Metabolic Profiling Implicates a Critical Role of Cyclooxygenase-2-Mediated Arachidonic Acid Metabolism in Radiation-Induced Esophageal Injury in Rats
Metabolic Profiling Implicates a Critical Role of Cyclooxygenase-2-Mediated Arachidonic Acid Metabolism in Radiation-Induced Esophageal Injury in Rats
复制标题
DOI：
10.1667/rade-20-00240.1
复制
发表时间：
2022-02
影响因子：
3.4
通讯作者：
Wenling Tu;Yahui Feng;Qiang Lai;Jinlong Wang;Weijun Yuan;Jingxuan Yang;Sheng Jiang;Ailing Wu-Ailin
中科院分区：
文献类型：
--
作者：
Wenling Tu;Yahui Feng;Qiang Lai;Jinlong Wang;Weijun Yuan;Jingxuan Yang;Sheng Jiang;Ailing Wu-Ailin
放射诱导的食道损伤(RIEI)是放射治疗的一个主要剂量限制性并发症，尤其是对食管癌和胸癌。RIEI是一个多因素、多步骤的过程，由DNA、RNA、蛋白质和代谢物组成的复杂网络调控。然而，目前还不清楚哪些食道代谢产物会被电离辐射改变，以及这些改变是如何影响RIEI进展的。在本工作中，我们建立了一种0-40GyX射线照射的RIEI大鼠模型。≥25Gy线照射大鼠食道后，体重、摄食量、饮水量和食道结构均发生明显变化。采用液质联用技术(LC-MS)研究了大鼠食道代谢产物的代谢变化及相关途径。180种代谢物呈剂量依赖性上调(35Gy25Gy2 5GyGt；对照组)，199种代谢物随照射剂量增加(35Gy≥25Gy2 5Gy2 5Gy2 5Gy2 t；对照组)呈剂量依赖性上调；≤2 5Gy2 5Gy2 5Gy2 5GyGt；KEGG分析表明，电离辐射严重扰乱了多种代谢途径，其中花生四烯酸代谢途径最为显著。花生四烯酸代谢异常的代谢产物有20种，其中25或35Gy组5种前列腺素(PGA2、PGJ2、PGD2、PGH2和PGI2)表达上调。环氧合酶-2(COX-2)是催化花生四烯酸生物合成前列腺素的关键酶，在受照大鼠的食道中高表达。此外，受试者工作特征(ROC)曲线分析显示，PGJ2有可能成为诊断RIEI的一种有前途的组织生物标志物。综上所述，这些发现表明电离辐射诱导了食道代谢的改变，从代谢的角度加深了我们对RIEI病理生理学的理解。
Radiation-induced esophageal injury (RIEI) is a major dose-limiting complication of radiotherapy, especially for esophageal and thoracic cancers. RIEI is a multi-factorial and multi-step process, which is regulated by a complex network of DNA, RNA, protein and metabolite. However, it is unclear which esophageal metabolites are altered by ionizing radiation and how these changes affect RIEI progression. In this work, we established a rat model of RIEI with 0–40 Gy X-ray irradiation. Esophageal irradiation using ≥25 Gy induced significant changes to rats, such as body weight, food intake, water intake and esophageal structure. The metabolic changes and related pathways of rat esophageal metabolites were investigated by liquid chromatography-mass spectrometry (LC-MS). One hundred eighty metabolites showed an up-regulation in a dose-dependent manner (35 Gy ≥ 25 Gy > controls), and 199 metabolites were downregulated with increasing radiation dose (35 Gy ≤ 25 Gy < controls). The KEGG analysis showed that ionizing radiation seriously disrupted multiple metabolic pathways, and arachidonic acid metabolism was the most significantly enriched pathway. 20 metabolites were dysregulated in arachidonic acid metabolism, including up-regulation of five prostaglandins (PGA2, PGJ2, PGD2, PGH2, and PGI2) in 25 or 35 Gy groups. Cyclooxygenase-2 (COX-2), the key enzyme in catalyzing the biosynthesis of prostaglandins from arachidonic acid, was highly expressed in the esophagus of irradiated rats. Additionally, receiver operating characteristic (ROC) curve analysis revealed that PGJ2 may serve as a promising tissue biomarker for RIEI diagnosis. Taken together, these findings indicate that ionizing radiation induces esophageal metabolic alterations, which advance our understanding of the pathophysiology of RIEI from the perspective of metabolism.