Rabender Christopher S, Mezzaroma Eleonora, Yakovlev Vasily A, Mauro Adolfo G, Bonaventura Aldo, Abbate Antonio, Mikkelsen Ross B
Department of Radiation Oncology, Division of Cardiology, Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia.
Department of Pharmacotherapy and Outcomes Science, School of Pharmacy, Division of Cardiology, Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia.
Radiat Res. 2021 May 1;195(5):463-473. doi: 10.1667/RADE-20-00249.1.
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.
辐射暴露后，由于一氧化氮生成受损，内皮依赖性血管舒张功能受到损害。内皮功能障碍的特征是内皮一氧化氮合酶活性解偶联，还原型辅因子四氢生物蝶呤氧化为二氢生物蝶呤，这是一种广为人知的机制。用四氢生物蝶呤前体司来吉兰进行口服治疗，可减少结肠炎小鼠中浸润的炎症细胞和细胞因子水平。因此，我们测试了一种合成的四氢生物蝶呤PTC923是否可以减轻辐射引起的心脏和肺部损伤。6至8周龄的C57L/J野生型雌雄小鼠接受5 Gy全身照射（TBI），随后对胸部进行6.5 Gy的补充剂量照射（胸部总剂量为11.5 Gy）。从照射后24小时开始，小鼠每天通过口服灌胃给予1 mg/kg PTC923，持续六天。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）进行超声心动图检查以评估心脏功能。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导致心脏收缩储备降低和舒张功能受损，每日口服PTC923可使其恢复。PTC923显著延迟了照射后肺损伤的发生。与未照射的小鼠相比，接受PTC923治疗的TBI小鼠存活时间更长（180天后存活小鼠分别为71%和40%）。接受PTC923治疗的小鼠炎症介质减少，尤其是IL-6和IL-1β。总之，这些发现支持了PTC923是TBI所致心脏和肺损伤的潜在缓解剂这一观点。
