Abstract：
Inflammation is a central process in most benign bladder disorders, and its control is a delicate balance between initiating factors and resolving factors. While recent discoveries have shown a central role for the NLRP3 inflammasome in initiation, the resolving pathways remain unexplored. Resolution is controlled by specialized pro-resolution mediators (SPMs) functioning through seven receptors (six in rodents). Here we demonstrate expression of all seven in humans (six in mice) through immunocytochemistry. Expression was universal in urothelia with most also expressed in smooth muscle. We next explored the therapeutic potential of three SPMs; Resolvin E1 (RvE1), Maresin 1 (MaR1), and Protectin D1 (PD1). SPMs promote epithelial wound/barrier repair and RvE1 triggered dose-dependent wound closure in urothelia in vitro (scratch assay) (EC90 = 12.5 nM). MaR1 and PD1 were equally effective at this concentration. In vivo analyses employed a cyclophosphamide (CP) model of bladder inflammation (Day 0-CP [150 mg/kg], Day 1 to 3 SPM [25 µg/kg/day], Day 4 - analysis). All three SPMs reduced bladder inflammation (Evans blue) and bladder weights to control levels. Effects of RvE1 were also examined by urodynamics. CP decreased void volume, increased frequency and decreased bladder capacity while RvE1 restored values to control levels. Finally, SPMs reduce fibrosis and RvE1 reduced urothelial expression of TGF-β and collagen I to control values. Together these results expand the known SPMs active in the bladder tissue and provide promising therapeutic targets for controlling inflammation in a wide variety of inflammation-associated benign bladder diseases.
摘要：
炎症是大多数良性膀胱疾病的核心过程，它的控制是启动因素和解决因素之间的微妙平衡。虽然最近的发现显示了NLRP3炎性体在启动中的核心作用，解决途径仍未探索。分辨率由通过七个受体（啮齿动物中有六个）起作用的专门的促分辨率介体（SPM）控制。在这里，我们通过免疫细胞化学证明了人类中所有7种（小鼠中6种）的表达。在尿路中表达普遍，大多数也在平滑肌中表达。接下来，我们探索了三种SPM的治疗潜力；ResolvinE1(RvE1)，Maresin1(MaR1),和保护素D1(PD1)。SPM促进上皮伤口/屏障修复和RvE1触发的剂量依赖性伤口闭合在体外尿路(划痕测定)(EC90=12.5nM)。MaR1和PD1在该浓度下同样有效。体内分析采用膀胱炎症的环磷酰胺（CP）模型（第0天-CP[150mg/kg]，第1天至第3天SPM[25µg/kg/天]，第4天-分析)。所有三种SPM均将膀胱炎症（伊文思蓝）和膀胱重量降低至对照水平。还通过尿动力学检查了RvE1的作用。CP减少了空隙体积，频率增加，膀胱容量降低，而RvE1恢复到对照水平。最后,SPM降低纤维化,RvE1降低TGF-β和I型胶原的尿路上皮表达至对照值。这些结果一起扩展了已知的在膀胱组织中活跃的SPM,并提供了用于控制多种炎症相关良性膀胱疾病中的炎症的有希望的治疗靶标。
