Inflammatory Pathways in BPH/LUTS

项目摘要/摘要 良性前列腺增生症(BPH)所致的下尿路症状(LUTS)是一种常见、复杂和 知之甚少的情况。炎症与LUTS严重程度的增加密切相关，也与 良性前列腺增生症的药物治疗失败，导致进展到外科手术。尽管这种复杂性，临床上 前列腺增生症的治疗通常遵循两种医学方法的脚本格式：α肾上腺素能阻滞剂(α- 阻滞剂)来放松肌肉张力，5种α还原酶抑制剂(5ARI)来缩小前列腺。很多男人都没能做到这些 医疗治疗，在美国每年大约有12万例外科手术。我们已经表明 晚期人类良性前列腺增生症的基因表达谱使人联想到自身免疫的变化 炎症(AI)条件，如类风湿性关节炎(RA)和牛皮癣。数据来自于对 12万名患者的记录表明，BPH与AI疾病的诊断呈正相关，以及 AI疾病的治疗，特别是使用肿瘤坏死因子α拮抗剂，减少了随后的良性前列腺增生症的诊断。这 良性前列腺增生症与其他炎症性疾病呈正相关，并表明使用特定的药物疗法来治疗这些疾病 疾病预示着良性前列腺增生症的治疗途径。报告了Th1/Th2和Th17/Treg平衡的丢失 几种炎症性自身免疫性疾病，可能是导致 拉。Th1和Th17细胞与人类和小鼠的许多炎症状态有关，而 相反的抗炎作用归因于Th2和Treg细胞。同样，我们的初步数据显示， 随着BPH的进展，M1/M2巨噬细胞平衡改变为更具炎症性的表型。M1型 巨噬细胞反过来驱动Th1/Th17极化，以维持前列腺的促炎状态。桅杆 细胞在良性前列腺增生症中发挥作用，也是疾病中炎症增加的公认媒介。 例如RA。我们假设免疫/炎症环境的变化是BPH的主要驱动因素 发病机制。拟议的工作围绕这一想法展开。我们将定义免疫/炎症 人类良性前列腺增生症进展期间的环境以量化相对于Th1/Th2、Th17/Treg增加的变化 M_1/M_2巨噬细胞比率随病情进展而变化。然后我们将利用一系列的小鼠模型来测试 根据存在的细胞类型操纵免疫/炎症环境的后果， 以及细胞间信号环境来测试特定的炎性细胞或 相关的趋化因子可以调节前列腺的生长。最终目标将检验当前医学的作用 针对特定细胞因子信号通路的方法，并确定这些途径是否对 减少前列腺炎性模型中的前列腺增生。

PROJECT SUMMARY/ABSTRACT Lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) is a common, complex and poorly understood condition. Inflammation is strongly associated with increased LUTS severity and also with the failure of medical treatment for BPH, resulting in progression to surgery. Despite this complexity, clinical BPH treatment normally follows a scripted format using two medical approaches: α-adrenergic blockers (α- blockers) to relax muscle tone and 5α-reductase inhibitors (5ARI) to shrink the prostate. Many men fail these medical treatments, resulting in around 120,000 surgical interventions annually in the U.S. We have shown that advanced human BPH has a profile of gene expression reminiscent of changes seen in autoimmune inflammatory (AI) conditions such as rheumatoid arthritis (RA) and psoriasis. Data from a review of over 120,000 patient records demonstrated that BPH is positively correlated with the diagnosis of AI conditions, and that treatment of AI conditions, specifically with TNFα antagonists, reduces subsequent BPH diagnoses. This positively links BPH to other inflammatory conditions and shows that specific drug regimens used to treat these diseases indicate avenues for BPH therapy. Loss of Th1/Th2 and Th17/Treg balance has been reported in several inflammatory autoimmune diseases and may be responsible for the development and progression of RA. Th1 and Th17 cells are implicated in many inflammatory conditions in humans and mice, while an opposing anti-inflammatory role is attributed to Th2 and Treg cells. Likewise, our preliminary data show that the M1/M2 macrophage balance changes to a more inflammatory phenotype as BPH progresses. M1 macrophages, in turn, drive Th1/Th17 polarization to maintain a proinflammatory state in the prostate. Mast cells play a role in BPH and are also recognized mediators of the increase in inflammation seen in diseases such as RA. We hypothesize that changes in the immune/inflammatory environment are major drivers of BPH pathogenesis. The proposed work centers around this idea. We will define the immune/inflammatory environment during human BPH progression to quantify changes relative to increases in Th1/Th2, Th17/Treg and M1/M2 macrophage ratios as the disease progresses. We will then utilize a series of murine models to test the consequences of manipulating the immune/inflammatory environment in relation to the cell types present, as well as the intercellular signaling environment to test the premise that specific inflammatory cell or associated chemokines can regulate prostate growth. The final aim will examine the role of current medical approaches aimed at specific cytokine signaling pathways and determine whether these are effective at reducing prostatic hyperplasia in a model of prostatic inflammation.