Striking regression of subcutaneous fibrosis induced by high doses of gamma rays using a combination of pentoxifylline and alpha-tocopherol: An experimental study

Purpose: To establish a successful treatment of subcutaneous fibrosis devel oping after high doses of gamma rays, suitable for use in clinical practice . Methods and Materials: We used an animal model of acute localized gamma irr adiation simulating accidental overexposure in humans. Three groups of 5 La rge White pigs were irradiated using a collimated Ir-192 source to deliver a single dose of 160 Gy onto the skin surface (100%) of the outer side of t he thigh. A well-defined block of necrosis developed within a few weeks whi ch had healed after 26 weeks to leave a block of subcutaneous fibrosis invo lving 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 dur ing its fabrication, and another group of 5 was dosed orally for the same p eriod 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 pig s were given normal food only. Animals were assessed for changes in the den sity of the palpated fibrotic block and in the dimensions of the projected cutaneous surface. Depth of scar tissue was determined by ultrasound. Physi cal and sonographic findings were confirmed by autopsy 26 weeks after treat ment started. The density, length, width, and depth of the block of fibroti c 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 . Results: The experimental animals exhibited no change in behavior and no ab normal clinical or anatomic signs. No modifications were observed in the bl ock of fibrotic scar tissue of pigs dosed with PTX alone. However, signific ant softening and shrinking of this block were noted in the pigs dosed with PTX + alpha-tocopherol 13 weeks after treatment started and at autopsy, wh en mean regression was similar to 30% for length, similar to 50% for width and depth, and similar to 70% for area and volume. Histologic examination s howed completely normal muscle and subcutaneous tissue surrounding the resi dual scar tissue. The 50% decrease in the linear dimensions of the scar tis sue, were comparable to the results obtained in our previous clinical studi es, and were highly significant compared to the clinical and autopsy result s for the controls. Histologic examination of the residual scar tissue reve aled tissue which was more homogenous and less cellular and inflammatory th an in control and PTX-dosed pigs. The tissular and cellular immunolocalizat ion of tumor necrosis factor alpha (TNF alpha) was similar in the residual fibrotic tissues of all three groups of pigs, whereas the immunostaining of transforming growth factor beta-1(TGF beta-1) diminished much more in the residual fibrotic scar tissue of the PTX + alpha-tocopherol-dosed pigs than in the two other groups. Conclusions: The present results showed a striking regression of the subcut aneous fibrotic scar tissue that develops as a consequence of high doses of gamma rays. (C) 1999 Elsevier Science Inc.