BPH and Inflammation: Pharmacological Effects of Permixon on Histological and Molecular

Inflammatory Markers. Results of a Double Blind Pilot Clinical AssayOriginal Research Article
European Urology, Volume 44, Issue 5, November 2003, Pages 549-555
R Vela Navarrete, J.V Garcia Cardoso, A Barat, F Manzarbeitia, A Lpez Farr
Abstract
Introduction: The role of infiltrating cells (I.C.), commonly observed in the adenoma interstitial tissue, is
unknown. We tested the hypothesis that I.C. are related with BPH progression by: phenotypically
characterising these cells; quantifying the expression of lymphokines and growth factors; investigating the
response to Permixon (P) in a clinical study. Permixon is a Lipido Sterolic Extract of Serenoa repens
possessing pharmacological activities and widely used in the treatment of men with BPH.
Material and Methods: A multicenter open pilot study of two parallel groups on BPH patients was carried
out. They were randomized to receive either oral Permixon (P) 160 mg bid for three months or to be
followed for 3 weeks without any treatment before surgery (control group C). Strict inclusion and exclusion
criteria were applied to conform homogeneous groups, avoiding interferences of inflammatory drugs or
others. Baseline clinical profile was almost identical in both groups in terms of age (65.75.1 vs. 67.15.8
years), IPSS (19.86.1 vs. 19.05.8), prostate volume (64.818.9 vs. 71.529.3 cc), Qmax (9.63.2 vs.
10.62.6 ml/s), and QL (4.01.1 vs. 3.50.7). Surgery was ultimately performed on 29 patients (17C, 12P)
by TURP or retropubic adenomectomy. Adenoma samples were routinely stained with HE and later
prepared for immunohistochemical studies using CD3, CD20 and CD68 antibodies. Counting of positives
cells, lymphoid aggregates and foci were done using EnVision technique and the Tech Mate processor.
Cytokines, growth factors and eicosanoids were determined by Elisa kits following the manufactured
recommendation.
Results: Histological: A difference was observed in the number of lymphocytes B between C (91.444.1)
and P treated (58.253.7) groups (p=0.097). Biological markers: TNF and IL-1 were dramatically lower
in the Permixon treated group. Other parameters did not show significant changes. Clinical: IPSS in the
Permixon treated group was significantly reduced (p<0.006) from 20.0+5.9 to 14.9+3.8 after three months
of treatment.
Comments: The BPH inflammatory hypothesis was tested in humans. Our pilot study shows a significant
reduction of some inflammatory parameters in prostatic tissues of patients treated with Permixon. These
biological findings justify a pharmacological effect of this drug on the inflammatory status of the adenoma.
A correlation with clinical improvement was observed.


111 Three key chemokines (CCL2, CXCL10 AND IL8) involved in benign prostatic
hyperplasia inflammation are reduced by Permixon treatment
European Urology Supplements, Volume 11, Issue 1, February 2012, Page e111
A. Latil, J. Rouquet, C. Issac, F Lantoine-Adam, C. Libon, T. Nguyen



Blood profile of interleukin-4 and gamma-interferon in patients with benign prostatic hyperplasia
European Urology Supplements, Volume 2, Issue 1, February 2003, Page 20
D. Ebralidze, D. Kochiashvii

