Mathiak G, Grass G, Herzmann T, Luebke T, Zetina C C, Boehm S A, Bohlen H, Neville L F, Hoelscher A H
I. Department of Surgery, University of Cologne, Cologne, Germany.
Br J Pharmacol. 2000 Oct;131(3):383-6. doi: 10.1038/sj.bjp.0703629.
The effect of acetyl - tyrosyl-valyl-alanyl-aspartyl - chloromethylketone (ac-YVAD-cmk), an irreversible caspase-1 (IL-1beta converting enzyme, ICE) inhibitor on mortality, leukocyte and platelet counts and cytokine levels was investigated in a double-blind rat model of endotoxaemia. Intravenous (i.v.) bolus administration of lipopolysaccharide (LPS) (25-75 mg kg(-1), n=12 per group) to anaesthetized rats induced a dose dependent increase in mortality over 8 h (LD(50)=48 mg kg(-1)). During this period, animals became leukopenic and thrombocytopenic. Serum levels of IL-beta, IL-6, and TNF-alpha were highly elevated. Pretreatment of rats with ac-YVAD-cmk at a dose of 12.5 micromol kg(-1) significantly reduced mortality from 83 to 33% using Log Rank analysis. However, ac-YVAD-cmk did not modify blood cell counts or cytokine profiles as compared with the LPS-drug vehicle group. These data lay credence to the potential importance of caspase-1-inhibition in modifying the inflammatory response to endotoxin. Further investigations are warranted in understanding the relationship between caspase-1 inhibition, cytokine production and animal survival in different experimental paradigms of sepsis.
在双盲内毒素血症大鼠模型中，研究了不可逆的半胱天冬酶 -1（白细胞介素 -1β转换酶，ICE）抑制剂乙酰 - 酪氨酰 - 缬氨酰 - 丙氨酰 - 天冬氨酰 - 氯甲基酮（ac - YVAD - cmk）对死亡率、白细胞和血小板计数以及细胞因子水平的影响。向内毒素血症大鼠模型静脉推注脂多糖（LPS）（25 - 75 mg·kg⁻¹，每组n = 12），诱导其在8小时内死亡率呈剂量依赖性增加（半数致死量LD(50)=48 mg·kg⁻¹）。在此期间，动物出现白细胞减少和血小板减少。血清白细胞介素 -β、白细胞介素 -6和肿瘤坏死因子 -α水平显著升高。使用对数秩检验分析，以12.5 μmol·kg⁻¹剂量的ac - YVAD - cmk预处理大鼠，可使死亡率从83%显著降低至33%。然而，与LPS - 药物载体组相比，ac - YVAD - cmk并未改变血细胞计数或细胞因子谱。这些数据证实了半胱天冬酶 -1抑制在改变对内毒素的炎症反应中的潜在重要性。有必要进一步研究以了解在不同脓毒症实验范式中半胱天冬酶 -1抑制、细胞因子产生与动物存活之间的关系。
