Inflammatory Pathways in BPH/LUTS

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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.