Is Benign Prostatic Hyperplasia (BPH) an Immune Inflammatory Disease? Review
Article
European Urology, Volume 51, Issue 5, May 2007, Pages 1202-1216
Gero Kramer, Dieter Mitteregger, Michael Marberger
Abstract
Objectives
Chronic inflammation has been documented for years in benign prostatic hyperplasia (BPH), but only now
has it become evident as a major factor in disease progression. This review highlights the immunologic
key features of chronic inflammation in BPH and the present interpretation of these changes in the
development and progression of BPH.
Results
Almost all BPH specimens show inflammatory infiltrates at histologic examination, but correlation to
bacterial or other foreign antigens has not been established. Recognition of prostate secretion products by
autoreactive T cells and animal models on experimental prostatitis demonstrate an autoimmune
component to chronic inflammation. The infiltrate consists predominantly of chronically activated CD4
+
T
lymphocytes, which are permanently recruited to prostate tissue via elevated expression of interleukin 15
(IL-15) and interferon (IFN-), proinflammatory cytokines produced by smooth muscle and T cells,
respectively. With the appearance of infiltrates, T cell-derived cytokine production of IFN-, IL-2, and
transforming growth factor increases, the former two ultimately reaching 10-fold and the latter 2-fold
higher levels in fully developed BPH than in normal prostates. As mature BPH nodules develop, IL-4 and
IL-13 expression increases >2-fold, corresponding to a T-helper (Th)0/Th2 cytokine pattern. Dysregulation
of the immune response in BPH may occur via elevated expression of proinflammatory IL-17, which
stimulates a multifold production of IL-6 and IL-8, key executors of stromal growth in BPH.
Conclusions
These data strongly suggest that BPH is an immune inflammatory disease. Unravelling the specific nature
of immune dysregulation may help design novel drugs with these specific targets in mind.

The Link Between Benign Prostatic Hyperplasia and Inflammation Review Article
European Urology Supplements, Volume 12, Issue 5, November 2013, Pages 103-109
Maria J. Ribal
Abstract
Context
Benign prostatic hyperplasia (BPH) is one of the most common diseases associated with the aging
process in men, particularly men aged >50 yr, yet only a few predictive factors have been identified. In
recent years, attention has focused on the role of prostatic inflammation in the pathogenesis and
progression of BPH.
Objective
This article reviews recent findings related to the potential link between local and systemic inflammation
and BPH.
Evidence acquisition
In March 2013, at the annual meeting of the European Association of Urology in Milan, Italy, a satellite
symposium entitled Benign Prostatic Hypertrophy (BPH) and Inflammation, from Lab to Clinic, was held
with the goal of reviewing the latest data relating to the link between inflammation and BPH. This paper is
based on one of the presentations at this symposium. A structured PubMed literature search was
performed, and emphasis was placed on results from the past 10 yr.
Evidence synthesis
BPH is characterized by progressive hyperplasia of stromal and glandular cells, and clinically it is defined
by lower urinary tract symptoms. In recent years, there has been accumulating evidence linking prostatic
inflammation with BPH. The inflammatory infiltrates observed in patients with BPH are composed primarily
of chronically activated T-lymphocytes. Cytokines and growth factors released from inflammatory cells
create a proinflammatory environment that may support the fibromuscular growth seen in BPH and may
also be responsible for inducing a state of relative hypoxia as a result of the increased oxygen demand of
the proliferating cells. A number of clinical studies have confirmed the presence of inflammatory infiltrate in
men with BPH, and this infiltrate has been shown to be involved in the pathogenesis, clinical appearance,
and progression of this disorder. There is evidence emerging that systemic inflammation may also play a
role in BPH, since in men with metabolic syndrome there was a significant correlation between prostate
diameter/volume and the number of metabolic syndrome components.
Conclusions
It is clear that a number of different mechanisms are involved in the development and progression of BPH.
Prostatic inflammation is an important feature, since it appears to be involved in the pathogenesis,
symptomatology, and progression of the disease.


