Novel Translational Approaches to BPH/LUTS

描述(由申请人提供)：我们的总体假设是1)前列腺炎症性和局灶性萎缩导致下尿路症状(LUTS)，无论移行区增生或良性前列腺增生症(BPH)的诊断；和2)非那雄胺减少炎症和萎缩的程度，因此下尿路症状。慢性炎症浸润物常见于组织学特征的BPH结节中，炎症程度可预测下尿路结石的进展：这些研究使用切除的组织作为适应证，这可能歪曲炎症程度或偏向炎症与下尿路结石的相关性。我们怀疑，整个前列腺的炎症，不仅是结节，可能与LUTS有关，因为它可能a)反映前列腺感染/损害的历史或对侮辱(包括结节)的炎症反应的倾向，以及b)通过免疫细胞阐述的细胞因子的直接刺激以及由此导致的组织损伤和再生来影响LUTS。此外，局灶性萎缩(一种可能的再生性病变，通常是炎性的(增殖性炎性萎缩))的形态变化是否与LUTS的病因有关尚不清楚。为了验证我们的假设，我们建议对600名参加前列腺癌预防试验(PCPT)的男性进行流行病学、病理学和免疫学相结合的研究，这些人在进入PCPT试验时没有临床上的BPH，根据方案在试验结束时接受了活检，而不考虑适应症。我们将根据试验结束时LUTS的严重程度和LUTS从开始到结束的7年变化对年龄和种族匹配的男性进行抽样。在安慰剂组，我们将评估是否a)炎性渗透或局灶性萎缩的程度以及b)前列腺活检中的免疫细胞图谱因LUTS的严重程度或随时间的变化而不同。我们将评估非那雄胺和安慰剂之间的a)和b)是否不同。炎症和萎缩将通过H&E染色活检切片的图像分析来量化。免疫细胞谱将通过免疫组织化学染色对中性粒细胞、肥大细胞(c-kit)、TH17细胞(CD4+、IL23R)、T调节细胞(CD4+、FoxP3+)、细胞毒性T细胞(CD8+、耗尽的PD-1+和LAG-3+)、巨噬细胞(CD68+、激活的MHC II+)和树突状细胞(CD11c+、激活的MHC II+)进行评估。我们的多学科团队将对基线上没有临床BPH的男性进行第一次大型研究，以1)确定无活检指征的男性的前列腺内免疫环境和局灶性萎缩与LUTS的关系，以及2)评估非那雄胺对炎症和萎缩的影响，从而评估LUTS。 公共卫生相关性：我们整合了流行病学、病理学和免疫学的研究结果，对前列腺癌内炎症的影响，包括免疫细胞图谱和局灶性萎缩对下尿路症状的影响，可能对预防或干预这种男性随着年龄增长而经常经历的令人烦恼的疾病具有重要意义。

DESCRIPTION (provided by applicant): Our overall hypotheses are 1) intraprostatic inflammation and focal atrophy contribute to lower urinary tract symptoms (LUTS) irrespective of transition zone hyperplasia or benign prostatic hyperplasia (BPH) diagnosis; and 2) finasteride reduces extent of inflammation and atrophy, and thus LUTS. Chronic inflammatory infiltrates are common in nodules characteristic of histologic BPH and inflammation extent predicts LUTS progression: these studies were conducted using tissue removed for indication, which might skew inflammation extent or bias the correlation of inflammation with LUTS. We suspect that inflammation throughout the prostate, not only nodular, may be associated with LUTS as it may a) reflect history of prostate infection/damage or propensity to mount an inflammatory response to insults, including in nodules, and b) influence LUTS via direct irritation by cytokines elaborated by immune cells and resultant tissue damage and regeneration. Further, whether morphological changes in focal atrophy, a probable regenerative lesion that is often inflamed (proliferative inflammatory atrophy), is etiologically linked with LUTS is unknown. To test our hypotheses, we propose studies integrating epidemiology, pathology, and immunology in 600 men who at entry in the Prostate Cancer Prevention Trial (PCPT) did not have clinical BPH and per protocol underwent biopsy at trial end irrespective of indication. We will sample age and race-matched men by LUTS severity at trial end and by 7-year change in LUTS from entry to end. In the placebo arm, we will evaluate whether a) extent of inflammatory infiltrates or focal atrophy and b) immune cell profiles in prostate biopsies differs by LUTS severity or change over time. We will assess whether a) and b) differ between finasteride and placebo arms. Inflammation and atrophy will be quantified by image analysis of H&E stained biopsy sections. Immune cell profiles will be evaluated by immunohistochemical staining for neutrophils, mast cells (c-KIT), TH17 cells (CD4+, IL23R), T regulatory cells (CD4+, FoxP3+), cytotoxic T cells (CD8+, exhausted PD-1+ and LAG-3+), macrophages (CD68+, activated MHC class II+), and dendritic cells (CD11c+, activated MHC class II+). Our multidisciplinary team will conduct the first large study of men without clinical BPH at baseline to 1) characterize the intraprostatic immune milieu and focal atrophy in relation to LUTS in men without indication for biopsy and 2) assess influence of finasteride on inflammation and atrophy, and thus LUTS. PUBLIC HEALTH RELEVANCE: The findings from our work integrating across epidemiology, pathology, and immunology on the influence of intraprostatic inflammation, including the immune cell profile, and focal atrophy on lower urinary tract symptoms may have important implications for preventing or intervening on this bothersome condition commonly experienced by men as they age.