Novel Translational Approaches to BPH/LUTS

描述（由申请人提供）：我们的总体假设是：1)前列腺内炎症和局灶性萎缩导致下尿路症状（LUTS），与过渡带增生或良性前列腺增生（BPH）诊断无关；2)非那雄胺减轻了炎症和萎缩的程度，从而减少了LUTS。慢性炎症浸润在组织学上的BPH结节中很常见，炎症程度预测LUTS进展：这些研究是用切除的组织作为指征进行的，这可能会扭曲炎症程度或炎症与LUTS的相关性。我们怀疑，不仅是结节性前列腺炎症，整个前列腺的炎症可能与LUTS有关，因为它可能a)反映了前列腺感染/损伤的历史或对损伤（包括结节性前列腺）产生炎症反应的倾向，b)通过免疫细胞产生的细胞因子的直接刺激和由此产生的组织损伤和再生来影响LUTS。此外，局灶性萎缩的形态学改变是否与LUTS有病因上的联系尚不清楚，局灶性萎缩可能是一种经常发炎的再生病变（增殖性炎性萎缩）。为了验证我们的假设，我们提出了一项综合流行病学、病理学和免疫学的研究，纳入了600名在前列腺癌预防试验（PCPT）开始时没有临床BPH的男性，并在试验结束时无论有无适应症均按方案进行了活检。我们将根据试验结束时LUTS的严重程度和从开始到结束的7年LUTS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a)炎症浸润或局灶性萎缩的程度和b)前列腺活检中的免疫细胞谱是否因LUTS严重程度或随时间变化而不同。我们将评估a)和b)在非那雄胺组和安慰剂组之间是否有差异。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评估中性粒细胞、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PD-1+和LAG-3+）、巨噬细胞（CD68+、活化MHC II+）和树突状细胞（CD11c+、活化MHC II+）。我们的多学科团队将对基线无临床BPH的男性进行首次大型研究，以1)表征前列腺内免疫环境和无活检指征的男性与LUTS相关的局灶性萎缩，2)评估非那雄胺对炎症和萎缩的影响，从而评估LUTS。

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.