The Controversial Relationship Between Benign Prostatic Hyperplasia and Prostate Cancer: The
Role of Inflammation Review Article
European Urology, Volume 60, Issue 1, July 2011, Pages 106-117
Cosimo De Nunzio, Gero Kramer, Michael Marberger, Rodolfo Montironi, William Nelson, Fritz Schrder,
Alessandro Sciarra, Andrea Tubaro

Context
Prostate cancer (PCa) is the most common cancer in the adult male, and benign prostatic hyperplasia
(BPH) represents the most frequent urologic diagnosis in elderly males. Recent data suggest that prostatic
inflammation is involved in the pathogenesis and progression of both conditions.
Objective
This review aims to evaluate the available evidence on the role of prostatic inflammation as a possible
common denominator of BPH and PCa and to discuss its possible clinical implication for the management,
prevention, and treatment of both diseases.
Evidence acquisition
The National Library of Medicine Database was searched for the following Patient population, Intervention,
Comparison, Outcome (PICO) terms: male, inflammation, benign prostatic hyperplasia, prostate cancer,
diagnosis, progression, prognosis, treatment, and prevention. Basic and clinical studies published in the
past 10 yr were reviewed. Additional references were obtained from the reference list of full-text
manuscripts.
Evidence synthesis
The histologic signature of chronic inflammation is a common finding in benign and malignant prostate
tissue. The inflammatory infiltrates are mainly represented by CD3
+
T lymphocytes (7080%, mostly CD4),
CD19 or CD20 B lymphocytes (1015%), and macrophages (15%). Bacterial infections, urine reflux,
dietary factors, hormones, and autoimmune response have been considered to cause inflammation in the
prostate. From a pathophysiologic standpoint, tissue damage associated with inflammatory response and
subsequent chronic tissue healing may result in the development of BPH nodules and proliferative
inflammatory atrophy (PIA). The loss of glutathione S-transferase P1 (GSTP1) may be responsible in
patients with genetic predisposition for the transition of PIA into high-grade intraepithelial neoplasia
(HGPIN) and PCa. Although there is growing evidence of the association among inflammatory response,
BPH, and PCa, we can only surmise on the immunologic mechanisms involved, and further research is
required to better understand the role of prostatic inflammation in the initiation of BPH and PCa. There is
not yet proof that targeting prostate inflammation with a pharmacologic agent results in a lower incidence
and progression or regression of either BPH or PCa.
Conclusions
Evidence in the peer-reviewed literature suggested that chronic prostatic inflammation may be involved in
the development and progression of chronic prostatic disease, such as BPH and PCa, although there is
still no evidence of a causal relation. Inflammation should be considered a new domain in basic and
clinical research in patients with BPH and PCa.

Benign Prostatic Hyperplasia and Its Aetiologies Review Article
European Urology Supplements, Volume 8, Issue 13, December 2009, Pages 865-871
Alberto Briganti, Umberto Capitanio, Nazareno Suardi, Andrea Gallina, Andrea Salonia, Marco Bianchi,
Manuela Tutolo, Valerio Di Girolamo, Giorgio Guazzoni, Patrizio Rigatti, Francesco Montorsi
Context
Benign prostatic hyperplasia (BPH) is a well-known condition characterised by prostate growth
accompanied by lower urinary tract symptoms. Several mechanisms seem to be involved in the
development and progression of BPH.
Objective
To review the most important findings regarding the key mechanisms involved in the pathophysiology of
BPH.
Evidence acquisition
During the 2009 annual meeting of the European Association of Urology in Stockholm, Sweden, a satellite
symposium was held on BPH and its treatment. This paper is based on one of the presentations at the
symposium. A structured, comprehensive literature review was performed using data retrieved from recent
review articles, original articles, and abstracts.
Evidence synthesis
Several mechanisms seem to be implicated in the pathophysiology of BPH. These represent age-related
tissue modifications, hormonal alterations, and metabolic syndrome as well as inflammation. Although
androgens do not cause BPH, the development of BPH requires the presence of androgens. Moreover,
several studies support the association between noninsulin-dependent diabetes mellitus, hypertension,
obesity, and low high-density lipoprotein cholesterol and the development of BPH. Finally, recent
increasing evidence seems to support the idea that BPH consists of an inflammatory-based disorder.
Inflammation would be initiated by an unknown stimulus that would create a proinflammatory milieu within
the gland. This theory is confirmed by several basic research and clinical studies that showed a statistically
significant association between inflammation and BPH severity and progression.
Conclusions
Although the pathogenesis of BPH is not yet fully understood, several mechanisms seem to be involved in
the development and progression of the disease. These mainly include systemic and local hormonal and
vascular alterations as well as prostatic inflammation that would stimulate cellular proliferation.
Inflammation would be initiated by an unknown stimulus that would create a proinflammatory environment
within the prostate. Therefore, from the recent clinical and basic research studies, a novel approach in the
clinical management of BPH might focus on the inflammatory process involved in the development and
progression of the disease.



