Novel Translational Approaches to BPH/LUTS

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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.