A Controlled Trial of Tyrosine Kinase Inhibitors in a Canine Model of Septic Sho

脓毒性休克似乎是由细胞因子的过度释放引起的[例如，肿瘤坏死因子-α（TNF-α）、IL-2等]和其它促炎物质[例如，一氧化氮（NO）]从单核细胞/巨噬细胞谱系的细胞中释放。这些细胞因子的产生以及它们的作用由诱导蛋白酪氨酸磷酸化的信号转导事件介导。理论上，抑制蛋白酪氨酸磷酸化可能对脓毒症有益。这些化合物将阻断依赖于酪氨酸磷酸化的潜在高细胞因子产生。这些蛋白激酶抑制剂将阻断细菌产物对细胞激酶的激活或产生以及细胞因子对靶细胞的作用。Tyrphostins AG 126和AG 556都是蛋白激酶抑制剂，并且已经显示在LPS和活细菌攻击期间改善小动物模型中的结果。此外，AG 126和AG 556均显示在体外抑制LPS诱导的犬外周血单核细胞的TNF产生。在我们开始人体临床试验以确定这些化合物的有效性和安全性之前，需要在大型动物模型中进行研究。我们与Novogrodsky博士及其同事合作，在犬腹膜炎模型中评估了AG 126和AG 556。在一项为期6个月的100只动物的对照临床试验中，AG 556而不是AG 126显著改善了犬败血性休克期间的存活率并预防了多器官衰竭。这种治疗剂（AG 556）正在进行人体临床试验。

Septic shock appears to result from excessive release of cytokines [e.g., tumor necrosis factor-a (TNF-a), IL-2, etc.] and other pro-inflammatory substances [e.g., nitric oxide (NO)] from cells of the monocyte/macrophage lineage in response to infection or lipopolysaccharide (LPS) administration. The production of these cytokines, as well as their action, is mediated by signal transduction events which induce protein tyrosine phosphorylation. Theoretically, inhibition of protein tyrosine phosphorylation may be beneficial in sepsis. These compounds would block the potentially high cytokine production which is dependent on tyrosine phosphorylation. These protein kinase inhibitors would block both activation or production of cytokinase by bacterial products and the effects of cytokines on target cells. Tyrphostins AG 126 and AG 556 are both protein kinase inhibitors and have been shown to improve outcome in small animal models during both LPS and live bacterial challenge. Further, both AG 126 and AG 556 have been shown to inhibit LPS-induced TNF production from dog peripheral blood mononuclear cells, in vitro. Studies in large animal model are needed before we can begin human clinical trials to establish efficacy and safety of these compounds. In collaboration with Dr. Novogrodsky and his colleagues, we evaluated AG 126 and AG 556 in our canine peritonitis model. In a controlled clinical trial in 100 animals over 6 months, AG 556 but not AG 126 significantly improved survival and prevented multiorgan failure during canine septic shock. This therapeutic agent (AG556) is proceeding to human clinical trials.