Inflammation et hyperplasie bnigne de la prostate : cause ou consquence ?
Progrs en Urologie, Volume 20, Issue 6, June 2010, Pages 402-407
G. Robert, M. Salagierski, J.A. Schalken, A. de La Taille
Rsum
Introduction et objectifs
Alors que lhyperplasie bnigne de la prostate (HBP) est la pathologie la plus frquente de lhomme g,
peu de facteurs de risque ont clairement t tablis. Rcemment, linflammation prostatique est apparue
comme une piste intressante. Lobjectif de cet article est de prsenter les principaux travaux scientifiques
qui tudient le rle de linflammation dans le dveloppement et lvolution de lHBP.
Matriel et mthode
Les articles traitant du rle de linflammation dans lHBP ont t identifis grce la base de donnes
PubMed et slectionns en fonction de leur intrt scientifique.
Rsultats
Plusieurs tudes cliniques ont mis en vidence une association entre linflammation et lHBP sans quil soit
possible de conclure quil sagissait dun facteur de risque ou dun piphnomne. Des cellules
inflammatoires ont t mises en vidence en grand nombre au sein du tissu prostatique de lhomme
adulte. Elles scrtent de grandes quantits de cytokines qui interagissent avec le tissu prostatique
environnant, provoquant une acclration de leur croissance et recrutant dautres cellules inflammatoires.
Mais les cellules prostatiques sont elles-mmes capables de scrter des mdiateurs de linflammation,
de stimuler leur propre croissance et de recruter des cellules inflammatoires. Une fois le processus
engag, il semble que linflammation puisse chapper aux mcanismes de rtrocontrle et provoquer une
augmentation du volume de la prostate.
Conclusion
LHBP est une pathologie multifactorielle mais linflammation prostatique chronique a t mise en vidence
comme lun des mcanismes importants de son dveloppement.
Summary
Introduction and objectives
Although benign prostatic hyperplasia (BPH) is the most frequent disease in elderly men, only a few
predictive factors have been clearly identified. Recently, chronic prostatic inflammation has emerged as
one of them. This review aims at describing the scientific proof of a relationship between chronic prostatic
inflammation and BPH.
Material and method
Searching in the PubMed database identified clinical studies and basic research experiments in relation
with the role of inflammation in BPH.
Results
Large clinical studies recently highlighted a relationship between chronic prostatic inflammation and
prostate volume or urinary symptoms. Microscopic studies also found numerous inflammatory cells
infiltrating BPH tissues. Immune cells are releasing cytokines and growth factors to modulate the immune
response but evidences are also showing that they are promoting the epithelial and stromal prostatic cells
growth. Moreover, prostatic cells by themselves are able to secrete inflammatory mediators and finally to
stimulate their own growth. Once the vicious circle has started, it appears that feedback controls can be
overwhelmed and that prostate volume progressively increases.
Conclusion
BPH is a complex disease but chronic prostatic inflammation is one of the mechanisms leading to prostatic
enlargement and urinary symptoms.
ASSOCIATION OF PROSTATIC INFLAMMATION WITH DOWN-REGULATION OF MACROPHAGE
INHIBITORY CYTOKINE-1 GENE IN SYMPTOMATIC BENIGN PROSTATIC HYPERPLASIA Original
Research Article
The Journal of Urology, Volume 171, Issue 6, Part 1, June 2004, Pages 2330-2335
RIKIYA TAOKA, FUMIO TSUKUDA, MASASHI ISHIKAWA, REIJI HABA, YOSHIYUKI KAKEHI
Purpose:
Our previous DNA microarray analyses revealed that the macrophage inhibitory cytokine-1 (MIC-1) gene
was significantly down-regulated in symptomatic benign prostatic hyperplasia (BPH) samples. We
compared the histopathological features of inflammatory changes in prostate adenoma tissues from
individuals with symptomatic and asymptomatic (histological only) BPH using MIC-1 mRNA levels.
Materials and Methods:
Prostate adenoma tissues were obtained from 25 patients who underwent transurethral prostatectomy to
relieve lower urinary tract symptoms due to BPH and 6 patients with bladder cancer who underwent
cystoprostatectomy due to bladder cancer. Inflammatory changes in the prostate were examined
histopathologically and immunohistochemically, and classified according to the consensus classification
system of the Chronic Prostatitis Collaborative Research Network and International Prostatitis
Collaborative Network advocated in 2001 with some modification. MIC-1 mRNA was assessed
quantitatively by real-time reverse transcriptase-polymerase chain reaction.
Results:
MIC-1 gene down-regulation was observed in 16 of 25 symptomatic BPH samples (64.0%), whereas MIC-
1 mRNA was high in 6 of 6 prostate adenoma samples from patients with bladder cancer (p = 0.0006).
MIC-1 gene down-regulation correlated with the grade of glandular/ periglandular inflammatory changes
with statistical significance (p = 0.0387). MIC-1 gene down-regulation was found in only 1 of 7 BPH
samples with a glandular predominant pattern, whereas it was found in 15 of 24 BPH samples with a
mixed type or stromal predominant pattern (p = 0.0373).
Conclusions:
Gland destruction by inflammatory infiltrates, followed by replacement of the stromal component in
symptomatic BPH may be induced by the down-regulation of the MIC-1 gene.


