Lefaix J L, Delanian S, Vozenin M C, Leplat J J, Tricaud Y, Martin M
CEA - DSV - DRR- Laboratoire de Radiobiologie et d'Etude du Génome, CEA-Saclay, Gif sur Yvette, France.
Int J Radiat Oncol Biol Phys. 1999 Mar 1;43(4):839-47. doi: 10.1016/s0360-3016(98)00419-2.
To establish a successful treatment of subcutaneous fibrosis developing after high doses of gamma rays, suitable for use in clinical practice.
We used an animal model of acute localized gamma irradiation simulating accidental overexposure in humans. Three groups of 5 Large White pigs were irradiated using a collimated 192Ir source to deliver a single dose of 160 Gy onto the skin surface (100%) of the outer side of the thigh. A well-defined block of necrosis developed within a few weeks which had healed after 26 weeks to leave a block of subcutaneous fibrosis involving skin and skeletal muscle. One experimental group of 5 pigs was dosed orally for 26 weeks starting 26 weeks after irradiation with 1600 mg/120 kg body weight of pentoxifylline (PTX) included in the reconstituted food during its fabrication, and another group of 5 was dosed orally for the same period with a daily dose of 1600 mg/120 kg body weight of PTX combined with 2000 IU/120 kg body weight of alpha-tocopherol. Five irradiated control pigs were given normal food only. Animals were assessed for changes in the density of the palpated fibrotic block and in the dimensions of the projected cutaneous surface. Depth of scar tissue was determined by ultrasound. Physical and sonographic findings were confirmed by autopsy 26 weeks after treatment started. The density, length, width, and depth of the block of fibrotic scar tissue, and the areas and volume of its projected cutaneous surface, were compared before treatment, 6 and 13 weeks thereafter, and at 26 weeks.
The experimental animals exhibited no change in behavior and no abnormal clinical or anatomic signs. No modifications were observed in the block of fibrotic scar tissue of pigs dosed with PTX alone. However, significant softening and shrinking of this block were noted in the pigs dosed with PTX + alpha-tocopherol 13 weeks after treatment started and at autopsy, when mean regression was approximately 30% for length, approximately 50% for width and depth, and approximately 70% for area and volume. Histologic examination showed completely normal muscle and subcutaneous tissue surrounding the residual scar tissue. The 50% decrease in the linear dimensions of the scar tissue, were comparable to the results obtained in our previous clinical studies, and were highly significant compared to the clinical and autopsy results for the controls. Histologic examination of the residual scar tissue revealed tissue which was more homogenous and less cellular and inflammatory than in control and PTX-dosed pigs. The tissular and cellular immunolocalization of tumor necrosis factor alpha (TNFalpha) was similar in the residual fibrotic tissues of all three groups of pigs, whereas the immunostaining of transforming growth factor beta-1(TGFbeta-1) diminished much more in the residual fibrotic scar tissue of the PTX + alpha-tocopherol-dosed pigs than in the two other groups.
The present results showed a striking regression of the subcutaneous fibrotic scar tissue that develops as a consequence of high doses of gamma rays.
建立一种适用于临床实践的、成功治疗高剂量伽马射线照射后发生的皮下纤维化的方法。
我们使用了一种急性局部伽马照射的动物模型，模拟人类意外过度暴露的情况。三组，每组5只大白猪，使用准直的铱-192源进行照射，在大腿外侧皮肤表面（100%）给予单次剂量160 Gy。几周内形成了明确的坏死块，26周后愈合，留下一块涉及皮肤和骨骼肌的皮下纤维化区域。一组5只猪在照射后26周开始口服给药26周，在配制食物时加入1600 mg/120 kg体重的己酮可可碱（PTX）；另一组5只猪在同一时期口服给药，每日剂量为1600 mg/120 kg体重的PTX与2000 IU/120 kg体重的α-生育酚联合使用。5只照射后的对照猪只给予正常食物。评估动物触诊纤维化块的密度变化以及预计皮肤表面尺寸的变化。通过超声确定瘢痕组织的深度。治疗开始26周后通过尸检确认物理和超声检查结果。比较治疗前、治疗后6周和13周以及26周时纤维化瘢痕组织块的密度、长度、宽度和深度，以及其预计皮肤表面的面积和体积。
实验动物行为无变化，无异常临床或解剖学体征。单独给予PTX的猪的纤维化瘢痕组织块未观察到变化。然而，在开始治疗13周后以及尸检时，给予PTX + α-生育酚的猪的该组织块出现明显软化和缩小，此时长度的平均缩小约为30%，宽度和深度约为50%，面积和体积约为70%。组织学检查显示残留瘢痕组织周围的肌肉和皮下组织完全正常。瘢痕组织线性尺寸减少50%，与我们之前临床研究的结果相当，与对照组的临床和尸检结果相比具有高度显著性。对残留瘢痕组织的组织学检查显示，与对照组和给予PTX的猪相比，该组织更均匀，细胞和炎症更少。三组猪残留纤维化组织中肿瘤坏死因子α（TNFα）的组织和细胞免疫定位相似，而给予PTX + α-生育酚的猪的残留纤维化瘢痕组织中转化生长因子β-1（TGFβ-1）的免疫染色比其他两组减少得多。
目前的结果显示，高剂量伽马射线照射后形成的皮下纤维化瘢痕组织有显著消退。
