎和穿孔（CLP）。然而，调查结果并不像预期的那样简单或明确。在本报告中，Remick博士和他的同事已经证明，用一种新型IL-18结合蛋白阻断内源性IL-18反应对结果有不同的影响，这取决于初始炎症反应的严重程度（通过CLP后6小时测量的血浆IL-6浓度确定）。在具有更温和的炎症反应的动物中，阻断内源性IL-18反应实际上使结果恶化，而相同的治疗对表现出更大炎症反应的动物的结果没有显著影响。Remick博士本人在早期的综述中已经指出，对于脓毒症这样复杂的综合征，阻断单一细胞因子可能过于简单化（2）。此外，Remick博士正确地认为，需要更好地了解脓毒症的病理学，以同时操纵多种细胞因子的活性，这可能包括同时增强和抑制不同的介质。这种治疗无疑是患者、时间和器官特异性的，然而，与这项研究相关的一些有趣的观点需要进一步考虑。首先，这些研究清楚地表明，基因相同的小鼠经历了一个可能相同的损伤过程，仍然表现出广泛的炎症反应，并对相同的治疗方案作出不同的反应。据推测，这不是由于作者进行的技术中的固有偏差，而是由于未完全识别或理解的响应变量。其次，Remick博士和他的同事现在已经证实了他们早期的发现，即CLP后6小时获得的血浆IL-6浓度可预测该模型的结果（3）。最后，作者证明了脓毒症小鼠中宿主对IL-18阻断的反应取决于炎症反应的初始严重程度。
Dr. Remick’s elegant research has added yet another piece to the puzzle of the complex syndrome of sepsis. His experiments reported in this issue of Critical Care Medicine (1) have demonstrated the importance of endogenously produced interleukin (IL)-18 in protecting mice from the mortality of sepsis in a well-defined murine model of cecal ligation and puncture (CLP). The findings, however, were not as simple or as clear-cut as might have been expected. In the present report, Dr. Remick and his colleagues have demonstrated that blocking an endogenous IL-18 response with a novel IL-18 binding protein had a variable effect on outcome that was dependent on the severity of the initial inflammatory response (as determined by plasma IL-6 concentrations measured 6 hrs after CLP). In animals with a more modest inflammatory response, blocking an endogenous IL-18 response actually worsened outcome, whereas the same treatment had no significant effect on outcome in the animals manifesting a greater inflammatory response. Dr. Remick himself has already argued in an earlier review that the blockade of a single cytokine is probably too simplistic a treatment approach for as complex a syndrome as sepsis (2). In addition, Dr. Remick has rightfully argued that a greater understanding of the pathology of sepsis will be required to simultaneously manipulate the activity of multiple cytokines, which may include concurrent augmentation and inhibition of different mediators. This therapy will undoubtedly be patient, time, and organ specific.However, a number of interesting points associated with this study require further consideration. First, the studies clearly demonstrate that genetically identical mice undergoing a presumably identical injury procedure still manifest a widely variant inflammatory response and react differently to the same therapeutic regimen. Presumably, this is not due to inherent deviations in the technique performed by the authors but rather to response variables not fully identified or understood. Second, Dr. Remick and his associates have now confirmed their earlier finding that plasma IL-6 concentrations obtained 6 hrs after CLP predict outcome in this model (3). Finally, the authors demonstrate that the host response to IL-18 blockade in septic mice is dependent on the initial severity of the inflammatory response.