Simvastatin Ameliorates Radiation Enteropathy Development After Localized, Fractionated Irradiation by a Protein C-Independent Mechanism

Abstract

Microvascular injury plays a key role in normal tissue radiation responses. Statins, in addition to their lipid-lowering effects, have vasculoprotective properties that may counteract some effects of radiation on normal tissues. We examined whether administration of simvastatin ameliorates intestinal radiation injury, and whether the effect depends on protein C activation. Rats received localized, fractionated small bowel irradiation. The animals were fed either regular chow or chow containing simvastatin from 2 weeks before irradiation until termination of the experiment. Groups of rats were euthanized at 2 weeks and 26 weeks for assessment of early and delayed radiation injury by quantitative histology, morphometry, and quantitative immunohistochemistry. Dependency on protein C activation was examined in thrombomodulin (TM) mutant mice with deficient ability to activate protein C. Simvastatin administration was associated with lower radiation injury scores (p < 0.0001), improved mucosal preservation (p = 0.0009), and reduced thickening of the intestinal wall and subserosa (p = 0.008 and p = 0.004), neutrophil infiltration (p = 0.04), and accumulation of collagen I (p = 0.0003). The effect of simvastatin was consistently more pronounced for delayed than for early injury. Surprisingly, simvastatin reduced intestinal radiation injury in TM mutant mice, indicating that the enteroprotective effect of simvastatin after localized irradiation is unrelated to protein C activation. Simvastatin ameliorates the intestinal radiation response. The radioprotective effect of simvastatin after localized small bowel irradiation does not appear to be related to protein C activation. Statins should undergo clinical testing as a strategy to minimize side effects of radiation on the intestine and other normal tissues.