University of Maryland, School of Pharmacy, Department of Pharmaceutical Sciences, Baltimore, MD.
Epistem Ltd., Manchester, UK.
Health Phys. 2020 Nov;119(5):604-620. doi: 10.1097/HP.0000000000001351.
Exposure to ionizing radiation results in injuries of the hematopoietic, gastrointestinal, and respiratory systems, which are the leading causes responsible for morbidity and mortality. Gastrointestinal injury occurs as an acute radiation syndrome. To help inform on the natural history of the radiation-induced injury of the partial body irradiation model, we quantitatively profiled the proteome of jejunum from non-human primates following 12 Gy partial body irradiation with 2.5% bone marrow sparing over a time period of 3 wk. Jejunum was analyzed by liquid chromatography-tandem mass spectrometry, and pathway and gene ontology analysis were performed. A total of 3,245 unique proteins were quantified out of more than 3,700 proteins identified in this study. Also a total of 289 proteins of the quantified proteins showed significant and consistent responses across at least three time points post-irradiation, of which 263 proteins showed strong upregulations while 26 proteins showed downregulations. Bioinformatic analysis suggests significant pathway and upstream regulator perturbations post-high dose irradiation and shed light on underlying mechanisms of radiation damage. Canonical pathways altered by radiation included GP6 signaling pathway, acute phase response signaling, LXR/RXR activation, and intrinsic prothrombin activation pathway. Additionally, we observed dysregulation of proteins of the retinoid pathway and retinoic acid, an active metabolite of vitamin A, as quantified by liquid chromatography-tandem mass spectrometry. Correlation of changes in protein abundance with a well-characterized histological endpoint, corrected crypt number, was used to evaluate biomarker potential. These data further define the natural history of the gastrointestinal acute radiation syndrome in a non-human primate model of partial body irradiation with minimal bone marrow sparing.
电离辐射暴露会导致造血、胃肠道和呼吸系统损伤，这些是导致发病率和死亡率的主要原因。胃肠道损伤是急性放射综合征的一种表现。为了帮助了解部分身体照射模型中辐射诱导损伤的自然史，我们定量分析了非人类灵长类动物在接受 12 Gy 部分身体照射后 3 周内的空肠蛋白质组，2.5%的骨髓保留率。通过液相色谱-串联质谱法分析空肠，并进行了途径和基因本体分析。在这项研究中，鉴定出超过 3700 种蛋白质，其中有 3245 种独特的蛋白质被定量。在至少三个辐照后时间点，总共 289 种定量蛋白的蛋白表现出显著且一致的反应，其中 263 种蛋白表现出强烈的上调，而 26 种蛋白表现出下调。生物信息学分析表明，高剂量照射后，显著改变了途径和上游调控因子，为辐射损伤的潜在机制提供了线索。受辐射改变的经典途径包括 GP6 信号通路、急性期反应信号通路、LXR/RXR 激活和内在凝血酶原激活途径。此外，我们还观察到视黄醇途径和视黄酸（维生素 A 的活性代谢物）的蛋白质失调，这是通过液相色谱-串联质谱法定量的。用蛋白质丰度变化与经过充分验证的组织学终点（校正隐窝数）的相关性来评估生物标志物的潜力。这些数据进一步定义了部分身体照射非人类灵长类动物模型中胃肠道急性放射综合征的自然史，该模型具有最小的骨髓保留率。
