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.

项目总结/摘要 良性前列腺增生（BPH）引起的下尿路症状（LUTS）是一种常见的、复杂的， 不太了解情况。炎症与LUTS严重程度的增加密切相关， BPH的药物治疗失败，导致进展到手术。尽管如此，临床 前列腺增生治疗通常遵循脚本格式，使用两种医学方法：α-肾上腺素能阻滞剂（α- 阻滞剂）以放松肌肉张力和5α-还原酶抑制剂（5ARI）以收缩前列腺。很多人都失败了 在美国，每年大约有120，000例外科手术。我们已经证明， 晚期人BPH的基因表达谱与自身免疫性前列腺增生相似， 炎症（AI）病症，如类风湿性关节炎（RA）和银屑病。数据来自对超过 120，000例患者记录表明，BPH与AI状况的诊断呈正相关， 治疗AI疾病，特别是用TNFα拮抗剂，可以减少随后的BPH诊断。这 良性前列腺增生症与其他炎症性疾病的积极联系，并表明用于治疗这些疾病的特定药物方案， 指出BPH治疗的途径。Th 1/Th 2和Th 17/Treg平衡的丧失已经在 几种炎性自身免疫性疾病，并可能负责的发展和进展 RA. Th 1和Th 17细胞与人类和小鼠中的许多炎症性疾病有关，而Th 1和Th 17细胞与人类和小鼠中的许多炎症性疾病有关。 相反的抗炎作用归因于Th 2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 反过来，巨噬细胞驱动Th 1/Th 17极化以维持前列腺中的促炎状态。桅杆 细胞在BPH中发挥作用，并且也是疾病中所见炎症增加的公认介质 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。我们将定义免疫/炎症 在人BPH进展过程中的环境，以量化相对于Th 1/Th 2，Th 17/Treg增加的变化 和M1/M2巨噬细胞比率。然后，我们将利用一系列小鼠模型来测试 操纵与存在的细胞类型相关的免疫/炎症环境的后果， 以及细胞间信号环境，以测试特定的炎症细胞或 相关趋化因子可调节前列腺生长。最后一个目标是研究当前医疗保健的作用。 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， 减少前列腺炎症模型中的前列腺增生。

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