Modulation of bleomycin-induced pulmonary toxicity in the hamster by the antioxidant amifostine

BACKGROUND, Bleomycin produces lung fibrosis in a wide variety of species. In humans, it can cause significant morbidity and mortality when used to treat malignancies such as lymphoma and testicular carcinoma. In rodents, it has been extensively used to study key mechanisms of lung injury and repair. Bleomycin pulmonary toxicity is mediated, at least in part, by the generation of active oxygen species. Amifostine, an aminothiol compound, is a cytoprotectant that is used with many antitumor agents and can act as a potent scavenger of free radicals. The authors hypothesized that amifostine could ameliorate bleomycin lung injury. METHODS. Hamsters weighing 120 g were given an intraperitoneal (IP) injection of amifostine (200 mg/kg, 1180 mg/m(2)) or saline with intratracheal (IT) bleomycin (1 unit) or saline, followed by daily IP amifostine or saline for 6 days. Lungs were assessed on Day 2 for acute lung injury, which was determined by wet-to-dry lung weight ratios. On Day 21, histologic assessment of fibrosis and biochemical analysis of lung hydroxyproline content were performed. RESULTS. No significant differences in morbidity or mortality were observed among the groups. Animals who received IT bleomycin, when compared with controls, had increased lung water measurements on Day 2 that were consistent with acute inflammation; on Day 21, they had pulmonary fibrosis, as measured by morphometric analysis, as well as increased hydroxyproline content. For animals treated with amifostine and bleomycin, significant decreases in wet-to-dry lung weight ratios were observed (mean +/- standard deviation, 4.5 +/- 1.2 vs. 10.2 +/- 2.7), as well as significant decreases in the percentage of fibrosis per lung (15.03% +/- 3.27 vs. 37.26%, +/- 5.76) and hydroxyproline content (1.132 +/- 0.30 vs. 1.831 +/- 0.243). CONCLUSIONS. Amifostine significantly decreased the amount of acute lung injury and subsequent fibrosis in the hamster model of bleomycin-induced lung injury. Cancer 1998;83:2008-14. (C) 1998 American Cancer Society.