Abstract
Background and Aim: Radiation-induced enteropathy is frequently observed after radiation therapy for abdominal and pelvic cancer or occurs secondary to accidental radiation exposure. The acute effects of irradiation on the intestine might be attributed to inhibition of mitosis in the crypts, as the loss of proliferative functions impairs development of the small intestinal epithelium and its barrier function. Especially, oxidative damage to intestinal epithelial cells is a key event in the initiation and progression of radiation-induced enteropathy. Pravastatin is widely used clinically to lower serum cholesterol levels and has been reported to have anti-inflammatory effects on endothelial cells. Here, we investigated the therapeutic effects of pravastatin on damaged epithelial cells after radiation-induced enteritis using in vitro and in vivo systems.Materials and Methods: To evaluate the effects of pravastatin on intestinal epithelial cells, we analyzed proliferation and senescence, oxidative damage, and inflammatory cytokine expression in an irradiated human intestinal epithelial cell line (InEpC). In addition, to investigate the therapeutic effects of pravastatin in mice, we performed histological analysis, bacterial translocation assays, and intestinal permeability assays, and also assessed inflammatory cytokine expression, using a radiation-induced enteropathy model.Results: Histological damage such as shortening of villi length and impaired intestinal crypt function was observed in whole abdominal-irradiated mice. However, damage was attenuated in pravastatin-treated animals, in which normalization of intestinal epithelial cell differentiation was also observed. Using in vitro and in vivo systems, we also showed that pravastatin improves the proliferative properties of intestinal epithelial cells and decreases radiation-induced oxidative damage to the intestine. In addition, pravastatin inhibited levels of epithelial-derived inflammatory cytokines including IL-6, IL-1β, and TNF-α in irradiated InEpC cells. We also determined that pravastatin could rescue intestinal barrier dysfunction via anti-inflammatory effects using the mouse model.Conclusion: Pravastatin has a therapeutic effect on intestinal lesions and attenuates radiation-induced epithelial damage by suppressing oxidative stress and the inflammatory response.
Highlights
As the intestine is highly sensitive to ionizing radiation, radiation-induced enteropathy is frequently observed radiation therapy for abdominal or pelvic cancers including gastric, pancreatic, and endometrial cancer or can occur secondary to accidental radiation exposure (Kavanagh et al, 2010)
Using in vitro and in vivo systems, we showed that pravastatin improves the proliferative properties of intestinal epithelial cells and decreases radiation-induced oxidative damage to the intestine
Pravastatin has a therapeutic effect on intestinal lesions and attenuates radiation-induced epithelial damage by suppressing oxidative stress and the inflammatory response
Summary
As the intestine is highly sensitive to ionizing radiation, radiation-induced enteropathy is frequently observed radiation therapy for abdominal or pelvic cancers including gastric, pancreatic, and endometrial cancer or can occur secondary to accidental radiation exposure (Kavanagh et al, 2010). The acute effects of irradiation on the intestine can be attributed to inhibition of mitosis in the crypts; the loss of proliferative function impairs the development of the small intestinal epithelium and increases intestinal permeability, which results in increased translocation of luminal bacteria into the systemic compartment, generating a local and systemic immune response (Son et al, 2013; Yu, 2013) Whereas these issues have prompted increased interest in the development of therapeutic agents for radiation enteropathy in cancer patients and victims of radiation disasters (Potten, 1990; Pritchard et al, 1999; Greenberger, 2009; Citrin et al, 2010), there are no FDA-approved agents for the prevention or treatment of this disease (Greenberger, 2009; Citrin et al, 2010; Yu, 2013). We investigated the therapeutic effects of pravastatin on damaged epithelial cells after radiation-induced enteritis using in vitro and in vivo systems
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