Wang J, Zheng H, Hauer-Jensen M
Departments of Surgery and Pathology, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA.
J Pharmacol Exp Ther. 2001 Apr;297(1):35-42.
The somatostatin analog octreotide was recently found to ameliorate radiation-induced tissue injury in rat intestine. The present study addressed whether octreotide reduces chronic intestinal radiation fibrosis, whether enteroprotection is conferred by direct or indirect mechanisms, and whether the effects are dose-dependent. Using a rat model designed for fractionated irradiation, a segment of small intestine was sham-irradiated or exposed to 67.2 Gy X-radiation in 16 daily fractions. Octreotide (0, 2, or 10 microg/kg/h) was administered subcutaneously by osmotic minipumps for 4 weeks, from 2 days before to 10 days after irradiation. Tissue injury was assessed at 2 weeks (early phase) and 26 weeks (chronic phase) by quantitative histopathology and morphometry. Epithelial and smooth muscle cell proliferation was assessed by proliferating cell nuclear antigen staining; connective tissue mast cell hyperplasia by metachromatic staining; and TGF-beta1 and collagen protein and mRNA by quantitative immunohistochemistry, in situ hybridization, and/or real-time fluorogenic probe reverse transcription-polymerase chain reaction. Octreotide conferred dose-dependent protection against early (p = 0.0003) and chronic (p < 0.0001) tissue injury. Octreotide abrogated radiation-induced chronic increases in extracellular matrix-associated TGF-beta (p < 0.0001), collagen I (p = 0.0001), and collagen III (p = 0.0002) immunoreactivity. Octreotide did not affect radiation-induced changes in steady-state TGF-beta1 mRNA levels, mast cell hyperplasia, or smooth muscle cell proliferation. Octreotide reduced crypt epithelial cell proliferation (p = 0.01), but did not otherwise affect unirradiated intestine. Octreotide confers dose-dependent protection against delayed small bowel radiation toxicity and ameliorates radiation fibrosis predominantly by reducing acute mucosal injury. These data strengthen the rationale for using somatostatin analogs as enteroprotective agents in clinical radiation therapy.
生长抑素类似物奥曲肽最近被发现可改善大鼠肠道的辐射诱导组织损伤。本研究探讨了奥曲肽是否能减轻慢性肠道辐射纤维化，肠保护是通过直接还是间接机制实现的，以及这些效应是否具有剂量依赖性。使用设计用于分次照射的大鼠模型，一段小肠接受假照射或在16天内每天接受67.2 Gy的X射线照射。奥曲肽（0、2或10微克/千克/小时）通过渗透微型泵皮下给药4周，从照射前2天至照射后10天。在2周（早期）和26周（慢性期）通过定量组织病理学和形态学评估组织损伤。通过增殖细胞核抗原染色评估上皮和平滑肌细胞增殖；通过异染性染色评估结缔组织肥大细胞增生；通过定量免疫组织化学、原位杂交和/或实时荧光探针逆转录-聚合酶链反应评估转化生长因子-β1、胶原蛋白以及蛋白质和mRNA。奥曲肽对早期（p = 0.0003）和慢性（p < 0.0001）组织损伤具有剂量依赖性保护作用。奥曲肽消除了辐射诱导的细胞外基质相关转化生长因子-β（p < 0.0001）、I型胶原蛋白（p = 0.0001）和III型胶原蛋白（p = 0.0002）免疫反应性的慢性增加。奥曲肽不影响辐射诱导的稳态转化生长因子-β1 mRNA水平、肥大细胞增生或平滑肌细胞增殖的变化。奥曲肽减少了隐窝上皮细胞增殖（p = 0.01），但对未照射的肠道没有其他影响。奥曲肽对延迟性小肠辐射毒性具有剂量依赖性保护作用，主要通过减轻急性黏膜损伤来改善辐射纤维化。这些数据加强了在临床放射治疗中使用生长抑素类似物作为肠保护剂的理论依据。
