Suppression of the clinical and cytokine response to endotoxin by RWJ-67657, a p38 mitogen-activated protein-kinase inhibitor, in healthy human volunteers
Suppression of the clinical and cytokine response to endotoxin by RWJ-67657, a p38 mitogen-activated protein-kinase inhibitor, in healthy human volunteers
复制标题
DOI：
10.1046/j.1365-2249.2001.01485.x
复制
发表时间：
2001-04-01
影响因子：
4.6
通讯作者：
Tulleken, JE
中科院分区：
文献类型：
--
作者：
Fijen, JW;Zijlstra, JG;Tulleken, JE
尽管人们试图干预免疫系统紊乱的潜在机制，但导致多器官衰竭和死亡的脓毒症仍然是重症监护医学的一个主要问题。这不仅是因为对脓毒症的免疫系统的了解持续缺乏，而且也是因为缺乏足够的干预工具。P38丝裂原活化蛋白激酶(P38MAPK)的抑制剂已被用于研究免疫反应的信号通路。体外和动物研究表明，阻断p38MAPK可以减轻内毒素血症后的促炎反应，提高存活率。利用健康志愿者的内毒素血症模型，我们评估了口服吡啶类咪唑类药物RWJ-67657抑制p38MAPK后对临床和细胞因子反应的抑制作用。测量临床参数体温、血压、心率。用双抗体夹心法测定24 h内不同时间点的促炎性细胞因子肿瘤坏死因子-α、白介素6和白介素8的水平。药物毒性通过常规临床和实验室检查进行评估。单剂量RWJ-67657后，体温和血压反应保持在基础水平。对TNF-α、IL-6和IL-8反应的抑制呈剂量依赖性。在最大剂量下，促炎症细胞因子的血清峰值水平降低了90%以上。没有药物相关的毒性。解释：我们得出结论，rWJ-67657抑制p38MAPK可能是一种干预脓毒症和其他炎症性疾病紊乱免疫反应的工具。
Sepsis resulting in multiorgan failure and death is still a major problem in intensive care medicine, despite extensive attempts to interfere in the supposed underlying mechanism of a deranged immune system. This is not only due to the persistent lacunae in knowledge about the immune system in sepsis but also due to the lack of sufficient instruments for intervention. Inhibitors of the p38 mitogen-activated protein kinase (p38MAPK) have been used to study the signalling pathway of the immune response. In vitro and animal studies have demonstrated that blocking p38MAPK could mitigate the proinflammatory response and improve survival after endotoxaemia.Using an endotoxaemia model in healthy human volunteers we evaluated the attenuation of clinical and cytokine response to endotoxin after inhibition of p38MAPK by an oral dose of RWJ-67657, a pyrindinyl imidazole. We measured the clinical parameters temperature, blood pressure and heart rate. The proinflammatory cytokines tumour necrosis factor-alpha, interleukin-6 and interleukin-8 were measured by ELISA at various points during a 24-h period. Drug toxicity was evaluated by routine clinical and laboratory examinations.After a single dose dose of RWJ-67657 the temperature and blood pressure response remained at the basal level. The inhibition of TNF-alpha, IL-6 and IL-8 response was a dose dependent. With the maximum dosage, reduction in peak serum levels of the proinflammatory cytokines was greater than 90%. There was no drug-related toxicity.Interpretation:We conclude that inhibition of p38MAPK by RWJ-67657 might be a tool to intervene in the deranged immune response in sepsis and other inflammatory diseases.