Jang Hyosun, Lee Janet, Park Sunhoo, Myung Hyunwook, Kang Jihoon, Kim Kyuchang, Kim Hyewon, Jang Won-Suk, Lee Sun-Joo, Shim Sehwan, Myung Jae K
Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea.
Department of Pathology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea.
Front Pharmacol. 2018 Oct 30;9:1215. doi: 10.3389/fphar.2018.01215. eCollection 2018.
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 and systems. 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. 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 and 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. Pravastatin has a therapeutic effect on intestinal lesions and attenuates radiation-induced epithelial damage by suppressing oxidative stress and the inflammatory response.
放射性肠病常见于腹部和盆腔癌症放疗后，或继发于意外辐射暴露。辐射对肠道的急性影响可能归因于隐窝有丝分裂的抑制，因为增殖功能的丧失会损害小肠上皮的发育及其屏障功能。特别是，肠道上皮细胞的氧化损伤是放射性肠病发生和发展的关键事件。普伐他汀在临床上广泛用于降低血清胆固醇水平，据报道对内皮细胞有抗炎作用。在此，我们使用[具体系统1]和[具体系统2]研究了普伐他汀对放射性肠炎后受损上皮细胞的治疗作用。为了评估普伐他汀对肠道上皮细胞的影响，我们分析了辐照后的人肠道上皮细胞系（InEpC）中的增殖和衰老、氧化损伤以及炎性细胞因子表达。此外，为了研究普伐他汀在小鼠中的治疗作用，我们使用放射性肠病模型进行了组织学分析、细菌移位测定和肠道通透性测定，并评估了炎性细胞因子表达。在全腹照射的小鼠中观察到了诸如绒毛长度缩短和肠道隐窝功能受损等组织学损伤。然而，在普伐他汀治疗的动物中损伤减轻，其中还观察到肠道上皮细胞分化正常化。使用[具体系统1]和[具体系统2]，我们还表明普伐他汀改善了肠道上皮细胞的增殖特性，并减少了辐射诱导的肠道氧化损伤。此外，普伐他汀抑制了辐照的InEpC细胞中包括IL-6、IL-1β和TNF-α在内的上皮源性炎性细胞因子水平。我们还确定，使用小鼠模型，普伐他汀可通过抗炎作用挽救肠道屏障功能障碍。普伐他汀对肠道病变具有治疗作用，并通过抑制氧化应激和炎症反应减轻辐射诱导的上皮损伤。
