Neutrophil-independent mechanisms of caspase-1- and IL-18-mediated ischemic acute tubular necrosis in mice.
Neutrophil-independent mechanisms of caspase-1- and IL-18-mediated ischemic acute tubular necrosis in mice.
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DOI：
10.1172/jci15623
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发表时间：
2002-10
期刊：
影响因子：
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通讯作者：
V. Y. Melnikov;S. Faubel;B. Siegmund;M. Lucia;D. Ljubanović;C. Edelstein
中科院分区：
文献类型：
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作者：
V. Y. Melnikov;S. Faubel;B. Siegmund;M. Lucia;D. Ljubanović;C. Edelstein
最近描述了半胱天冬酶-1介导的促炎细胞因子IL-18的产生在缺血性急性肾功能衰竭（ARF）中的损伤作用，我们在此报告了新开发的半胱天冬酶抑制剂Quinoline-Val-Asp（Ome）-CH（2）-OPH（OPH-001）对缺血性ARF中半胱天冬酶-1，IL-18，中性粒细胞浸润和肾功能的影响。与溶剂处理的小鼠相比，用OPH-001处理的患有缺血性ARF的C57 BL/6小鼠的血尿素氮（BUN）和血清肌酐显著（100%）降低，并且形态学急性肾小管坏死（ATN）评分高度显著降低。OPH-001显著降低缺血性ARF期间caspase-1活性和IL-18的增加，并防止中性粒细胞浸润肾脏。为了评价中性粒细胞浸润的缺乏是否有助于防止缺血性ARF，开发了中性粒细胞耗竭模型。中性粒细胞耗竭小鼠在缺血性ARF期间血清肌酐小幅（18%）降低，但尽管肾脏中缺乏中性粒细胞浸润，ATN评分未降低。值得注意的是，caspase-1活性和IL-18在ARF的嗜中性粒细胞耗竭小鼠的肾脏中显著增加。此外，与溶剂处理的嗜中性粒细胞耗竭小鼠相比，IL-18抗血清处理的嗜中性粒细胞耗竭小鼠的缺血性ARF血清肌酐显著降低（75%），ATN评分显著降低。这些结果表明，IL-18介导的缺血性ARF的一种新的非嗜中性粒细胞依赖性机制。
Having recently described the injurious role of caspase-1-mediated production of the proinflammatory cytokine IL-18 in ischemic acute renal failure (ARF), we report here on the effect of the newly developed caspase inhibitor Quinoline-Val-Asp(Ome)-CH(2)-OPH (OPH-001) on caspase-1, IL-18, neutrophil infiltration, and renal function in ischemic ARF. C57BL/6 mice with ischemic ARF treated with OPH-001 had a marked (100%) reduction in blood urea nitrogen (BUN) and serum creatinine and a highly significant reduction in morphological acute tubular necrosis (ATN) score compared with vehicle-treated mice. OPH-001 significantly reduced the increase in caspase-1 activity and IL-18 and prevented neutrophil infiltration in the kidney during ischemic ARF. To evaluate whether this lack of neutrophil infiltration was contributing to the protection against ischemic ARF, a model of neutrophil depletion was developed. Neutrophil-depleted mice had a small (18%) reduction in serum creatinine during ischemic ARF but no reduction in ATN score despite a lack of neutrophil infiltration in the kidney. Remarkably, caspase-1 activity and IL-18 were significantly increased in the kidney in neutrophil-depleted mice with ARF. In addition, IL-18 antiserum-treated neutrophil-depleted mice with ischemic ARF had a significant (75%) reduction in serum creatinine and a significant reduction in ATN score compared with vehicle-treated neutrophil-depleted mice. These results suggest a novel neutrophil-independent mechanism of IL-18-mediated ischemic ARF.