Prostate development and growth in benign prostatic hyperplasia Review Article
Differentiation, Volume 82, Issues 45, NovemberDecember 2011, Pages 173-183
Barry G. Timms, Luke E. Hofkamp
The etiology of benign prostatic hyperplasia [BPH] in elderly men has intrigued anatomists, pathologists
and scientists for centuries. Studies of morbid anatomy, clinical observations and contemporary cellular
biology have contributed to an evolving interpretation of the causality of the disease. Insights into the
detailed microanatomy and ductal architecture of the prostate during stages of fetal and early postnatal
development suggest that mechanisms involved in the early growth period become aberrantly expressed
in elderly men. Age, hormones and epithelialmesenchymal interactions are all contributing factors to the
pathogenesis of BPH. Control of the microenvironment in normal and abnormal growth is a multifactorial
process. Susceptibility to the disease may include clinical comorbid diseases, region-specific changes in
cellcell interactions and a variety of signaling pathways including a novel hypothesis regarding the role of
the primary cilium as a regulator of signal transduction mechanisms. Recent work in animal models has
shown that there are region-specific differences within the prostate that may be significant because of the
dynamic and intricate interplay between the epithelium and mesenchyme. Because of the focal nature of
BPH a closer examination of normal morphogenesis patterns, which defines the gland's architecture, may
facilitate a detailed understanding of the atypical growth patterns.


