A novel human fibroblast growth factor treats experimental intestinal inflammation
A novel human fibroblast growth factor treats experimental intestinal inflammation
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DOI：
10.1053/gast.2002.36041
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发表时间：
2002-10-01
期刊：
影响因子：
29.4
通讯作者：
Lichenstein, HS
中科院分区：
文献类型：
--
作者：
Jeffers, M;McDonald, WF;Lichenstein, HS
背景与目的：我们最近发现了人成纤维细胞生长因子信号分子家族中的一个新成员，命名为成纤维细胞生长因子-20。在本研究中，我们在两种急性肠炎动物模型和体外机制研究中检测了该蛋白的活性。方法：用小鼠葡聚糖硫酸钠(DSS)结肠炎模型和大鼠小肠溃疡/炎症模型进行体内实验。检测细胞生长、修复、基因表达(环氧合酶-2[COX-2]和肠三叶因子[ITF])和前列腺素E-2(PGE(2))水平。结果：在DSS-结肠炎模型中，预防性给予成纤维细胞生长因子-20显著降低了粘膜损伤的严重程度和程度，与给药对照组相比，腔出血、远端结肠水肿、组织学炎症和上皮细胞丢失减少了55%-93%。正常对照组应用成纤维细胞生长因子-20期间未见毒性反应。此外，治疗性应用成纤维细胞生长因子-20可提高该模型的存活率。在吲哚美辛-小肠溃疡/炎症模型中，给予成纤维细胞生长因子-20可减少小肠重量增加、坏死、炎症和体重减轻(与赋形剂对照组相比，减少36%-53%)。体外研究表明，成纤维细胞生长因子-20可促进人肠上皮细胞的生长、修复、COX-2、ITF和PGE2的mRNA表达，并促进人肠成纤维细胞的生长。结论：成纤维细胞生长因子-20在两种实验性肠炎模型中显示了治疗活性，是治疗人类炎症性肠病的一种有前途的新候选药物。
Background & Aims: We recently identified a novel member of the human fibroblast growth factor (FGF) family of signaling molecules, designated FGF-20. In the present study, we examined the activity of this protein in 2 animal models of acute intestinal inflammation and in mechanistic studies in vitro. Methods: In vivo experiments consisted of a murine dextran sulfate sodium (DSS) model of colitis and a rat indomethacin model of small intestinal ulceration/inflammation. Cell growth, restitution, gene expression (cyclooxygenase-2 [COX-2] and intestinal trefoil factor [ITF]), and prostaglandin E-2 (PGE(2)) levels were examined in vitro. Results: In the DSS-colitis model, prophylactic administration of FGF-20 significantly reduced the severity and extent of mucosal damage as indicated by a 55%-93% reduction in luminal blood loss, distal colonic edema, histologic inflammation, and epithelial cell loss relative to animals administered vehicle control. No toxicity was noted during administration of FGF-20 to normal controls. In addition, therapeutic administration of FGF-20 enhanced survival in this model. In the indomethacin-small bowel ulceration/inflammation model, administration of FGF-20 reduced small intestinal weight gain, necrosis, inflammation, and weight loss (36%-53% relative to vehicle control). In vitro studies demonstrated that FGF-20 stimulates growth, restitution, mRNA expression of COX-2 and ITF, and PGE2 levels in human intestinal epithelial cells and enhances the growth of human intestinal fibroblasts. Conclusions: FGF-20, having demonstrated therapeutic activity in 2 experimental models of intestinal inflammation, represents a promising new candidate for the treatment of human inflammatory bowel disease.