Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.
Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.
Oxid Med Cell Longev. 2022 Aug 31;2022:7957255. doi: 10.1155/2022/7957255. eCollection 2022.
Abdominal or pelvic radiotherapy (RT) often results in small intestinal injury, such as apoptosis of epithelial cells and shortening of the villi. Atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, has many biological effects including cholesterol reduction, protection from cell damage, and autophagy activation. To reduce the extent of radiotherapy- (RT-) induced enteritis, we investigated the protective effects of atorvastatin against RT-induced damage of the intestinal tract. In this study, C57BL/6 mice were randomly distributed into the following groups ( = 8 per group): (1) control group: mice were fed water only, (2) atorvastatin group (Ator): mice were administered atorvastatin, (3) irradiation group (IR): mice received abdominal RT, (4) Ator+IR group: mice received abdominal RT following atorvastatin administration, and (5) Ator+IR+3-MA group: abdominal RT following atorvastatin and 3-methyladenine (an autophagy inhibitor) administration. Based on the assessment of modified Chiu's injury score and villus/crypt ratio, we found that atorvastatin administration significantly reduced intestinal mucosal damage induced by RT. Atorvastatin treatment reduced apoptosis (cleaved caspase-3 and cleaved poly (ADP-ribose) polymerase), DNA damage (H2AX and 53BP1), oxidative stress (OS, 4-hydroxynonenal), inflammatory molecules (phospho-NF-B p65 and TGF-), fibrosis (collagen I and collagen III), barrier leakage (claudin-2 and fluorescein isothiocyanate-dextran), disintegrity (fatty acid-binding protein 2), and dysfunction (lipopolysaccharide) caused by RT in small intestinal tissue. In addition, atorvastatin upregulated the expression of autophagy-active molecules (LC3B), antioxidants (heme oxygenase 1 and thioredoxin 1), and tight junction proteins (occludin and zonula occludens 1). However, the biological functions of atorvastatin in decreasing RT-induced enteritis were reversed after the administration of 3-MA; the function of antioxidant molecules and activity of thioredoxin reductase were independent of autophagy activation. Our results indicate that atorvastatin can effectively relieve RT-induced enteritis through autophagy activation and associated biological functions, including maintaining integrity and function and decreasing apoptosis, DNA damage, inflammation, OS, and fibrosis. It also acts via its antioxidative capabilities.
腹部或骨盆放疗（RT）常导致小肠损伤，如上皮细胞凋亡和绒毛缩短。阿托伐他汀是一种 3-羟基-3-甲基戊二酰辅酶 A 还原酶抑制剂，具有许多生物学作用，包括降低胆固醇、保护细胞免受损伤和激活自噬。为了减轻放疗（RT）引起的肠炎的程度，我们研究了阿托伐他汀对 RT 诱导的肠道损伤的保护作用。在这项研究中，C57BL/6 小鼠被随机分为以下几组（每组 8 只）：（1）对照组：只给小鼠喂水，（2）阿托伐他汀组（Ator）：给小鼠喂阿托伐他汀，（3）照射组（IR）：给小鼠进行腹部 RT，（4）阿托伐他汀+IR 组：给小鼠进行腹部 RT 后给予阿托伐他汀，（5）阿托伐他汀+IR+3-MA 组：给小鼠进行腹部 RT 后给予阿托伐他汀和 3-甲基腺嘌呤（自噬抑制剂）。基于改良的 Chiu 损伤评分和绒毛/隐窝比的评估，我们发现阿托伐他汀给药显著减轻了 RT 引起的肠黏膜损伤。阿托伐他汀治疗降低了凋亡（cleaved caspase-3 和 cleaved poly (ADP-ribose) polymerase）、DNA 损伤（H2AX 和 53BP1）、氧化应激（OS，4-羟壬烯醛）、炎症分子（phospho-NF-B p65 和 TGF-）、纤维化（胶原 I 和胶原 III）、屏障渗漏（claudin-2 和荧光素异硫氰酸酯-葡聚糖）、完整性破坏（脂肪酸结合蛋白 2）和功能障碍（脂多糖）。此外，阿托伐他汀上调了自噬活性分子（LC3B）、抗氧化剂（血红素加氧酶 1 和硫氧还蛋白 1）和紧密连接蛋白（occludin 和 zonula occludens 1）的表达。然而，在给予 3-MA 后，阿托伐他汀在降低 RT 诱导的肠炎中的生物学功能被逆转；抗氧化分子的功能和硫氧还蛋白还原酶的活性与自噬激活无关。我们的结果表明，阿托伐他汀通过自噬激活及其相关的生物学功能（包括维持完整性和功能以及减少凋亡、DNA 损伤、炎症、氧化应激和纤维化）有效缓解 RT 诱导的肠炎。它还通过其抗氧化能力起作用。
