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

脓毒性休克似乎是由于单核/巨噬细胞系在感染或脂多糖（LPS）给药时过度释放细胞因子[如肿瘤坏死因子-a （TNF-a）、IL-2等]和其他促炎物质[如一氧化氮（NO）]所致。这些细胞因子的产生及其作用是由诱导蛋白酪氨酸磷酸化的信号转导事件介导的。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的产生。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，在LPS和活细菌攻击的小动物模型中显示出改善结果。此外，在体外实验中，AG 126和AG 556均可抑制lps诱导的犬外周血单个核细胞产生TNF。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，需要进行大型动物模型研究。在Novogrodsky博士及其同事的合作下，我们在犬腹膜炎模型中评估了ag126和AG 556。在一项为期6个月的100只动物对照临床试验中，AG 556而不是AG 126显著提高了犬感染性休克的存活率，并防止了多器官衰竭。该治疗剂（AG556）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.