Hirudin ameliorates intestinal radiation toxicity in the rat: support for thrombin inhibition as strategy to minimize side-effects after radiation therapy and as countermeasure against radiation exposure
Hirudin ameliorates intestinal radiation toxicity in the rat: support for thrombin inhibition as strategy to minimize side-effects after radiation therapy and as countermeasure against radiation exposure
复制标题
DOI：
10.1111/j.1538-7836.2004.00960.x
复制
发表时间：
2004-11-01
影响因子：
10.4
通讯作者：
Hauer-Jensen, M
中科院分区：
文献类型：
--
作者：
Wang, J;Zheng, H;Hauer-Jensen, M
背景：小肠是腹部和骨盆恶性肿瘤放射治疗中的剂量限制正常组织，也是非治疗性放射暴露后生存的重要决定因素。包括肠道在内的正常组织的辐射会导致血管抗血栓能力丧失和凝血酶受体上调。辐射引起的内皮功能障碍被认为与早期和延迟的辐射反应有关。因此，凝血酶可能是改善正常组织辐射毒性的潜在靶点。目的：评估直接凝血酶抑制作为小肠辐射毒性的保护策略。方法：将大鼠小肠暴露于局部正伏X射线。从照射前2天到照射后14天输注重组水蛭素、直接凝血酶抑制剂或载体。在照射后2周（早期毒性）和26周（慢性毒性）对肠道放射损伤的结构、细胞和分子方面进行评估。结果：与未照射的肠道相比，照射的肠道表现出组织因子表达增加、酶活性凝血酶的免疫反应性增加以及血管外纤维蛋白（原）沉积增加。水蛭素治疗显着减轻了辐射引起的粘膜损伤（P = 0.04）、反应性肠壁增厚（P = 0.02）、转化生长因子-β免疫反应水平（P = 0.0002）和III型胶原沉积（P = 0.003）。水蛭素处理组和对照组大鼠之间的差异在照射后 2 周比 26 周时更为明显。水蛭素治疗不影响放射后粒细胞浸润。结论：短期凝血酶抑制可减轻肠道放射毒性的重要方面。凝血酶是一个有希望的靶标，可以最大限度地减少癌症放射治疗后的正常组织损伤，以及保护正常组织免受非治疗性辐射暴露的不利影响。
Background: The small bowel is a dose-limiting normal tissue in radiation therapy of malignancies in the abdomen and pelvis, as well as an important determinant of survival after non-therapeutic radiation exposure. Irradiation of normal tissues, including intestine, causes loss of vascular thromboresistance and upregulation of thrombin receptors. Radiation-induced endothelial dysfunction is thought to be involved in both early and delayed radiation responses. Hence, thrombin may be a potential target for ameliorating normal tissue radiation toxicity.Objective: To assess direct thrombin inhibition as a protective strategy against small bowel radiation toxicity.Methods: Rat small intestine was exposed to localized orthovoltage X-radiation. Recombinant hirudin, a direct thrombin inhibitor, or vehicle was infused from 2 days before irradiation to 14 days after irradiation. Structural, cellular, and molecular aspects of intestinal radiation injury were assessed at 2 weeks (early toxicity) and 26 weeks (chronic toxicity) after irradiation.Results: Compared with unirradiated intestine, irradiated intestine showed increased expression of tissue factor, increased immunoreactivity for enzymatically active thrombin, and increased extravascular fibrin(ogen) deposition. Hirudin treatment significantly attenuated radiation-induced mucosal damage (P = 0.04), reactive intestinal wall thickening (P = 0.02), transforming growth factor-beta immunoreactivity levels (P = 0.0002), and collagen III deposition (P = 0.003). The differences between hirudin-treated and control rats were more pronounced at 2 weeks than at 26 weeks after irradiation. Hirudin treatment did not affect postradiation granulocyte infiltration.Conclusions: Short-term thrombin inhibition attenuates important aspects of intestinal radiation toxicity. Thrombin is a promising target for minimizing normal tissue injury after radiation therapy of cancer, as well as for protecting normal tissues from the adverse effects of non-therapeutic radiation exposure.