Physical Activity, Benign Prostatic Hyperplasia, and Lower Urinary Tract Symptoms Original
Research Article
European Urology, Volume 53, Issue 6, June 2008, Pages 1228-1235
J. Kellogg Parsons, Carol Kashefi
Background
While some studies have indicated that physical activity may protect against benign prostatic hyperplasia
(BPH) and lower urinary tract symptoms (LUTS), others have not.
Objective
To evaluate the association of physical activity with BPH and LUTS.
Design, Setting, and Participants
Systematic review and meta-analysis using MEDLINE, the Cochrane Library, EMBASE, and abstracts
from the Annual Meeting of the American Urological Association. We selected observational studies that
provided empirical data and analyzed abstracted data with random effects models.
Measurements
BPH, LUTS, and physical activity levels.
Results and Limitations
Eleven (n = 43 083 men) studies met selection criteria. Eight studies observed inverse, 2 studies null, and
1 study equivocal associations of physical activity with BPH or LUTS. Eight studies (n = 35 675) were
eligible for pooled analyses. We stratified physical activity levels into light, moderate, and vigorous
categories, with a sedentary category for reference. Compared to the sedentary group, the pooled odds
ratios for BPH or LUTS were 0.70 (95% CI 0.441.13, p = 0.14), 0.74 (95% CI 0.600.92, p = 0.005), and
0.74 (95% CI 0.590.92, p = 0.006) for men engaging in light, moderate, and heavy physical activity,
respectively.
Conclusions
Physical activity reduces the risks of BPH and LUTS. These findings are consistent with other studies
demonstrating that the BPH/LUTS complex is associated with modifiable risk factors of cardiovascular
disease and suggest that increased physical activity may prevent or attenuate these conditions.

PPAR: A molecular link between systemic metabolic disease
and benign prostate hyperplasia Review Article
Differentiation, Volume 82, Issues 45, NovemberDecember 2011, Pages 220-236
Ming Jiang, Douglas W. Strand, Omar E. Franco, Peter E. Clark, Simon W. Hayward
The emergent epidemic of metabolic syndrome and its complex list of sequelae mandate a more thorough
understanding of benign prostatic hyperplasia and lower urinary tract symptoms (BPH/LUTS) in the
context of systemic metabolic disease. Here we discuss the nature and origins of BPH, examine its role as
a component of LUTS and review retrospective clinical studies that have drawn associations between
BPH/LUTS and type II diabetes, inflammation and dyslipidemia. PPAR signaling, which sits at the nexus
of systemic metabolic disease and BPH/LUTS through its regulation of inflammation and insulin
resistance, is proposed as a candidate for molecular manipulation in regard to BPH/LUTS. Finally, we
introduce new cell and animal models that are being used to study the consequences of obesity, diabetes
and inflammation on benign prostatic growth.


Distribution of Inflammation, Pre-Malignant Lesions, Incidental Carcinoma in Histologically
Confirmed Benign Prostatic Hyperplasia: A Retrospective AnalysisOriginal Research Article
European Urology, Volume 43, Issue 2, February 2003, Pages 164-175
Franco Di Silverio, Vincenzo Gentile, Anna De Matteis, Gianna Mariotti, Voria Giuseppe, Pastore Antonio
Luigi, Alessandro Sciarra
Objectives: We analyze our experience on BPH through 20 years of histopathological examinations
performed by the same pathologist.
Methods: We retrospectively reviewed all histopathological examinations performed from January 1979 to
December 1998 in patients undergoing surgery in our urological clinic who were diagnosed with BPH. We
limited our evaluation to the following variables in each BPH case analyzed: inflammatory aspects
associated with BPH, presence of focal acinar atrophy, atypical adenomatous hyperplasia (AAH), prostatic
intraepithelial neoplasia (PIN), incidental prostate carcinoma (IC). These histological variables were
analyzed according to some clinical parameters such as age, prostate volume and serum PSA.
Results: The study population was comprised of 3942 cases with histological diagnosis of BPH. The
mean patient age was 68.857.67 years. In particular, inflammatory aspects were associated with BPH in
a high percentage of cases (43.1%=1700 cases), predominantly as chronic inflammation. Observation of
focal acinar atrophy significantly increased according to patient decade of age (p=0.027). There was a
significant trend to increase with age decades (p=0.036) for high grade PIN. A significant difference was
found in IC (T1a, T1b) distribution in the different decades of age and especially in regards to both T1a
and T1b tumors, there was a trend to increase with patient age (p=0.020 and p=0.025, respectively). On
the contrary, the distribution of inflammatory aspects (p<0.001) and AAH (p=0.003) significantly varied
according to prostate volume, and particularly in regards to chronic inflammation, there was a trend to
increase depending on the prostate volume (p=0.002). Only the presence of T1b tumor but not of the other
histological parameters associated to BPH, was able to significantly influence serum PSA.
Conclusion: In our analysis different histological variables associated to BPH are differently influenced by
the age of patients and prostate volume, and they differently influence serum PSA levels.


