Structural Stability of Human Fibroblast Growth Factor-1 Is Essential for Protective Effects Against Radiation-Induced Intestinal Damage
Structural Stability of Human Fibroblast Growth Factor-1 Is Essential for Protective Effects Against Radiation-Induced Intestinal Damage
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DOI：
10.1016/j.ijrobp.2012.04.042
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发表时间：
2013-02-01
影响因子：
7
通讯作者：
Imai, Takashi
中科院分区：
文献类型：
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作者：
Nakayama, Fumiaki;Umeda, Sachiko;Imai, Takashi
目的：人成纤维细胞生长因子-1（FGF 1）对肠道具有辐射防护作用，尽管其结构不稳定性限制了其实际应用的潜力。产生了几种稳定的FGF 1突变体，其以野生型FGF 1、单突变体（Q40 P、S47 I和H93 G）、Q40 P/S47 I和Q40 P/S47 I/H93 G的顺序增加稳定性。本研究评估了FGF 1的结构稳定性的贡献，其radioprotective effect.Methods和Materials：每个FGF 1突变体在没有肝素的情况下，在全身照射（TBI）前或后24小时，在8-12戈伊的γ射线，BALB/c小鼠腹腔内给药。结果：Q40 P/S47 I/H93 G在体外能激活FGF受体的所有亚型，在无外源性或内源性肝素的情况下，其激活强度明显高于野生型。在10或12戈伊TBI后，用Q40 P/S47 I/H93 G预照射治疗比野生型FGF 1显著增加隐窝存活，并且在10、11或12戈伊TBI后用Q40 P/S47 I/H93 G照射后治疗有效促进隐窝存活。此外，照射后用Q40 P/S47 I/H93 G处理可显著促进隐窝细胞增殖、隐窝深度和上皮分化。FGF 1突变体的稳定性水平与它们在体外的促有丝分裂活性在肝素的情况下，然而，预照射处理的突变体增加的隐窝数量几乎相同的水平Q40 P/S47 I/H93 G。在10戈伊TBI后24 h给予时，所有FGF 1突变体均比野生型FGF 1增加隐窝存活，并且Q40 P/S47 I/H93 G在辐射损伤后的肠上皮细胞中具有最强的促有丝分裂作用。结论：TGF-1结构稳定性的增强可能与其对放射性肠损伤的保护作用有关。因此，Q40 P/S47 I/H93 G是最有希望用于放射性胃肠综合征临床应用的候选物之一。(C)2013 Elsevier Inc.
Purpose: Human fibroblast growth factor-1 (FGF1) has radioprotective effects on the intestine, although its structural instability limits its potential for practical use. Several stable FGF1 mutants were created increasing stability in the order, wild-type FGF1, single mutants (Q40P, S47I, and H93G), Q40P/S47I, and Q40P/S47I/H93G. This study evaluated the contribution of the structural stability of FGF1 to its radioprotective effect.Methods and Materials: Each FGF1 mutant was administered intraperitoneally to BALB/c mice in the absence of heparin 24 h before or after total body irradiation (TBI) with gamma-rays at 8-12 Gy. Several radioprotective effects were examined in the jejunum.Results: Q40P/S47I/H93G could activate all subtypes of FGF receptors in vitro much more strongly than the wild-type without endogenous or exogenous heparin. Preirradiation treatment with Q40P/S47I/H93G significantly increased crypt survival more than wild-type FGF1 after TBI at 10 or 12 Gy, and postirradiation treatment with Q40P/S47I/H93G was effective in promoting crypt survival after TBI at 10, 11, or 12 Gy. In addition, crypt cell proliferation, crypt depth, and epithelial differentiation were significantly promoted by postirradiation treatment with Q40P/S47I/H93G. The level of stability of FGF1 mutants correlated with their mitogenic activities in vitro in the absence of heparin; however, preirradiation treatment with the mutants increased the crypt number to almost the same level as Q40P/S47I/H93G. When given 24 h after TBI at 10 Gy, all FGF1 mutants increased crypt survival more than wild-type FGF1, and Q40P/S47I/H93G had the strongest mitogenic effects in intestinal epithelial cells after radiation damage. Moreover, Q40P/S47I/H93G prolonged mouse survival after TBI because of the repair of intestinal damage.Conclusion: These findings suggest that the structural stability of FGF1 can contribute to the enhancement of protective effects against radiation-induced intestinal damage. Therefore, Q40P/S47I/H93G is pharmacologically one of the most promising candidates for clinical applications for radiation-induced gastrointestinal syndrome. (C) 2013 Elsevier Inc.