Mitigation of Radiation-Induced Lung and Heart Injuries in Mice by Oral Sepiapterin after Irradiation.
Mitigation of Radiation-Induced Lung and Heart Injuries in Mice by Oral Sepiapterin after Irradiation.
复制标题
DOI：
10.1667/rade-20-00249.1
复制
发表时间：
2021-05-01
影响因子：
3.4
通讯作者：
Mikkelsen RB
中科院分区：
文献类型：
--
作者：
Rabender CS;Mezzaroma E;Yakovlev VA;Mauro AG;Bonaventura A;Abbate A;Mikkelsen RB
在辐射暴露后，内皮依赖性血管舒张由于一氧化氮产生受损而受损。内皮功能障碍的特征在于解偶联内皮一氧化氮合酶活性，还原型辅因子四氢生物蝶呤氧化为二氢生物蝶呤是一种公认的机制。用四氢生物蝶呤前体Sepiapterin口服治疗可降低结肠炎小鼠的浸润性炎症细胞和细胞因子水平。因此，我们测试了合成的sepiapterin，PTC 923，是否可以减轻辐射引起的心脏和肺损伤。C57 L/J野生型6-8周龄小鼠（两种性别）接受5戈伊全身照射（TBI），然后胸部补充剂量为6.5戈伊（胸部总剂量为11.5戈伊）。从辐射后24小时开始，通过口服管饲法用lmg/kg PTC 923每天一次处理小鼠六天。每隔一周通过呼吸频率评估肺损伤，并在不同时间点（8、30、60、90和180天）进行超声心动图评估心脏功能。还评估了血浆蛋白（纤维蛋白原、中性粒细胞弹性蛋白酶、C反应蛋白和IL-6）。TBI导致心脏收缩储备下降，每日口服PTC 923可恢复舒张功能受损。PTC 923可明显延迟放射后肺损伤。与未照射的小鼠相比，用PTC 923治疗的TBI小鼠经历了更长的存活期（180天后71%对40%的小鼠存活）。PTC 923治疗的小鼠显示炎性介质减少，特别是IL-6和IL-1b。总之，这些发现支持PTC 923是TBI引起的心脏和肺损伤的潜在缓解剂的提议。
After radiation exposure, endothelium-dependent vasorelaxation is impaired due to impaired nitric oxide production. Endothelial dysfunction is characterized by uncoupled endothelial nitric oxide synthase activity, oxidation of the reduced cofactor tetrahydrobiopterin to dihydrobiopterin as one well recognized mechanism. Oral treatment with sepiapterin, a tetrahydrobiopterin precursor, decreased infiltrating inflammatory cells and cytokine levels in mice with colitis. We therefore tested whether a synthetic sepiapterin, PTC923, might mitigate radiation-induced cardiac and pulmonary injuries. C57L/J wild-type 6–8-week-old mice of both sexes received 5 Gy total-body irradiation (TBI), followed by a top-up dose of 6.5 Gy to the thorax (total thoracic dose of 11.5 Gy). Starting from 24 h postirradiation, mice were treated once daily with 1 mg/kg PTC923 for six days by oral gavage. Assessment of lung injury by breathing rate was measured every other week and echocardiography to assess heart function was performed at different time points (8, 30, 60, 90 and 180 days). Plasma proteins (fibrinogen, neutrophil elastase, C-reactive protein, and IL-6) were assessed as well. TBI induced a reduction in cardiac contractile reserve and an impairment in diastolic function restored by daily oral PTC923. Postirradiation lung injury was significantly delayed by PTC923. TBI mice treated with PTC923 experienced a longer survival compared to nonirradiated mice (71% vs. 40% of mice alive after 180 days). PTC923-treated mice showed a reduction in inflammatory mediators, especially IL-6 and IL-1b. In conclusion, these findings support the proposal that PTC923 is a potential mitigator of cardiac and lung injury caused by TBI.