Association of Interleukin-4 and Interleukin-1 Receptor Antagonist Gene Polymorphisms and Risk
of Benign Prostatic Hyperplasia Original Research Article
Urology, Volume 71, Issue 5, May 2008, Pages 868-872
Rituraj Konwar, Rishi Gara, Manmohan Singh, Vishwajeet Singh, Naibedya Chattopadhyay, Hemant
Kumar Bid
The genetic and cellular processes involved in the etiopathology of benign prostatic hyperplasia (BPH) are
unknown. Although evidence of BPH as an immune-mediated disease distinct from prostate cancer is
growing, the cytokine gene polymorphisms associated with the risk of BPH have been explored less. The
purpose of this study was to investigate the genetic association of polymorphisms of important cytokine
genes (IL-4 and IL-1Ra) with the risk of BPH in a case-control study of a North Indian population.
Methods
The IL-4 and IL-1Ra gene polymorphisms were genotyped with variable number of tandem repeats-
polymerase chain reaction in 150 patients with BPH and normal healthy controls. On the basis of their
response to combined therapy of alpha-adrenergic inhibitor plus 5-alpha-reductase inhibitor, patients were
grouped as responders and nonresponders. The genotype distribution and allelic frequencies between the
patients and controls were compared, and odds ratios with 95% confidence intervals were calculated using
Statistical Package for Social Sciences software, version 11.5.
Results
The difference in genotype frequency distribution for the IL-4 and IL-1Ra gene polymorphisms between the
BPH and control groups were statistically significant (P <0.05). A significant difference (P <0.05) was also
observed between the responder and nonresponder groups in the IL-4 gene variants.
Conclusions
IL-4 and IL-1Ra gene polymorphisms are associated with the risk of BPH. This study for the first time has
demonstrated an association between the IL-4 polymorphism and BPH and particularly influences the
therapeutic response of patients.



Elevated Epithelial Expression of Interleukin-8 Correlates with Myofibroblast Reactive Stroma
in Benign Prostatic Hyperplasia Original Research Article
Urology, Volume 72, Issue 1, July 2008, Pages 205-213
Isaiah G. Schauer, Steven J. Ressler, Jennifer A. Tuxhorn, Truong D. Dang, David R. Rowley
Numerous inflammatory diseases display elevated interleukin (IL)-8, and most are associated with a
reactive stroma. IL-8 expression is also elevated in benign prostatic hyperplasia (BPH), yet little is known
about reactive stroma in BPH. Whether a reactive stroma response exists in BPH, whether this correlates
with elevated IL-8, and whether IL-8 can induce a reactive stroma phenotype have not been determined.
This study was designed to specifically address these issues.
Methods
Normal prostate transition zone tissue and BPH specimens, as identified by the Baylor College of Medicine
pathology department, were examined by quantitative immunohistochemistry to correlate IL-8, smooth
muscle alpha-actin, vimentin, calponin, and tenascin-C. In addition, human prostate stromal cell cultures
were used to evaluate the effect of IL-8 on the expression of reactive stroma biomarkers.
Results
BPH nodules exhibited elevated epithelial IL-8 immunoreactivity, and this correlated with elevated smooth
muscle alpha-actin, reduced calponin, and altered deposition of tenascin-C, relative to the normal prostate
transition zone tissue (P <0.05). Multiple vimentin-positive prostate stromal fibroblast cultures were
induced by IL-8 to also co-express smooth muscle alpha-actin and tenascin-C, typical of a reactive stroma
myofibroblast phenotype.


