Experimental rodent models of prostatitis: limitations and potential

Vykhovanets, Eugene V.; Resnick, Martin I.; MacLennan, Gregory T.; Gupta, Sanjay

doi:10.1038/sj.pcan.4500930

Cited by 96 publications

(106 citation statements)

References 172 publications

(205 reference statements)

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“…While these models share some histologic features with CPPS in humans, induced prostatitis may not accurately reflect spontaneous disease. Spontaneous prostatitis has been described in several aged rat strains and even in aged NOD mice, but the mechanism by which these strains render the host susceptible to prostatitis is unclear (16,17). To our knowledge, none of the prostate antigens identified in these mouse models have been shown to date to be relevant for the human disease.…”

Section: Introductionmentioning

confidence: 92%

An aberrant prostate antigen–specific immune response causes prostatitis in mice and is associated with chronic prostatitis in humans

Hou¹,

DeVoss²,

Dao³

et al. 2009

J. Clin. Invest.

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Chronic prostatitis is a common disease of unclear etiology and has no specific treatment. Mice deficient in the expression of the autoimmune regulator (Aire) gene, which are defective in thymic expression of self antigens and central tolerance, develop spontaneous prostatitis. In this study, we found that Aire-deficient mice developed spontaneous B and T cell immune responses to a prostate autoantigen, seminal vesicle secretory protein 2 (SVS2), which we believe to be novel. We show that thymic expression of this self antigen was Aire dependent. Moreover, prostatitis was induced in WT mice through immunization with SVS2, demonstrating that immunity to SVS2 was sufficient to induce prostatitis. The clinical relevance of this antigen was highlighted by our observation that patients with chronic prostatitis possessed specific autoantibodies against the human SVS2-like seminal vesicle protein semenogelin. These results provide direct evidence that spontaneous chronic prostatitis is an autoimmune disease and is regulated by both central and peripheral tolerance. Moreover, SVS2 and semenogelin are among the relevant autoantigens in mice and humans, respectively.

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Section: Introductionmentioning

confidence: 92%

An aberrant prostate antigen–specific immune response causes prostatitis in mice and is associated with chronic prostatitis in humans

Hou¹,

DeVoss²,

Dao³

et al. 2009

J. Clin. Invest.

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“…It is also the most common outpatient condition seen in men under 50 years of age and accounts for more clinical visits than either PCa and/or benign prostatic hyperplasia. 1,2 At present our knowledge of prostatitis is lacking, with 90% to 95% of cases having an unknown etiology. This represents a significant problem, particularly as prostatitis has also been implicated in the development of PCa.…”

mentioning

confidence: 99%

Increased Endogenous Estrogen Synthesis Leads to the Sequential Induction of Prostatic Inflammation (Prostatitis) and Prostatic Pre-Malignancy

Ellem

Wang

Poutanen

et al. 2009

The American Journal of Pathology

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Prostatitis causes substantial morbidity to men, through associated urinary symptoms, sexual dysfunction, and pelvic pain; however, 90% to 95% of cases have an unknown etiology. Inflammation is associated with the development of carcinoma, and, therefore, it is imperative to identify and study the causes of prostatitis to improve our understanding of this disease and its role in prostate cancer. As estrogens cause prostatic inflammation, here we characterize the murine prostatic phenotype induced by elevated endogenous estrogens due to aromatase overexpression (AROM؉). Early-life development of the AROM؉ prostate was normal; however, progressive changes culminated in chronic inflammation and pre-malignancy. The AROM؉ prostate was smaller at puberty compared with wild-type controls. Mast cell numbers were significantly increased at puberty and preceded chronic inflammation, which emerged by 40 weeks of age and was characterized by increased mast cell, macrophage, neutrophil, and T-lymphocyte numbers. The expression of key inflammatory mediators was also significantly altered, and premalignant prostatic intraepithelial neoplasia lesions emerged by 52 weeks of age. Taken together, these data link estrogens to prostatitis and premalignancy in the prostate, further implicating a role for estrogen in prostate cancer. These data also establish the AROM؉ mouse as a novel, non-bacterial model for the study of prostatitis. Prostatitis, an exceedingly common condition in the male population worldwide, has an incidence of ϳ9% and a prevalence of ϳ14%, and, unlike benign prostatic hyperplasia and prostate cancer (PCa), which are predominantly diseases of older men, prostatitis afflicts men of all ages. It is also the most common outpatient condition seen in men under 50 years of age and accounts for more clinical visits than either PCa and/or benign prostatic hyperplasia.1,2 At present our knowledge of prostatitis is lacking, with 90% to 95% of cases having an unknown etiology. This represents a significant problem, particularly as prostatitis has also been implicated in the development of PCa.3-5 Given the prevalence of prostatitis and this putative link to PCa, it is vitally important to identify the unknown causes of prostatitis.Several causes of prostatitis have been postulated, including hormonal variation or exposure, infection due to sexually transmitted disease, 6 dietary factors, and physical trauma from urine reflux. 7 However, of particular interest is an apparent link between estrogen and prostatic inflammation, 8 which has emerged mainly from the administration of pharmacological levels of exogenous estrogen to rodents.9 Additional data obtained from further rodent studies show that the prostate gland is particularly sensitive to estrogenic exposure during development in fetal and neonatal life; transient estrogen exposure before puberty results in inflammation later in life, well after the exposure has occurred.10,11 Several decades of research from various laboratories, including our own, has demonstrated that...

