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URRENT
C
OPINION
Purpose of review
This review aims to evaluate the available evidence on the role of prostatic inflammation in the
pathogenesis and progression of benign prostatic hyperplasia (BPH).
Recent findings
Although there is still no evidence of a causal relation, accumulating evidence suggests that inflammation
may contribute to the development of BPH and lower urinary tract symptoms (LUTS). Inflammatory infiltrates
are frequently observed in prostate tissue specimens from men with BPH and the presence or degree of
inflammation has been found to be correlated with prostate volume and weight. The inflammatory injury
may contribute to cytokine production by inflammatory cells driving local growth factor production and
angiogenesis in the prostatic tissue. This proinflammatory microenvironment is closely related to BPH
stromal hyperproliferation and tissue remodeling with a local hypoxia induced by increased oxygen
demands by proliferating cells which supports chronic inflammation as a source of oxidative stress leading
to tissue injury in infiltrating area.
Summary
Although the pathogenesis of BPH is not yet fully understood and several mechanisms seem to be involved
in the development and progression, recent studies strongly suggest that BPH is an immune inflammatory
disease. The T-cell activity and associated autoimmune reaction seem to induce epithelial and stromal cell
proliferation. Further understanding of the role of inflammation in BPH and clinical detection of this
inflammation will expand the understanding of BPH pathogenesis and its histologic and clinical
progression, allow risk stratification for patients presenting with BPH-related LUTS, and suggest novel
treatment strategies.
Keywords
benign prostate hyperplasia, cytokines, immune response, inflammation, lower urinary tract symptoms,
pathogenesis
INTRODUCTION
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 [1].
Aging and the presence of androgens are necessary
for the development of BPH, but the pathogenesis
of BPH is still largely unresolved [23]. 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.
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KEY POINTS
Although the pathogenesis of BPH is not yet fully
understood and several mechanisms seem to be
involved in the development and progression, recent
studies strongly suggest that BPH is an immune
inflammatory disease.
The T-cell activity and associated autoimmune reaction
seem to induce epithelial and stromal cell proliferation.
Understanding of the role of inflammation in BPH and
clinical detection of this inflammation will expand the
understanding of BPH pathogenesis and its histologic
and clinical progression.
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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 [18].
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 [19]. Di Silverio
et al. [11] 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 [20]. Different pathogens are described,
including bacterial infections, urine reflux with
chemical inflammation, dietary factors, hormones,
autoimmune response [2123], and a combination
of these factors. As proposed by De Marzo et al. [21],
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.
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&&
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 [4145]. Unfortunately, there are few good
data available to assess the clinical response of antiinflammatory 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 [46]. Sutcliffe et al. [47]
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 [48]. 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 [50], whereas
Olmsted County Study observed a strong inverse
association between daily NSAID use and incident
BPH and LUTS [46].
Minnery and Getzenberg [51] 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
&&
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CONCLUSION
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.
Volume 23 Number 1 January 2013
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Acknowledgements
None.
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.
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&&
10
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