Department of Gynecology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China.
Department of Gynecology, Longling People's Hospital, YunNan, LongLing County, China.
J Obstet Gynaecol. 2024 Dec;44(1):2415669. doi: 10.1080/01443615.2024.2415669. Epub 2024 Nov 4.
Pelvic organ prolapse (POP), characterised by the downward displacement of pelvic organs, is a prevalent disorder that affects adult women. This study explored the therapeutic potential of PX-478, a selective hypoxia-inducible factor-1α (HIF-1α) inhibitor, in a murine POP model.
A murine POP model was established through ovariectomy, mimicking oestrogen deprivation. Fifteen C57BL/6J mice were randomly assigned to control, POP, and PX-478 groups. PX-478, targeting HIF-1α, was administered intravaginally. The analysis of fibroblasts, macrophage and inflammation was performed through Masson staining, immunofluorescence, and ELISA. Collagen distribution was assessed using Sirius Red staining. Expression levels of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMP-1) were determined through immunohistochemistry and western blot. Fibroblast proliferation and apoptosis were evaluated by CCK-8 assay and flow cytometry.
PX-478 treatment significantly reduced vaginal length, indicating a therapeutic effect on POP severity. Masson staining revealed reduced fibrotic changes and collagen disruption in PX-478-treated mice. Immunofluorescence showed increased fibroblast markers (Vimentin, α-SMA) and collagen fibres by PX-478. Sirius Red staining indicated PX-478 mitigated damage to Type I and Type III collagen fibres. PX-478 significantly reduced MMP-2 and MMP-9 expression while increased TIMP-1. In macrophages, PX-478 decreased M1 and M2 markers (CD80, CD206) and IL-18 secretion. Fibroblasts exhibited increased proliferation, reduced apoptosis, and altered MMP/TIMP expression under PX-478 influence.
PX-478 demonstrates a therapeutic potential in the mice POP model. It reduces vaginal length, attenuates fibrosis, and modulates collagen synthesis. Its immunomodulation is evident through reduced M1 and M2 macrophages and suppressed IL-18 secretion.
盆腔器官脱垂（POP）是一种以盆腔器官向下移位为特征的常见疾病，影响成年女性。本研究探讨了 PX-478（一种选择性缺氧诱导因子-1α（HIF-1α）抑制剂）在小鼠 POP 模型中的治疗潜力。
通过卵巢切除术建立小鼠 POP 模型，模拟雌激素缺乏。将 15 只 C57BL/6J 小鼠随机分为对照组、POP 组和 PX-478 组。通过阴道内给药 PX-478 靶向 HIF-1α。通过 Masson 染色、免疫荧光和 ELISA 分析成纤维细胞、巨噬细胞和炎症。使用天狼星红染色评估胶原分布。通过免疫组化和 Western blot 测定基质金属蛋白酶（MMPs）和金属蛋白酶组织抑制剂（TIMP-1）的表达水平。通过 CCK-8 测定和流式细胞术评估成纤维细胞增殖和凋亡。
PX-478 治疗显著降低了阴道长度，表明对 POP 严重程度有治疗作用。Masson 染色显示 PX-478 治疗组纤维化变化和胶原破坏减少。免疫荧光显示 PX-478 增加了成纤维细胞标志物（波形蛋白、α-SMA）和胶原纤维。天狼星红染色表明 PX-478 减轻了 I 型和 III 型胶原纤维的损伤。PX-478 显著降低了 MMP-2 和 MMP-9 的表达，同时增加了 TIMP-1。在巨噬细胞中，PX-478 降低了 M1 和 M2 标志物（CD80、CD206）和 IL-18 的分泌。在 PX-478 作用下，成纤维细胞表现出增殖增加、凋亡减少以及 MMP/TIMP 表达改变。
PX-478 在小鼠 POP 模型中具有治疗潜力。它可降低阴道长度，减轻纤维化，调节胶原合成。其免疫调节作用表现为 M1 和 M2 巨噬细胞减少和 IL-18 分泌抑制。
