Benign prostatic hyperplasia (BPH) is a prevalent and chronic progressive disease that may be correctly defined as prostate gland enlargement secondary to hyperproliferation of stromal and glandular cells, with predominance of mesenchymal cells . Aging and the presence of androgens are necessary for the development of BPH, but the pathogenesis of BPH is still largely unresolved [2–3]. Several parameters including inflammatory mediators, hormones, dietary factors, inflammatory genes, and oxidative stress have been considered to play a role for the development of BPH, but there is no consensus as to which is the primary one. To date, these multifactorial and chronic conditions have been studied to prevent BPH progression.
In the last few years, a potentially important role of inflammation in BPH development and progression has emerged [4–5], and recent clinical trials have suggested a relationship between prostatic inflammations and lower urinary tract symptoms (LUTS) related to BPH [6–7]. Today, even though it is not yet known exactly when and why chronic inflammation occurs, it has been hypothesized that BPH is an immune-mediated inflammatory disease and inflammation may directly contribute to prostate growth [8–10].
INFLAMMATION AND PROSTATE
Acute and chronic prostate inflammation is a common finding in histologic prostate specimens obtained from aging men which reported in 43–98% of specimens [11–12]. Studies on the pathogenesis of BPH have provided an evidence-based thesis that strongly suggests a role of inflammation in the propagation of histologic BPH [9,13–14]. However, it has been more difficult to determine whether the inflammation arose as a normal biologic part of the aging process or whether inflammation actually contributes to prostatic enlargement and development of LUTS .
Investigators have suggested that BPH might have an autoimmune component, whereby antigenic stimuli may result in the development of a chronic inflammatory response within the prostate that leads to tissue rebuilding and stromal growth in the prostate [8,16]. The inflammation-induced damage of the prostatic tissue represents a chronic process of wound healing which activates hyperproliferative programs resulting in BPH nodules . Inflammatory processes may contribute to prostatic enlargement directly through stimulation of prostate growth, or, alternatively, through decreasing prostatic apoptosis.
All baseline biopsies from the Medical Therapy of Prostatic Symptoms (MTOPS) study were examined for the presence of inflammation and 2.6% of the men had acute inflammation, while 43% had chronic inflammation, in prostatic biopsy specimens at baseline. Men with acute or chronic inflammation (ACI) had larger prostate volumes (41.1 vs. 36.8 ml; P = 0.0002) and a greater risk of acute urinary retention (AUR) due to BPH than those without ACI (2.4 vs. 0.6%; P = 0.011). Furthermore, there was a trend for increased overall clinical progression in men with ACI compared with those without ACI, although this was not statistically significant. From these data, it was hypothesized that the presence of histologic inflammation may be a predictor of progression of BPH and need for invasive therapy .
In another prospective study of autopsy specimens obtained from 93 men who had histologic evidence of BPH, chronic inflammation was found in 75% of prostates examined compared with 55% of prostates not affected by BPH . Di Silverio et al. showed that 69% of inflammation was also chronic inflammation, inflammation in the prostate increased significantly with the increase in prostate volume and age.
Although the presence of inflammatory infiltrates in human prostates is a well described situation, the origin of inflammation in the prostate remains a subject of debate and is likely to be multifactorial . Different pathogens are described, including bacterial infections, urine reflux with chemical inflammation, dietary factors, hormones, autoimmune response [21–23], and a combination of these factors. As proposed by De Marzo et al., all of these mechanisms of chronic epithelial injury may be responsible for a decreased barrier function and facilitate the growth of infectious agents, with a chain reaction that further sustains and stimulates the inflammatory response and increases the prostatic inflammatory infiltrates.
INFLAMMATION AND CLINICAL BENIGN PROSTATIC HYPERPLASIA
Clinical evidence reports that chronic inflammation represents a key condition leading to prostate enlargement and to an increased symptoms score as well as a major risk of complications . Furthermore, when inflammation is clinically supposed and then proven histologically, it may be taken into account in the management and treatment of BPH .
Prostatic inflammation is correlated with symptomatic progression, risk for urinary retention, and need for surgery . In cross-sectional studies, patients referred to urology clinics with AUR were more likely to have evidence of inflammation in prostatic specimens compared to men referred for benign prostatic obstruction [26–27]. Intraprostatic inflammation was also present in 70% of men requiring transurethral prostatic resection for AUR compared to 45% of men requiring resection to treat LUTS . Additionally, Roehrborn et al. found that MTOPS participants with acute inflammation in their biopsy specimens were slightly more likely to develop worsening LUTS compared to those without acute inflammation. Taken together, these studies suggest that inflammatory processes may contribute to the development and exacerbation of BPH and LUTS.
