ATRAB-Applied and Translational Radiobiology, Medical University of Vienna, Vienna, Austria.
ATRAB-Applied and Translational Radiobiology, Medical University of Vienna, Vienna, Austria; Department of Molecular Medicine, Iran University of Medical Science, Tehran, Iran.
Int J Radiat Oncol Biol Phys. 2020 Jun 1;107(2):377-385. doi: 10.1016/j.ijrobp.2020.01.028. Epub 2020 Feb 5.
This preclinical study aimed to investigate the role of nuclear factor (NF)-κB in early and late radiogenic sequelae of urinary bladder dysfunction in mice. Thalidomide was applied either during the early or late response phase to determine potential effects of NF-κB inhibition on functional bladder impairment.
After pelvic irradiation on day 0, female C3H/Neu mice were observed over a period of 360 days and radiation response was evaluated for alterations in bladder functionality and NF-κB activation. Functionality was determined in graded dose experiments (14-24 Gy) and assessed by micturition frequency analysis and transurethral cystotonometry to reveal alterations in voiding and volume. The induction of the NF-κB proteins p50 and p65 was evaluated by immunohistochemistry in response to a single dose of 23 Gy (ED). Thalidomide (100 mg/kg/d) was applied intraperitoneally in 3 treatment groups: daily from day 1 to 15, daily from day 16 to 30, and in 2-day-intervals from day 150 to 180.
Immunohistochemical analysis showed a biphasic activation of p50 and p65 during the early radiation cystitis phase (day 1-30). After a transient decrease, p50, but not p65, was reactivated permanently leading to increased levels, which suggests an occurrence of chronic inflammation correlated with functional impairment. Both early thalidomide treatments reduced NF-κB activation and shifted the ED value for early radiation cystitis and late radiation sequelae to higher doses.
These data clearly demonstrate the involvement of NF-κB signaling in the pathogenesis of radiation-induced urinary bladder dysfunction. Additionally, this study emphasizes that biological targeting of early radiogenic processes has enormous effect on chronic symptoms. The late administration of thalidomide showed no significant effect on functionality.
本临床前研究旨在探讨核因子（NF）-κB 在小鼠放射性膀胱功能障碍早期和晚期后遗症中的作用。噻唑来膦酸在早期或晚期反应期应用，以确定 NF-κB 抑制对功能性膀胱损伤的潜在影响。
在第 0 天进行骨盆照射后，对 C3H/Neu 雌性小鼠进行了 360 天的观察，并对膀胱功能和 NF-κB 激活的变化进行了放射反应评估。在分级剂量实验（14-24 Gy）中确定了功能，通过排尿频率分析和经尿道膀胱测压术评估了排空和容量的变化。通过免疫组化评估单次 23 Gy（ED）照射后 NF-κB 蛋白 p50 和 p65 的诱导。噻唑来膦酸（100mg/kg/d）以 3 种治疗组腹腔内给药：从第 1 天到第 15 天每天给药，从第 16 天到第 30 天每天给药，从第 150 天到第 180 天每两天给药一次。
免疫组化分析显示，早期放射性膀胱炎阶段（第 1-30 天）p50 和 p65 呈双相激活。短暂下降后，p50 而非 p65 被永久重新激活，导致水平升高，这表明与功能障碍相关的慢性炎症的发生。早期噻唑来膦酸治疗均降低了 NF-κB 的激活，并将早期放射性膀胱炎和晚期放射性后遗症的 ED 值转移到更高剂量。
这些数据清楚地表明 NF-κB 信号在放射性诱导的膀胱功能障碍发病机制中的作用。此外，本研究强调，对早期放射过程的生物学靶向对慢性症状有巨大影响。噻唑来膦酸的晚期给药对功能没有显著影响。