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“…Several animal models that induce histological inflammation of the prostate by spontaneous, immune-mediated, and/or infectious methodologies have been developed to recapitulate aspects of CP/CPPS (35). Infection-based models of prostatitis have relied on bacterial strains isolated from cystitis or acute prostatitis cases (7), of which UPEC is one of the most commonly isolated pathogens (2).…”

mentioning

confidence: 99%

Uropathogenic Escherichia coli Induces Chronic Pelvic Pain

et al. 2011

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Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a debilitating syndrome of unknown etiology often postulated, but not proven, to be associated with microbial infection of the prostate gland. We hypothesized that infection of the prostate by clinically relevant uropathogenic Escherichia coli (UPEC) can initiate and establish chronic pain. We utilized an E. coli strain newly isolated from a patient with CP/CPPS (strain CP1) and examined its molecular pathogenesis in cell culture and in a murine model of bacterial prostatitis. We found that CP1 is an atypical isolate distinct from most UPEC in its phylotype and virulence factor profile. CP1 adhered to, invaded, and proliferated within prostate epithelia and colonized the prostate and bladder of NOD and C57BL/6J mice. Using behavioral measures of pelvic pain, we showed that CP1 induced and sustained chronic pelvic pain in NOD mice, an attribute not exhibited by a clinical cystitis strain. Furthermore, pain was observed to persist even after bacterial clearance from genitourinary tissues. CP1 induced pelvic pain behavior exclusively in NOD mice and not in C57BL/6J mice, despite comparable levels of colonization and inflammation. Microbial infections can thus serve as initiating agents for chronic pelvic pain through mechanisms that are dependent on both the virulence of the bacterial strain and the genetic background of the host.Prostatitis is a common urologic disease that results in over 2 million outpatient visits per year in the United States, including 8% of all visits to urologists and 1% of those to primary care physicians (5). The disease is classified into four categories, including acute bacterial prostatitis, chronic bacterial prostatitis, chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), and asymptomatic inflammatory prostatitis.The third disease category, CP/CPPS, accounts for approximately 90% of all chronic prostatitis cases and is clinically manifested as chronic pain in the perineum, rectum, prostate, penis, testicles, and abdomen (5). Despite the predominantly nonbacterial nature of CP/CPPS, up to 8% of patients with CP/CPPS harbor uropathogens that have traditionally been deemed to be of no significance (25). Numerous studies have also identified bacterial DNA in prostate samples from CP/ CPPS patients (9,19,20,22,25). CP/CPPS accompanied by uropathogens is differentiated from chronic bacterial prostatitis by the requirement for clinical symptoms of pelvic pain and the lack of recurrent urinary tract infections (UTIs).It has been suggested that the virulence of major uropathogens such as UPEC is dependent on the expression of multiple virulence factors (10, 15). Phylogenetic analysis suggests that prostatitis-causing uropathogenic Escherichia coli (UPEC) strains largely belong to the B2 phylogenetic group and exhibit a wide variety of virulence traits, including nonhemagglutinin adhesin-siderophore receptor (ihA), type 1 fimbriae (fimH), the salmochelin siderophore receptor (iroN), and outer membrane protease T (ompT) (1,12,...

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Experimental rodent models of prostatitis: limitations and potential

Cited by 96 publications

References 172 publications

An aberrant prostate antigen–specific immune response causes prostatitis in mice and is associated with chronic prostatitis in humans

An aberrant prostate antigen–specific immune response causes prostatitis in mice and is associated with chronic prostatitis in humans

Increased Endogenous Estrogen Synthesis Leads to the Sequential Induction of Prostatic Inflammation (Prostatitis) and Prostatic Pre-Malignancy

Uropathogenic Escherichia coli Induces Chronic Pelvic Pain

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