Okoshi Kae, Kubo Hajime, Nagayama Satoshi, Tabata Chiharu, Kadokawa Yoshio, Hisamori Shigeo, Yonenaga Yoshikuni, Fujimoto Akihisa, Mori Akira, Onodera Hisashi, Watanabe Go, Sakai Yoshiharu
Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
J Surg Res. 2008 Nov;150(1):53-9. doi: 10.1016/j.jss.2007.12.762. Epub 2008 Jan 9.
Intestinal fibrosis leading to severe bowel dysmobility or obstruction is a troublesome adverse effect of abdominal or pelvic radiation therapy. We have recently reported that all-trans-retinoic acid (ATRA) prevents radiation- or bleomycin-induced lung fibrosis. Here, we examined the impact of ATRA on the mouse model of radiation-induced intestinal fibrosis.
We evaluated the histology of late radiation fibrosis in surgical samples. We then performed histological examinations and quantitative measurements of mRNA of interleukin-6 and transforming growth factor-beta(1) in intestinal tissues of irradiated mice with or without intraperitoneal administration of ATRA and investigated the effect of ATRA on the transdifferentiation and the production of collagen of irradiated human intestinal fibroblasts.
Human samples of late radiation enteritis showed thickened submucosa and serosa, consistent with mouse model. Administration of ATRA attenuated irradiation-induced intestinal fibrosis and reduced mRNA of interleukin-6 and transforming growth factor-beta(1). In vitro studies disclosed that ATRA suppressed the transdifferentiation of irradiated intestinal fibroblasts and diminished the production of collagen from the cells.
Our findings indicate that ATRA ameliorates irradiation-induced intestinal fibrosis. ATRA could be a novel approach in the treatment of fibrosis associated with chronic radiation enteritis.
肠道纤维化导致严重的肠道运动障碍或梗阻是腹部或盆腔放射治疗令人困扰的不良反应。我们最近报道，全反式维甲酸（ATRA）可预防辐射或博来霉素诱导的肺纤维化。在此，我们研究了ATRA对辐射诱导的肠道纤维化小鼠模型的影响。
我们评估了手术样本中晚期放射性纤维化的组织学情况。然后，我们对接受或未接受腹腔注射ATRA的受辐照小鼠的肠道组织进行了组织学检查，并对白细胞介素-6和转化生长因子-β（1）的mRNA进行了定量测量，还研究了ATRA对受辐照的人肠道成纤维细胞转分化和胶原蛋白产生的影响。
晚期放射性肠炎的人体样本显示黏膜下层和浆膜层增厚，这与小鼠模型一致。给予ATRA可减轻辐射诱导的肠道纤维化，并降低白细胞介素-6和转化生长因子-β（1）的mRNA水平。体外研究表明，ATRA可抑制受辐照肠道成纤维细胞的转分化，并减少细胞胶原蛋白的产生。
我们的研究结果表明，ATRA可改善辐射诱导的肠道纤维化。ATRA可能是治疗与慢性放射性肠炎相关纤维化的一种新方法。