Expression analysis of thrombospondin 2 in prostate cancer and benign prostatic
hyperplasia Original Research Article
Experimental and Molecular Pathology, Volume 94, Issue 3, June 2013, Pages 438-444
A.R. Matos, C.M. Coutinho-Camillo, L.C.S. Thuler, F.P. Fonseca, F.A. Soares, E.A. Silva, E.R. Gimba
Thrombospondin 2 (TSP2) is a protein with important roles in different tumor types, mainly related to tumor
inhibition. However, there are limiting data regarding TSP2 in prostate cancer (PCa) and benign prostatic
hyperplasia (BPH). We aimed to investigate TSP2 transcript and protein expression in tumoral and non-
tumoral prostate tissues and cell lines, and its implications for PCa diagnosis and progression. TSP2
transcript expression was evaluated by real time PCR in PCa and BPH tissue samples and in tumoral and
non-tumoral cell lines. TSP2 protein expression analysis was conducted by immunohistochemistry in a
tissue microarray (TMA) containing PCa and BPH tissue samples. TSP2 transcript was down-regulated in
PCa tissue samples and cell lines, when compared to BPH and non-tumoral samples (P < 0.01). Receiver
Operating Curve (ROC) analysis demonstrated that TSP2 transcript levels can better distinguish PCa from
BPH tissue samples (P < 0.01) than serum PSA levels (P = 0.299). TSP2 protein expression has been
observed in the cytoplasm of both PCa and BPH epithelial and stromal compartments. TSP2 stromal
staining scores were significantly lower in PCa than in BPH tissues (P < 0.01), while similar TSP2 epithelial
staining patterns were observed in both diseases. Notably, the TSP2 epithelial staining score was
significantly correlated to vascular invasion and biochemical recurrence in PCa tissue samples (P < 0.05).
Our data indicate that TSP2 is down-regulated at PCa tissues and cell lines, especially at stroma
compartment, which could be related to PCa progression. TSP2 levels could potentially be applied for
differential PCa and BPH diagnosis.


Seminal Plasma Cytokines and Chemokines in Prostate Inflammation: Interleukin 8 as a Predictive
Biomarker in Chronic Prostatitis/Chronic Pelvic Pain Syndrome and Benign Prostatic
Hyperplasia Original Research Article
European Urology, Volume 51, Issue 2, February 2007, Pages 524-533
Giuseppe Penna, Nicola Mondaini, Susana Amuchastegui, Selene Degli Innocenti, Marco Carini, Gianluca
Giubilei, Benedetta Fibbi, Enrico Colli, Mario Maggi, Luciano Adorini



Interleukin-8 Is a Paracrine Inducer of Fibroblast Growth Factor 2, a Stromal and Epithelial Growth
Factor in Benign Prostatic Hyperplasia Original Research Article
The American Journal of Pathology, Volume 159, Issue 1, July 2001, Pages 139-147
Dipak Giri, Michael Ittmann



Interleukin-1 Is a Paracrine Inducer of FGF7, a Key Epithelial Growth Factor in Benign Prostatic
Hyperplasia Original Research Article
The American Journal of Pathology, Volume 157, Issue 1, July 2000, Pages 249-255
Dipak Giri, Michael Ittmann


Evaluation of Interleukin-8 in Expressed Prostatic Secretion as a Reliable Biomarker of
Inflammation in Benign Prostatic Hyperplasia Original Research Article
Urology, Volume 74, Issue 2, August 2009, Pages 340-344
Liangren Liu, Qijun Li, Ping Han, Xiang Li, Hao Zeng, Yuchun Zhu, Qiang Wei