Relaxin-2 therapy reverses radiation-induced fibrosis and restores bladder function in mice
Relaxin-2 therapy reverses radiation-induced fibrosis and restores bladder function in mice
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DOI：
10.1002/nau.23721
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发表时间：
2018-11-01
影响因子：
2
通讯作者：
Kanai, Anthony J.
中科院分区：
文献类型：
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作者：
Ikeda, Youko;Zabbarova, Irina V.;Kanai, Anthony J.
目的探讨人松弛素2（human relaxin-2，hRLX 2）对放射性膀胱纤维化和下尿路功能障碍（lower urinary tract dysfunction，LUTD）的逆转作用。放射性膀胱炎是盆腔恶性肿瘤放射治疗的结果。急性，辐射导致尿路上皮细胞中的活性氧/氮物质，细胞凋亡，屏障破坏和炎症。慢性地，这导致胶原蛋白沉积、膀胱纤维化和减弱的储存和排泄功能。在严重的情况下，由于目前的治疗方法不能逆转纤维化，因此进行膀胱切除术。我们开发了一种选择性膀胱照射（10戈瑞; 1戈伊=100拉德）的小鼠模型，在6周内导致慢性纤维化，膀胱顺应性、收缩性和溢流性尿失禁下降。照射后7周，通过皮下渗透泵向雌性C57 B1/6小鼠连续输注hRLX 2（400 μ g/kg/天/14天）或载体（盐水）。小鼠在体内进行了评估，采用尿点分析，膀胱测压和尿道外括约肌肌电图;并在体外使用长度张力测量，蛋白质印迹，组织学，和cytochemistry.ResultsConclusionhRLX2逆转纤维化，降低胶原含量，改善膀胱壁结构，并增加膀胱顺应性，逼尿肌平滑肌Cav 1. 2表达和逼尿肌收缩性在慢性放射性膀胱炎小鼠。hRLX 2治疗结果可能是由逼尿肌上表达的RXFP 1/2受体激活引起的。hRLX 2可能是挽救慢性放射性膀胱炎膀胱的新治疗选择。
AimMethodsTo determine the efficacy of human relaxin-2 (hRLX2) in reversing radiation-induced bladder fibrosis and lower urinary tract dysfunction (LUTD). Radiation cystitis is a consequence of radiotherapy for pelvic malignancies. Acutely, irradiation leads to reactive oxygen/nitrogen species in urothelial cells, apoptosis, barrier disruption, and inflammation. Chronically, this results in collagen deposition, bladder fibrosis, and attenuated storage and voiding functions. In severe cases, cystectomies are performed as current therapies do not reverse fibrosis.We developed a mouse model for selective bladder irradiation (10 Gray; 1 Gy=100 rads) resulting in chronic fibrosis within 6 weeks, with decreased bladder compliance, contractility, and overflow incontinence. Seven weeks post-irradiation, female C57Bl/6 mice were continuously infused with hRLX2 (400g/kg/day/14 days) or vehicle (saline) via subcutaneous osmotic pumps. Mice were evaluated in vivo using urine spot analysis, cystometrograms and external urethral sphincter electromyograms; and in vitro using length-tension measurements, Western blots, histology, and immunohistochemistry.ResultsConclusionhRLX2 reversed fibrosis, decreased collagen content, improved bladder wall architecture, and increased bladder compliance, detrusor smooth muscle Cav1.2 expression and detrusor contractility in mice with chronic radiation cystitis. hRLX2 treatment outcomes were likely caused by the activation of RXFP1/2 receptors which are expressed on the detrusor.hRLX2 may be a new therapeutic option for rescuing bladders with chronic radiation cystitis.