IPW-5371 Proves Effective as a Radiation Countermeasure by Mitigating Radiation-Induced Late Effects.
IPW-5371 Proves Effective as a Radiation Countermeasure by Mitigating Radiation-Induced Late Effects.
复制标题
IPW-5371通过减轻辐射引起的迟到效应而被证明是辐射对策。
DOI：
10.1667/rr14403.2
复制
发表时间：
2016-11
影响因子：
3.4
通讯作者：
Mikkelsen R
中科院分区：
文献类型：
--
作者：
Rabender C;Mezzaroma E;Mauro AG;Mullangi R;Abbate A;Anscher M;Hart B;Mikkelsen R
存在对辐射对策的持续且显著的需求，以减少与辐射或核事故中心脏和肺的暴露相关的发病率和死亡率。辐射诱导的晚期效应发生在暴露后数月至数年，源于显著的组织损伤和重塑，导致纤维化和功能丧失。据报道，TGF-β在肺纤维化和心脏纤维化中起作用。我们研究了小分子TGF-β受体1抑制剂IPW-5371减轻C57 L/J小鼠胸部照射效应的能力，C57 L/J小鼠是一种小鼠模型，在诱导纤维化和剂量反应方面与在人类中观察到的最相似。为了模拟放射学事件，以两种剂量给予辐射：5戈伊全身辐射（引发全身反应），然后立即进行6.5戈伊的胸部“补充”辐射，胸部总剂量为11.5戈伊。IPW-5371以10 mg/kg或30 mg/kg的剂量每天一次经口给药，从辐射后24 h开始，持续6或20周。监测动物存活180天，并通过超声心动图、呼吸频率和动脉血氧饱和度评估心肺损伤。胸部暴露（11.5戈伊）引起肺和心脏损伤，导致寿命缩短，中位生存期为135天。以10 mg/kg和30 mg/kg的IPW-5371治疗6周，延迟了疾病发作和死亡，中位生存期为165天。以30 mg/kg的IPW-5371治疗20周，保持了动脉O2饱和度和心脏收缩储备，并导致呼吸频率以及心脏和肺纤维化的显著降低。这导致与辐照的赋形剂治疗组相比存活率的显著改善（P < 0.001），并且与未辐照组相比在统计学上不显著。我们观察到IPW-5371处理导致pSmad 3组织水平降低，证实了IPW-5371对TGF-β信号传导的作用。这些结果表明，IPW-5371代表了一种潜在的有希望的辐射对策，用于治疗辐射诱导的迟发效应。
There is an ongoing and significant need for radiation countermeasures to reduce morbidities and mortalities associated with exposure of the heart and lungs from a radiological or nuclear incidents. Radiation-induced late effects occur months to years after exposure, stemming from significant tissue damage and remodeling, resulting in fibrosis and loss of function. TGF-β is reported to play a role in both pulmonary and cardiac fibrosis. We investigated the ability of a small molecule TGF-β receptor 1 inhibitor, IPW-5371, to mitigate the effects of thoracic irradiation in C57L/J mice, a murine model that most closely resembles that observed in humans in the induction of fibrosis and dose response. To simulate a radiological event, radiation was administered in two doses: 5 Gy total-body irradiation (eliciting a whole-body response) and immediately after that, a thoracic “top-up” of 6.5 Gy irradiation, for a total dose of 11.5 Gy to the thorax. IPW-5371 was administered once daily, orally, starting 24 h postirradiation for 6 or 20 weeks at a dose of 10 mg/kg or 30 mg/kg. Animals were monitored for a period of 180 days for survival, and cardiopulmonary injury was assessed by echocardiography, breathing rate and arterial oxygen saturation. Exposure of the thorax (11.5 Gy) induced both pulmonary and cardiac injury, resulting in a reduced life span with median survival of 135 days. IPW-5371 treatment for 6 weeks, at both 10 mg/kg and 30 mg/kg, delayed disease onset and mortality, with median survival of 165 days. Twenty weeks of IPW-5371 treatment at 30 mg/kg preserved arterial O2 saturation and cardiac contractile reserve and resulted in significant decreases in breathing frequency and cardiac and pulmonary fibrosis. This led to dramatic improvement in survival compared to the irradiated, vehicle-treated group (P < 0.001), and was statistically insignificant from the nonirradiated group. We observed that IPW-5371 treatment resulted in decreased pSmad3 tissue levels, confirming the effect of IPW-5371 on TGF-β signaling. These results demonstrate that IPW-5371 represents a potentially promising radiation countermeasure for the treatment of radiation-induced late effects.