Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, Northern Ireland, United Kingdom.
PLoS One. 2018 Mar 7;13(3):e0193923. doi: 10.1371/journal.pone.0193923. eCollection 2018.
Radiation-induced bladder toxicity is associated with radiation therapy for pelvic malignancies, arising from unavoidable irradiation of neighbouring normal bladder tissue. This study aimed to investigate the acute impact of ionizing radiation on the contractility of bladder strips and identify the radiation-sensitivity of the mucosa vs the detrusor. Guinea-pig bladder strips (intact or mucosa-free) received ex vivo sham or 20Gy irradiation and were studied with in vitro myography, electrical field stimulation and Ca2+-fluorescence imaging. Frequency-dependent, neurogenic contractions in intact strips were reduced by irradiation across the force-frequency graph. The radiation-difference persisted in atropine (1μM); subsequent addition of PPADs (100μM) blocked the radiation effect at higher stimulation frequencies and decreased the force-frequency plot. Conversely, neurogenic contractions in mucosa-free strips were radiation-insensitive. Radiation did not affect agonist-evoked contractions (1μM carbachol, 5mM ATP) in intact or mucosa-free strips. Interestingly, agonist-evoked contractions were larger in irradiated mucosa-free strips vs irradiated intact strips suggesting that radiation may have unmasked an inhibitory mucosal element. Spontaneous activity was larger in control intact vs mucosa-free preparations; this difference was absent in irradiated strips. Spontaneous Ca2+-transients in smooth muscle cells within tissue preparations were reduced by radiation. Radiation affected neurogenic and agonist-evoked bladder contractions and also reduced Ca2+-signalling events in smooth muscle cells when the mucosal layer was present. Radiation eliminated a positive modulatory effect on spontaneous activity by the mucosa layer. Overall, the findings suggest that radiation impairs contractility via mucosal regulatory mechanisms independent of the development of radiation cystitis.
放射性膀胱毒性与盆腔恶性肿瘤的放射治疗有关，源于对邻近正常膀胱组织的不可避免的照射。本研究旨在探讨电离辐射对膀胱条带收缩性的急性影响，并确定黏膜与逼尿肌的辐射敏感性。豚鼠膀胱条带（完整或无黏膜）接受离体假照射或 20Gy 照射，并通过离体肌电图、电刺激和 Ca2+荧光成像进行研究。跨力频图的完整条带中，频率依赖性、神经源性收缩在照射后减少。在阿托品（1μM）中，这种辐射差异仍然存在；随后加入 PPADs（100μM），在更高的刺激频率下阻断了辐射效应，并降低了力频图。相反，无黏膜的条带对神经源性收缩具有辐射抗性。照射对完整或无黏膜条带中激动剂诱发的收缩（1μM 卡巴胆碱，5mM ATP）没有影响。有趣的是，与照射后的完整条带相比，照射后的无黏膜条带中激动剂诱发的收缩更大，这表明辐射可能揭示了一种抑制性黏膜因素。在对照完整条带中，自发活动比无黏膜条带大；这种差异在照射条带中不存在。在组织制剂中，平滑肌细胞内的自发 Ca2+瞬变被辐射减少。当存在黏膜层时，辐射会影响神经源性和激动剂诱发的膀胱收缩，并减少平滑肌细胞中的 Ca2+信号事件。辐射消除了黏膜层对自发活动的正向调节作用。总的来说，这些发现表明，辐射通过独立于放射性膀胱炎发展的黏膜调节机制损害收缩性。
