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/jci200215623
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发表时间：
2002-10-01
影响因子：
15.9
通讯作者：
Edelstein, CL
中科院分区：
文献类型：
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作者：
Melnikov, VY;Faubel, S;Edelstein, CL
在最近描述了caspase-1介导的促炎细胞因子IL-18在缺血性急性肾功能衰竭(ARF)中的损伤作用后，我们报道了新开发的caspase抑制剂Quinoline-Val-Asp(Ome)-CH2-OPH(OPH-001)对缺血性ARF中caspase-1、IL-18、中性粒细胞浸润和肾功能的影响。与赋形剂治疗组相比，OPH-001治疗的C57BL/6缺血性ARF小鼠血尿素氮(BUN)和血肌酐(Scr)显著降低(100%)，形态学急性肾小管坏死(ATN)评分显著降低。Oph-001可显著降低缺血性ARF时caspase-1活性和IL-18的升高，并阻止中性粒细胞在肾脏的浸润。为了评估这种中性粒细胞的缺乏是否有助于对缺血性ARF的保护，建立了一个中性粒细胞耗竭的模型。中性粒细胞耗竭的小鼠在缺血性ARF期间血清肌酐有小幅下降(18%)，但ATN评分没有下降，尽管肾脏中缺乏中性粒细胞的渗透。中性粒细胞耗竭的ARF小鼠肾脏caspase-1活性和IL-18显著升高。此外，IL-18抗血清治疗的中性粒细胞耗竭的缺血性ARF小鼠与赋形剂治疗的中性粒细胞耗竭小鼠相比，血清肌酐显著降低(75%)，ATN评分显著降低。这些结果提示了IL-18介导的缺血性ARF的一种新的中性粒细胞非依赖性机制。
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)-CH2-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.