Wang Junru, Zheng Huaien, Kulkarni Ashwini, Ou Xuemei, Hauer-Jensen Martin
Department of Surgery, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA.
Int J Radiat Oncol Biol Phys. 2006 Apr 1;64(5):1528-36. doi: 10.1016/j.ijrobp.2005.12.035.
Mast cells protect against the early manifestations of intestinal radiation toxicity, but promote chronic intestinal wall fibrosis. Intestinal sensory nerves are closely associated with mast cells, both anatomically and functionally, and serve an important role in the regulation of mucosal homeostasis. This study examined the effect of sensory nerve ablation on the intestinal radiation response in an established rat model.
Rats underwent sensory nerve ablation with capsaicin or sham ablation. Two weeks later, a localized segment of ileum was X-irradiated or sham irradiated. Structural, cellular, and molecular changes were examined 2 weeks (early injury) and 26 weeks (chronic injury) after irradiation. The mast cell dependence of the effect of sensory nerve ablation on intestinal radiation injury was assessed using c-kit mutant (Ws/Ws) mast cell-deficient rats.
Capsaicin treatment caused a baseline reduction in mucosal mast cell density, crypt cell proliferation, and expression of substance P and calcitonin gene-related peptide, two neuropeptides released by sensory neurons. Sensory nerve ablation strikingly exacerbated early intestinal radiation toxicity (loss of mucosal surface area, inflammation, intestinal wall thickening), but attenuated the development of chronic intestinal radiation fibrosis (collagen I accumulation and transforming growth factor beta immunoreactivity). In mast cell-deficient rats, capsaicin treatment exacerbated postradiation epithelial injury (loss of mucosal surface area), but none of the other aspects of radiation injury were affected by capsaicin treatment.
Ablation of capsaicin-sensitive enteric neurons exacerbates early intestinal radiation toxicity, but attenuates development of chronic fibroproliferative changes. The effect of capsaicin treatment on the intestinal radiation response is partly mast cell dependent.
肥大细胞可预防肠道辐射毒性的早期表现，但会促进慢性肠壁纤维化。肠道感觉神经在解剖学和功能上均与肥大细胞密切相关，在调节黏膜稳态中起重要作用。本研究在已建立的大鼠模型中检测了感觉神经消融对肠道辐射反应的影响。
大鼠接受辣椒素感觉神经消融或假消融。两周后，对一段局部回肠进行X射线照射或假照射。在照射后2周（早期损伤）和26周（慢性损伤）检查结构、细胞和分子变化。使用c-kit突变（Ws/Ws）肥大细胞缺陷大鼠评估感觉神经消融对肠道辐射损伤影响的肥大细胞依赖性。
辣椒素处理导致黏膜肥大细胞密度、隐窝细胞增殖以及感觉神经元释放的两种神经肽P物质和降钙素基因相关肽的表达在基线时降低。感觉神经消融显著加剧了早期肠道辐射毒性（黏膜表面积丧失、炎症、肠壁增厚），但减弱了慢性肠道辐射纤维化的发展（I型胶原蛋白积累和转化生长因子β免疫反应性）。在肥大细胞缺陷大鼠中，辣椒素处理加剧了辐射后上皮损伤（黏膜表面积丧失），但辣椒素处理对辐射损伤的其他方面均无影响。
对辣椒素敏感的肠神经元消融会加剧早期肠道辐射毒性，但会减弱慢性纤维增生性变化的发展。辣椒素处理对肠道辐射反应的影响部分依赖于肥大细胞。
