Inflammatory Pathways in BPH/LUTS

BPH/LUTS 的炎症通路

• 批准号: 10205048
• 负责人: Simon W Hayward
• 金额: $ 54.58万
• 依托单位: NORTHSHORE UNIVERSITY HEALTHSYSTEM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10205048
• 关键词: 5 Alpha-Reductase Inhibitor; Address; Adrenergic alpha-Antagonists; Androgens; Anti-Inflammatory Agents; Area; Autoimmune; Autoimmune Diseases; Benign Prostatic Hypertrophy; Bladder; Cells; Choristoma; Chronic; Clinical; Complex; Cytokine Signaling; Data; Development; Diabetes Mellitus; Diagnosis; Disease; Disease Outcome; Disease Progression; Elderly man; Environment; Epithelial; Epithelial Cells; Equilibrium; Failure; Gene Expression; Genes; Growth; Human; Hyperplasia; Immune; Immune response; Inbred BALB C Mice; Inbred NOD Mice; Incidence; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interferon Type II; Interleukin-13; Interleukin-4; Interleukin-5; Interleukin-6; Link; Mediating; Mediator of activation protein; Medical; Modeling; Mononuclear; Mus; Muscle Tonus; Non obese; Obesity; Operative Surgical Procedures; Oxidoreductase; Pain; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Play; Procedures; Prostate; Prostatic; Prostatic hypertrophy; Psoriatic Arthritis; Records; Regimen; Regulatory T-Lymphocyte; Reporter; Reporting; Resolution; Rheumatoid Arthritis; Role; Sampling; Series; Severities; Signal Pathway; Signal Transduction; Source; Stromal Cells; T-Lymphocyte Subsets; TNF gene; Testing; Th1 Cells; Time; Tissues; Work; cell type; chemokine; comorbidity; cytokine; diabetic; improved; inflammatory milieu; lower urinary tract symptoms; macrophage; mast cell; men; monocyte; mouse model; novel; novel therapeutics; probasin; response; tissue repair

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.

项目摘要/摘要 由于良性前列腺增生（BPH）而引起的尿路症状较低（LUTS）是一种常见，复杂而 不了解情况。炎症与LUTS严重程度的增加密切相关，也与 BPH的医学治疗失败，导致手术进展。尽管这种复杂性，临床 BPH治疗通常使用两种医学方法遵循脚本格式：α-肾上腺素阻滞剂（α- 阻滞剂）放松肌肉张力和5α-还原酶抑制剂（5ARI）以收缩前列腺。许多男人失败了 医疗治疗，每年在美国进行大约12万手术干预措施 高级人BPH具有基因表达的特征，让人想起自身免疫性中看到的变化 炎症（AI）疾病，例如类风湿关节炎（RA）和牛皮癣。来自评论的数据 120,000例患者记录表明，BPH与AI疾病的诊断呈正相关，并且 AI条件（特别是TNFα拮抗剂）的治疗可减少随后的BPH诊断。这 将BPH的正面联系到其他炎症状况，并表明用于治疗这些方案的特定药物方案 疾病表示BPH疗法的途径。据报道，TH1/TH2和TH17/TREG余额的损失已在 几种炎症性自身免疫性疾病，可能是导致的 RA。 Th1和Th17细胞在许多炎症条件下在人类和小鼠中实施，而 相反的抗炎作用归因于Th2和Treg细胞。同样，我们的初步数据表明 随着BPH的进展，M1/M2巨噬细胞平衡变为更炎症的表型。 M1 反过来，巨噬细胞驱动TH1/TH17极化以维持前列腺中的促炎状态。桅杆 细胞在BPH中起作用，也是疾病中炎症增加的介质 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。拟议的工作围绕着这个想法。我们将定义免疫/炎症 人类BPH进展过程中的环境相对于Th1/Th2，Th17/Treg的增加而定量变化 随着疾病的发展，M1/M2巨噬细胞比率。然后，我们将利用一系列鼠模型进行测试 操纵与存在的细胞类型有关的免疫/炎症环境的后果， 以及细胞间信号传导环境，以测试特定炎症细胞或 相关的趋化因子可以调节前列腺生长。最终目标将检查当前医学的作用 针对特定细胞因子信号通路的方法，并确定这些方法是否有效 在前列腺注射模型中减少前列腺增生。

项目成果

Could TNF-antagonists be a novel treatment strategy for BPH patients?

• DOI: 10.15698/cst2022.06.268
• 发表时间: 2022-06
• 期刊: Cell stress
• 影响因子: 6.4