Apogee Biotechnology Corporation, Hershey Center for Applied Research, 1214 Research Blvd, Suite 1016, Hummelstown, PA 17036, USA.
Inflammopharmacology. 2010 Apr;18(2):73-85. doi: 10.1007/s10787-010-0032-x. Epub 2010 Feb 12.
Activation of sphingosine kinase (SK) is a key response to many inflammatory processes. The present studies test the hypothesis that an orally available SK inhibitor, ABC294640, would be effective in rodent models of Crohn's disease.
Trinitrobenzene sulfonic acid (TNBS) was administered rectally to mice and rats. Rats were treated with ABC294640 orally alone or in combination with olsalazine and disease progression was monitored.
For both rodent species, treatment with ABC294640 attenuated disease progression. Colon samples from the ABC294640-treated animals had improved histology and cytokine parameters when compared with vehicle-treated animals. The expression of SK was similarly increased in TNBS-treated animals and in human colon tissue specimens from inflammatory bowel disease patients relative to normal, control patients.
Sphingosine kinase may be a critical mediator of colonic damage during intestinal inflammation, and pharmacologic inhibitors of this enzyme may prove useful in the treatment of Crohn's disease.
鞘氨醇激酶（SK）的激活是许多炎症过程的关键反应。本研究旨在验证一种口服可用的 SK 抑制剂 ABC294640 对克罗恩病啮齿动物模型有效的假说。
三硝基苯磺酸（TNBS）直肠给药于小鼠和大鼠。大鼠单独口服或联合奥沙拉嗪给予 ABC294640 治疗，并监测疾病进展情况。
对于两种啮齿动物，ABC294640 治疗均减轻了疾病进展。与载体处理动物相比，ABC294640 处理的动物的结肠样本具有改善的组织学和细胞因子参数。在 TNBS 处理的动物以及炎症性肠病患者的人结肠组织标本中，SK 的表达也相应增加，与正常对照患者相比。
鞘氨醇激酶可能是肠道炎症过程中结肠损伤的关键介质，该酶的药理抑制剂可能在治疗克罗恩病方面具有重要作用。