The Reduction by Dutasteride of Prostate Cancer Event (REDUCE) trial [6,7] confirmed these data. Among 8224 men enrolled in the REDUCE trial, chronic histologic inflammation was found in greater than 78% of men. Chronic inflammation was more common than acute inflammation (78 vs. 15%, respectively). Statistically significant but clinically small increases in IPSS symptoms were noted in men with inflammation compared with those without. Similarly, statistically significant correlations were found between average chronic inflammation score and the IPSS variables. However, the magnitude of these correlations was small, indicating very weak associations which demonstrate that inflammation in BPH may be important.
The data from the placebo arm of the PCPT demonstrated that when controlled for age and race, high C-reactive protein and interleukin-6 (IL-6) concentrations and low sTNF-RII concentrations may increase the risk of BPH [29▪]. The authors suggested that systemic inflammation or lower levels of soluble receptors that bind inflammatory cytokines may increase BPH risk.
In a cohort study of 282 patients with and without BPH, Robert et al. observed chronic prostatic inflammation in 79, 48, and 20% of severe, intermediate, and no BPH patients, respectively. A significant association among the degree of prostatic inflammation, prostate volume, and urinary symptoms was also confirmed; mean prostate volume was 62 ml with low-grade inflammation and 77 ml in high-grade inflammation (P = 0.002). Similarly, the mean IPSS score was 12 and 21 in low-grade and high-grade inflammation (P = 0.02), respectively.
Although a number of potential markers (C-reactive protein, IL-8, and markers of oxidative stress) have been evaluated, these markers are generally nonspecific for prostate or BPH . However, it opens the search for biomarkers that could be used to stratify patients as to the risk of developing BPH or related BPH adverse outcomes, or to monitor symptoms and response to medical therapy for BPH.
CYTOKINES AND ROLE OF INFLAMMATION IN THE PATHOGENESIS OF HISTOLOGIC BENIGN PROSTATIC HYPERPLASIA
Chronic inflammation can be considered the third component of BPH pathogenesis, taking part with the androgen receptor signaling in the induction of the tissue remodeling typical of the advanced stages of the disease. Prostatic inflammation observed in BPH may cause cytokine release from inflammatory cells and a condition of relative hypoxia resulting from the increasing oxygen demand of proliferating cells that may end up in tissue injury . Cytokines and growth factors released from inflammatory cells may not just interact with immune effectors but also with stromal and epithelial cells of the prostate . Inflammatory mediators may contribute to prostatic epithelial and stromal cell growth both directly, through induction of growth via cytokines that stimulate the production of prostatic growth factors, and indirectly through decreases in prostate cell death via downregulation of prostate cell apoptosis .
In the last years, specific inflammatory mediator pathways have been studied in detail to elucidate the potential role of these pathways in BPH pathogenesis. A large number of inflammatory cells and proinflammatory cytokines may be involved in the proliferation of the prostate. Kramer et al. first investigated the effect of lymphocyte-derived growth factors on prostatic stromal cell growth. They confirmed that BPH tissue contains infiltrates of T lymphocytes, B lymphocytes, and macrophages that are chronically activated and responsible for the release of cytokines – mostly IL-2, IFN-γ, and TGF-β – that may support fibromuscular growth in BPH. Furthermore, an upregulation of different proinflammatory cytokines has been reported in BPH tissue – particularly IL-15 in stromal cells, IL-17 in infiltrating T cells, IFN-γ in basal and stromal cells, and IL-8 in epithelial cells .
Proinflammatory cytokines released from adjacent inflammatory cells were shown to induce the expression of cyclooxygenase-2 (COX-2) in epithelial cells, which then elevated the proliferation rate of cells in the prostate. In 79% of patients with BPH, IL-17 produced by activated T-cells was increased and this overexpression of IL-17 could play a role in increasing COX 2 expression [9,36]. In a report by Penna et al., human prostate stromal cells were shown to act as antigen-presenting cells, activating alloantigen-specific CD4+ T cells to produce IFN-γ and IL-17. It appears that prostate stromal cells may induce and maintain an autoimmune response .
