MCP-1/CCR2/MCPIP1介导的巨噬细胞招募与极化在BOO诱导膀胱重塑中的作用及其机制研究

Bladder remodeling induced by Bladder Outlet Obstruction (BOO) is the result of progression from inflammation to fibrosis, but the mechanism of the progression is unclear yet. Macrophage polarization, which regulates inflammation and fibrosis, is an important mechanism of fibrosis. But it has not been reported in bladder. Previous studies have found that BOO can activate MCP-1 / CCR2 / MCPIP1 signal, which induces bladder macrophage infiltration and polarization to M2 subtype, and stimulation of MCP-1 can up-regulate the expression of TGFβ / CTGF in macrophages. Accordingly, we propose a hypothesis: in BOO environment, macrophages are recruited and polarized by stimulation with MCP-1, and promote the transition of bladder smooth muscle cells to fibroblast phenotype via the paracrine pathway, thereby promoting the process of BOO bladder remodeling. This project intends to use BOO rats and co-cultured cells to explore the MCP-1 / CCR2 / MCPIP1 signal on macrophage recruitment, polarization, its impact on bladder inflammation and fibrosis, and to confirm the paracrine mechanisms of polarized macrophage regulate the phenotype and function of bladder smooth muscle cells. In this study, we consider MCP-1 signaling as a therapeutic target, that regulates the recruitment and polarization of bladder macrophages, which provide a new idea for the clinical treatment of BOO bladder remodeling.

膀胱出口梗阻（BOO）诱导的膀胱重塑是从炎症向纤维化演进的结果，但演进机制尚不清楚。巨噬细胞极化调节炎症与纤维化反应，是纤维化病变的重要机制，在膀胱中却尚未见报道。经前期研究发现，BOO能活化MCP-1/CCR2/MCPIP1信号，诱导膀胱巨噬细胞浸润并向M2亚型极化，而且MCP-1体外刺激可上调巨噬细胞TGFβ/CTGF信号表达。据此，我们提出假说：BOO环境中，巨噬细胞在MCP-1刺激下完成招募与极化，经旁分泌途径促进膀胱平滑肌细胞向纤维化表型转变，从而推动BOO膀胱重塑进程。本课题拟分别对BOO大鼠与共培养细胞进行干预，探究MCP-1/CCR2/MCPIP1信号对巨噬细胞招募、极化的调控及其对膀胱炎症与纤维化的影响，证实极化后的巨噬细胞调控膀胱平滑肌细胞的表型与功能的旁分泌机制。本研究将MCP-1信号作为治疗靶点，调控膀胱巨噬细胞的招募与极化，为BOO膀胱重塑的临床治疗提供新的思路。

膀胱出口梗阻（BOO）诱导的膀胱重塑是从炎症向纤维化演进的结果，但演进机制尚不清楚。巨噬细胞极化调节炎症与纤维化反应，是纤维化病变的重要机制，在膀胱中却尚未见报道。本研究在前期研究基础上，基于动物实验，构建不同梗阻时间点BOO大鼠模型，验证MCP-1/CCR2的表达变化规律，揭示巨噬细胞招募与极化在膀胱重塑中的作用；并进一步明确了通过干预MCP-1/CCR2信号活化，可有效缓解膀胱纤维化。基于细胞实验，验证了MCP-1/CCR2通路活化对巨噬细胞极化及功能的影响，并进一步揭示了MCP-1/CCR2/MCPIP1介导的病理性静水压下膀胱平滑肌细胞增殖与收缩。此外，本课题首次发现巨噬细胞在膀胱重塑过程中表现出肌成纤维细胞特性，分泌细胞外基质，直接促进纤维化。该研究有助于明确巨噬细胞在膀胱重塑中的关键作用，进而为更有效治疗膀胱纤维化提供新策略。