Impact of hyperglycemic memory on innate immune response to urogynecologic mesh

妇科网片常用于治疗压力性尿失禁和盆腔器官。 脱垂，两种最常见的盆底疾病。虽然围手术期血糖控制是护理的标准， 患有糖尿病的女性患网眼相关并发症的风险要高出约5倍 暴露于阴道腔和盆腔慢性疼痛。这些并发症严重损害了女性的生活质量 并增加医疗成本。由于美国每10名成年女性中就有1人患有糖尿病，而且发病率仍在持续上升 增加，确定糖尿病相关网状并发症风险的潜在机制对于 改善患者护理，降低社会支出。 研究表明，强化血糖控制的有益效果在以下情况下显著降低 治疗前长时间的高血糖发作被称为“高血糖记忆”(HGM)。到目前为止， 目前还没有关于这一现象如何影响妇女接受治疗的结果的调查 泌尿外科网状物。我们在大鼠模型中的初步数据支持高血糖对阴道有害 从长远来看，对MESH的免疫反应以及骨髓(BM)细胞中的HGM可能影响MESH的结果。 在这里，我们假设高血糖会在BM祖细胞中留下表观遗传标记，从而驱动 网状组织界面巨噬细胞功能障碍，导致网状并发症风险增加，尽管 稍后血糖正常化。由于表观遗传修饰在长期血糖正常化过程中是可逆的，我们 进一步假设，严格和长期的围手术期血糖控制可以减轻 HGM，从而改善糖尿病女性的网状结局。 我们已经组建了一个跨学科的团队来测试这些假设，具体目标如下：(1)定义 HGM在宿主对MESH反应中的作用。高血糖影响的骨髓与正常骨髓的体外实验 将进行细胞实验，以确定hGM对巨噬细胞表型和功能的影响。活体实验 在糖尿病大鼠模型中使用骨髓移植，并通过固定术植入网片 明确骨髓细胞中的hGM与阴道组织中的hGM对90天后长期移植结果的影响。(2) 明确围手术期血糖控制方案对宿主对MESH和长期MESH反应的影响 结果。三种围手术期血糖控制程序--及早、严格、手术前和 实行血糖控制不佳。短期、中期和长期(即7-、42-和 术后90天)将在不同组之间进行比较。(3)界定HGM与糖尿病的关系- 通过对人体网眼组织样本中宿主反应的深入分析，网眼并发症的相关风险 从患有网眼并发症的妇女那里获得的。 这项研究将为糖尿病女性种植体长期并发症的机制提供洞察力。 并为未来的预防战略提供信息，以改善这一迅速增长的人口中的健康结果。

Urogynecologic meshes are often implanted in women to treat stress urinary incontinence and pelvic organ prolapse, two most common pelvic floor disorders. While peri-operative glycemic control is the standard of care, women with diabetes experience ~5-fold higher risk of developing mesh-related complications such as mesh exposure into vaginal cavity and pelvic chronic pain. These complications significantly impair women’s life quality and increase health costs. Since diabetes affects 1 in 10 adult women in the US and the incidence continues to increase, defining the mechanism underlying the diabetes-associated risk of mesh complications is critical to improve patient care and decrease societal expenses. Studies have demonstrated that the beneficial effects of intensive glycemic control are markedly decreased if long episodes of hyperglycemia precede the treatment, referred to as “hyperglycemic memory” (HgM). To date, there has been no investigation into how this phenomenon impacts the outcomes of women receiving urogynecologic meshes. Our preliminary data in a rat model support that hyperglycemia is harmful to vaginal immune response to mesh in the long term and that HgM in bone marrow (BM) cells may impact mesh outcomes. Here we hypothesize that hyperglycemia leaves epigenetic marks in BM progenitor cells, which drives macrophage dysfunction at mesh-tissue interface, leading to an increased risk of mesh complications despite later glucose normalization. As epigenetic modification is reversible with long-term glycemic normalization, we further hypothesize that tight and long-term peri-operative glycemic control attenuates the negative impact of HgM, thereby improves mesh outcomes in women with diabetes. We have assembled an interdisciplinary team to test the hypotheses with the following specific aims: (1) Define the role of HgM in host response to mesh. In vitro experiments using hyperglycemia-impacted vs. normal BM cells will be performed to define impact of HgM on macrophage phenotype and function. In vivo experiments using BM transplantation in a diabetic rat model with mesh implanted via sacrocolpopexy will be performed to define the impact of HgM in BM cells vs. HgM in vaginal tissue on the long-term mesh outcomes at 90 days. (2) Define the effect of peri-operative glycemic control regimens on host response to mesh and long-term mesh outcomes. Three peri-operative glycemic control procedures – early and strict, immediately before surgery, and poor glycemic control will be implemented. Mesh outcomes at short-, medium-, and long-terms (i.e., 7-, 42-, and 90-days post-surgery) will be compared between groups. (3) Define the relationship between HgM and diabetes- associated risk of mesh complications via an in-depth analysis of host response in human mesh-tissue samples obtained from women with mesh complications. This study will provide insight into the mechanism of long-term implant complications in women with diabetes and inform future preventive strategies to improve health outcomes in this rapidly expanding demographic.