Local hypoxia can play a role as one of the inflammatory mediators by inducing lower levels of reactive oxygen species (ROS), which can promote transdifferentiation of fibroblasts to myofibroblast and neovascularization . As a response to hypoxia, prostatic stromal cells upregulate the secretion of several growth factors that can determine prostatic growth. In particular, increased secretion of vascular endothelial growth factors, fibroblast growth factors, FGF-7, TGF-β, FGF-2, and IL-8 was observed under the hypoxic condition in vitro.
The possible role of TGF-β has also been extensively evaluated [8,39▪▪,40]. TGF-β, an inflammatory cytokine, has been shown to regulate stromal proliferation and differentiation in BPH, and it is a key factor for androgen control of prostatic growth. Descazeaud et al.[39▪▪] investigated the transforming growth factor β-receptor II (TGFBRII) protein expression in BPH patients. They observed a significant association between TGFBRII stromal staining and prostatic volume; BPH inflammation was also associated with TGFBRII staining.
PROSTATIC INFLAMMATION AS A TARGET FOR PREVENTION AND TREATMENT
Prostatic inflammation has been considered a possible target for BPH prevention and treatment, and so far, different anti-inflammatory agents have been tested in vitro and in vivo for the management of BPH [41–45]. Unfortunately, there are few good data available to assess the clinical response of anti-inflammatory therapy in BPH. Several drugs may reduce prostate volume by acting at various points in the inflammatory pathway, possibly through direct action on the antiapoptotic protein bcl-2, indirectly through the COX-2 pathway, or through as yet unidentified mechanisms.
Epidemiological studies showed an inverse correlation between the daily use of NSAIDs and the onset of moderate-to-severe urinary symptoms, low maximum urinary flow rate, increased prostate volume, and elevated PSA levels . Sutcliffe et al. found a positive association between a history of young-onset prostatitis and later development of LUTS; another study suggested that elevated circulating C-reactive protein concentration might be an indicator of ACI in symptomatic BPH . Sutcliffe et al.[49▪▪] found no association for NSAIDs use with the risk of BPH and LUTS. Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial observed a weak positive association between regular NSAID use and prevalent BPH and LUTS , whereas Olmsted County Study observed a strong inverse association between daily NSAID use and incident BPH and LUTS .
Minnery and Getzenberg  showed that doxazosin, as well as ibuprofen, significantly decreased cell viability and induced apoptosis in BPH prostate cell lines. In addition, it decreased the expression of JM-27, a protein particularly expressed in the prostate that appears to be highly upregulated in symptomatic BPH.
Di Silverio et al. hypothesized that the association of rofecoxib with finasteride induced a more rapid improvement in clinical results until the effect of finasteride becomes predominant and they found that, although there was not a significant difference between symptom improvement at 24 weeks, there was a statistically significant advantage of the combination therapy compared with finasteride alone in a short-term interval.
Phytotherapy has become one of the most popular treatment modalities for BPH. One of the primary mechanisms of why these herbal agents work is the anti-inflammatory effects of the various herbal preparations [33,45,52–55]. Vela Navarrete et al. found that patients taking a common phytotherapy for BPH had fewer inflammatory infiltrates in resected prostate specimens, suggesting that this agent may have anti-inflammatory properties.
BXL-628, a potent vitamin D receptor agonist, was able to inhibit prostatic growth and control prostatic inflammation by reducing intraprostatic cell infiltrates (CD4+, CD8+, macrophages, and B cells) and decreasing IFN-γ and IL-17 secretion in in-vitro BPH cell cultures and in an in-vivo experimental model of autoimmune prostatitis [33,43]. At the very least, the potential of anti-inflammatory agents in preventing the progression of BPH merits close examination .
Although we do not completely understand the pathways of prostatic inflammation, accumulating evidence suggests that inflammatory processes affecting both the prostate and the bladder may play essential roles in the development and maintenance of prostate growth and LUTS. In all prostatic diseases, immunologic processes and inflammation either have a role in pathogenesis or are discussed as potential triggers of disease progression. T-cell activity in inflammatory infiltrates may result in the stimulation of stromal and epithelial cell proliferation that is sustained by autoimmune mechanism. Tissue damage and the subsequent chronic process of repetitive wound healing induced by inflammation end up in the development of BPH nodules. There is not yet proof that targeting prostate inflammation with a pharmacologic agent results in a lower incidence and progression or regression of BPH. Further research is required to better understand the role of prostatic inflammation in the initiation, development, and progression of BPH.
Conflicts of interest
Disclaimers: All authors have read and approved the final draft. There is no financial or commercial interest on this article. This work has not already been published and has not been submitted simultaneously to any other journal.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
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