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Basic study on development of combination treatments for curative radiotherapy and surgery using regererative medicine

再生医学开展根治性放疗和手术联合治疗的基础研究

基本信息

批准号：
14571293
负责人：
SUGIYAMA Kenji
金额：
$ 2.11万
依托单位：
National Cancer Center Research Institute
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

Pre-operative cancer radiotherapy frequently prevents the following surgical operation, since effective dose of ionized radiation induces wound complication. The purposes in this study are to clarify causes for the impaired wound healing, and to accelerate the wound healing using animal models.One week after X-ray (30Gy) irradiation to the back of rat, full-thickness skin (2 cm-length) was incised and sutured. Impairment of wound healing was characterized by depilation, continuous inflammation, epidermal desquamation and acanthosis, in addition to absence of granulation tissue and impaired vascularization.When incisional wounds of irradiated and non-irradiated skins were sutured each other as a model of end-to-end implantation, granulation tissues in the non-irradiated region expanded in the irradiated region of the skin. The skin of mouse, whose bone marrow has been replaced with GFP-expressing bone marrow cells, was wounded. In the non-irradiated skin, number of GFP-positive cells in … More creased after wounding, whereas, number of GFP-positive cells decreased in the irradiated skin. These findings suggested that infiltration of bone marrow-derived fibrocytes and/or activation of dermal fibroblasts may be disordered in the irradiated skin.The expression of transforming growth factor-β(TGF-β) increased during wound healing of irradiated skins. So, to interfere with TGF-β signaling, recombinant interferon-γ was subcutaneously injected. Granulation formation by myofibroblasts was found in the region of subepidermal bulla in the irradiated skin. Moreover, the inhibitor of TGF-β receptor kinase accelerated the wound healing by suppressing continuous inflammation and ancanthosis.Next, rat groins were irradiated, and the femoral artery and vein in skin flap were anastomosed with that of recipient rat. The irradiated femoral artery showed pachytic tunica intima, and angeitis.In conclusion, to suppress radiation-induced impairment of wound healing, the treatment to enhance the recruitment of bone marrow derived fibrocytes and vascularization may be effective in addition to the treatment of inhibitors for TGF-β signaling. Less

由于有效剂量的电离辐射会引起伤口并发症，术前癌症放射治疗经常阻止后续的外科手术。本研究采用大鼠背部X线照射（30 Gy）后1周，切取2cm厚的全层皮肤，缝合，观察其愈合情况。伤口愈合障碍的特征是脱毛、持续性炎症、表皮脱落和棘皮症，以及肉芽组织的缺乏和血管化受损。当将照射和未照射皮肤的切口伤口彼此缝合作为端对端植入模型时，非照射区域的肉芽组织在皮肤的照射区域中扩张。骨髓已被表达GFP的骨髓细胞取代的小鼠皮肤受伤。在未照射的皮肤中， ...更多信息伤后增加，而GFP阳性细胞的数量在照射皮肤中减少。结果提示，照射后皮肤中骨髓源性纤维细胞浸润和/或真皮成纤维细胞活化发生紊乱，皮肤创伤愈合过程中转化生长因子-β（TGF-β）表达增加。因此，为了干扰TGF-β信号传导，皮下注射重组干扰素-γ。肉芽形成的肌成纤维细胞被发现在该地区的表皮下大疱在照射皮肤。TGF-β受体激酶抑制剂通过抑制持续性炎症反应，促进创面愈合。照射大鼠腹股沟，将皮瓣内股动、静脉与受体大鼠股动、静脉吻合。照射后的股动脉显示厚图尼卡内膜和血管炎。总之，除了TGF-β信号传导抑制剂的治疗外，增强骨髓源性纤维细胞的募集和血管化的治疗可能是抑制辐射诱导的伤口愈合障碍的有效方法。少