Byrne Fergus R, Farrell Catherine L, Aranda Richard, Rex Karen L, Scully Sheila, Brown Heather L, Flores Silvia A, Gu Li H, Danilenko Dimitry M, Lacey David L, Ziegler Thomas R, Senaldi Giorgio
Department of Pharmacology, Amgen, Thousand Oaks, California 91320, USA.
Am J Physiol Gastrointest Liver Physiol. 2002 Apr;282(4):G690-701. doi: 10.1152/ajpgi.00314.2001.
There is an acute need for effective therapy for inflammatory bowel disease (IBD), particularly at the level of repair of the damaged epithelium. We evaluated the efficacy of recombinant human keratinocyte growth factor (rHuKGF) in both the dextran sodium sulfate (DSS) and the CD4(+)CD45RB(Hi) T cell transfer models of IBD. Disease was induced either by the ad libitum administration to normal mice of 4% DSS in the drinking water or by the injection of 4 x 10(5) CD4(+)CD45RB(Hi) T cells into immunodeficient scid/scid mice. rHuKGF was administered by subcutaneous injection at doses of 1.0 or 3.0 mg/kg in both preventative and therapeutic regimens during both studies. rHuKGF significantly improved survival and body weight loss in the DSS model in both preventative and therapeutic dosing regimens. It also improved diarrhea, hematochezia, and hematological parameters, as well as large intestine histopathology. In the T cell transfer model, rHuKGF improved body weight loss, diarrhea, and levels of serum amyloid A, as well as large intestine histopathology. In both models of IBD, the colonic levels of intestinal trefoil factor (ITF) were elevated by the disease state and further elevated by treatment with rHuKGF. These data suggest that rHuKGF may prove useful in the clinical management of IBD and its effects are likely mediated by its ability to locally increase the levels of ITF.
炎症性肠病（IBD）亟需有效的治疗方法，尤其是在受损上皮的修复层面。我们在葡聚糖硫酸钠（DSS）和IBD的CD4(+)CD45RB(Hi) T细胞转移模型中评估了重组人角质形成细胞生长因子（rHuKGF）的疗效。通过给正常小鼠自由饮用含4% DSS的水或向免疫缺陷的scid/scid小鼠注射4×10(5)个CD4(+)CD45RB(Hi) T细胞来诱导疾病。在两项研究的预防和治疗方案中，rHuKGF均通过皮下注射给药，剂量为1.0或3.0 mg/kg。在DSS模型中，无论是预防给药还是治疗给药方案，rHuKGF均显著提高了生存率并减轻了体重下降。它还改善了腹泻、便血和血液学参数，以及大肠组织病理学。在T细胞转移模型中，rHuKGF改善了体重下降、腹泻和血清淀粉样蛋白A水平，以及大肠组织病理学。在两种IBD模型中，疾病状态会使结肠中肠三叶因子（ITF）水平升高，而rHuKGF治疗会使其进一步升高。这些数据表明，rHuKGF可能在IBD的临床管理中有用，其作用可能是通过局部增加ITF水平来介导的。
