Wang Wei, Sun Wenjin, Gao Xiaoshuai, Peng Liao, Lin Lede, Xiao Kaiwen, Liu Yu, Di Xingpeng, Zhu Shiyu, Chen Huiling, Zhou Liang
Laboratory of Reconstructive Urology, Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China.
Department of General Practice, West China Hospital, Sichuan University, Chengdu, China.
Neurourol Urodyn. 2022 Mar;41(3):787-796. doi: 10.1002/nau.24896. Epub 2022 Feb 16.
Bladder outlet obstruction (BOO) is a common problem that can affect bladder structure and function. Currently, there is no effective drugs available to prevent BOO-induced remodeling. Previous reports have demonstrated that the pathogenesis of BOO is associated with macrophage infiltration and polarization, which is physiologically dependent on colony-stimulating factor 1 receptor (CSF-1R) activation. Here we utilized a highly selective CSF-1R inhibitor, GW2580, to determine its preventive effects on BOO-induced remodeling.
A total of 24 Sprague-Dawley rats were randomly divided into sham, BOO + vehicle, and BOO + GW2580 group. GW2580 or vehicle control was administrated by oral gavage at daily doses of 40 mg/kg for 6 weeks. Bladder samples were collected for histopathology, immunohistochemistry, immunofluorescence, western blotting, and flow cytometry analysis.
Our results demonstrated that bladder fibrosis was ameliorated by GW2580 compared with the vehicle group (22.01% ± 5.13% vs. 32.15% ± 7.24%, p < 0.01). Furthermore, treatment with GW2580 induced an inhibition of macrophage infiltration (4.41% ± 1.28% vs. 13.57% ± 3.42%, p < 0.001) and M2 macrophage polarization (10.67% ± 4.15% vs. 28.59% ± 6.38%, p < 0.001). There was also a decrease of profibrotic F4/80 α-smooth muscle actin (α-SMA ) macrophage to myofibroblast transition (9.11% ± 2.58% vs. 17.33% ± 4.01%, p < 0.001) and CD163 TGF-β1 cells (7.68% ± 2.10% vs. 14.17% ± 4.09%, p < 0.01) in the GW2580 group when compared with the vehicle group.
In summary, our findings showed that GW2580 is a worthwhile candidate for a follow-up study to test in the treatment of BOO-induced remodeling.
膀胱出口梗阻（BOO）是一个常见问题，可影响膀胱结构和功能。目前，尚无有效的药物可预防BOO引起的重塑。先前的报道表明，BOO的发病机制与巨噬细胞浸润和极化有关，这在生理上依赖于集落刺激因子1受体（CSF-1R）的激活。在此，我们使用一种高度选择性的CSF-1R抑制剂GW2580来确定其对BOO诱导的重塑的预防作用。
总共24只Sprague-Dawley大鼠被随机分为假手术组、BOO+溶剂对照组和BOO+GW2580组。GW2580或溶剂对照通过口服灌胃给药，每日剂量为40mg/kg，持续6周。收集膀胱样本进行组织病理学、免疫组织化学、免疫荧光、蛋白质印迹和流式细胞术分析。
我们的结果表明，与溶剂对照组相比，GW2580改善了膀胱纤维化（22.01%±5.13%对32.15%±7.24%，p<0.01）。此外，GW2580治疗可抑制巨噬细胞浸润（4.41%±1.28%对13.57%±3.42%，p<0.001）和M2巨噬细胞极化（10.67%±4.15%对28.59%±6.38%，p<0.001）。与溶剂对照组相比，GW2580组中促纤维化的F4/80α平滑肌肌动蛋白（α-SMA）巨噬细胞向肌成纤维细胞的转变（9.11%±2.58%对17.33%±4.01%，p<0.001）以及CD163 TGF-β1细胞（7.68%±2.10%对14.17%±4.09%，p<0.01）也有所减少。
总之，我们的研究结果表明，GW2580是后续研究中测试治疗BOO诱导的重塑的一个有价值的候选药物。
