Abstract
Benign prostatic hyperplasia (BPH) is a progressive disease in elderly men, but potential factors accelerating its progression remain largely unknown. The aim of this study was to elucidate the factors affecting BPH progression by understanding the complex mechanisms causing early- progressed BPH, which progresses rapidly and requires surgical intervention before the age of 50. Three groups of human prostate tissue samples, from patients with early-progressed BPH, age-matched prostate and elderly BPH tissues, were collected (n = 25 each). We compared these tissues to determine the histologic features and molecular mechanisms underlying BPH progression. We found that early-progressed BPH samples were characterised by aberrant stromal hyper-proliferation, collagen deposition and increased M2 macrophage infiltration, compared to those from age-matched prostate and elderly BPH tissues. The M2 macrophage–fibroblast co-culture system demonstrated that the myofibroblast phenotypes were strongly induced only in fibroblasts from the early-progressed BPH samples, while the co-cultured M2 macrophages expressed high levels of pro-fibrotic cytokines, such as IL4 and TGFβ1. M2 macrophage-derived IL4, but not TGFβ1, selectively induced the myofibroblast phenotype through the JAK/STAT6, PI3K/AKT and MAPK/ERK signalling pathways in the early-progressed BPH prostate fibroblasts. Taken together, our results indicate that induction of the myofibroblast phenotype may lead to BPH progression through M2 macrophage-mediated IL4 signalling, and that IL4 may represent a potential therapeutic target, allowing the prevention of M2 macrophage activation and fibroblast-to-myofibroblast differentiation.
Highlights
Benign prostatic hyperplasia (BPH) is the most frequently diagnosed urological disease in elderly men[1]
BPH is a slowly-progressive disease in elderly men, early-progressed BPH is a special type, with rapid clinical progression and severe lower urinary-tract symptoms (LUTS), requiring surgery before the age of 50
We showed that M2 macrophages induce myofibroblast phenotype and promote stromal fibrotic tissue remodelling in the early-progressed BPH
Summary
Benign prostatic hyperplasia (BPH) is the most frequently diagnosed urological disease in elderly men[1]. Multiple risk factors, including ageing, hormonal alterations, increased sympathetic nerve activity and chronic inflammation have been proposed to be involved in the pathogenesis and progression of BPH8, but no consensus on the main cause of this disease has been reached. The majority of aetiological postulates indicated that chronic histological inflammation could be an originator and facilitator of BPH9. Almost all prostate tissues from patients with BPH showed increased infiltration of immune cells, as well as enrichment of inflammatory mediators and growth factors in the tissue environment[10]. Subsequent inflammatory tissue damage and chronic process of repetitive wound healing and tissue remodelling could lead to a prominent proliferation of stromal and epithelial cells, facilitating BPH progression[9]. The histologic features and molecular mechanisms leading to the rapid progression of BPH were explored
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