Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea.
Comprehensive Radiation Irradiation Center, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea.
EBioMedicine. 2021 Nov;73:103641. doi: 10.1016/j.ebiom.2021.103641. Epub 2021 Oct 21.
Radiotherapy or accidental exposure to ionizing radiation causes severe damage of healthy intestinal tissues. Intestinal barrier function is highly sensitive to ionizing radiation, and loss of epithelial integrity results in mucosal inflammation, bacterial translocation, and endotoxemia. Few studies have of epithelial integrity as a therapeutic target to treat radiation toxicity. Here, we examined the effects of pravastatin (PS) and the molecular mechanisms underlying epithelial integrity on radiation-induced enteropathy.
The radio-mitigative effects of PS were evaluated in a minipig model by quantifying clinical symptoms, and performing histological and serological analyses and mRNA sequencing in intestinal tissues. To evaluate the role of intercellular junctions on radiation damage, we used tight junction regulator and metallothionein 2 (MT2) as treatments in a mouse model of radiation-induced enteropathy. Caco-2 monolayers were used to examine functional epithelial integrityand intercellular junction expression.
Using a minipig model of pharmaceutical oral bioavailability, we found that PS mitigated acute radiation-induced enteropathy. PS-treated irradiated minipigs had mild clinical symptoms, lower intestinal inflammation and endotoxin levels, and improved gastrointestinal integrity, compared with control group animals. The results of mRNA sequencing analysis indicated that PS treatment markedly influenced intercellular junctions by inhibiting p38 MAPK signaling in the irradiated intestinal epithelium. The PS-regulated gene MT2 improved the epithelial barrier via enhancement of intercellular junctions in radiation-induced enteropathy.
PS regulated epithelial integrity by modulating MT2 in radiation-damaged epithelial cells. These findings suggested that maintenance of epithelial integrity is a novel therapeutic target for treatment of radiation-induced gastrointestinal damage.
As stated in the Acknowledgments.
放射治疗或意外接触电离辐射会对健康的肠道组织造成严重损伤。肠道屏障功能对电离辐射高度敏感，上皮完整性的丧失会导致黏膜炎症、细菌易位和内毒素血症。很少有研究将上皮完整性作为治疗辐射毒性的治疗靶点。在这里，我们研究了普伐他汀（PS）对辐射诱导的肠病的上皮完整性的放射缓解作用及其分子机制。
通过量化临床症状、进行组织学和血清学分析以及对肠道组织进行 mRNA 测序，在小型猪模型中评估 PS 的放射缓解作用。为了评估细胞间连接对辐射损伤的作用，我们在辐射诱导的肠病小鼠模型中使用紧密连接调节剂和金属硫蛋白 2（MT2）作为治疗方法。使用 Caco-2 单层细胞来检测功能性上皮完整性和细胞间连接表达。
使用具有口服生物利用度的小型猪模型，我们发现 PS 减轻了急性辐射诱导的肠病。与对照组动物相比，PS 治疗的辐照小型猪的临床症状较轻，肠道炎症和内毒素水平较低，胃肠道完整性得到改善。mRNA 测序分析的结果表明，PS 通过抑制辐射肠上皮中的 p38 MAPK 信号通路，显著影响细胞间连接。PS 调节的基因 MT2 通过增强辐射诱导的肠病中的细胞间连接来改善上皮屏障。
PS 通过调节辐射损伤上皮细胞中的 MT2 来调节上皮完整性。这些发现表明，维持上皮完整性是治疗辐射诱导的胃肠道损伤的一种新的治疗靶点。
如致谢中所述。
