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Prostatic inflammation induces fibrosis in a mouse model of chronic bacterial infection.

ABSTRACT: Inflammation of the prostate is strongly correlated with development of lower urinary tract symptoms and several studies have implicated prostatic fibrosis in the pathogenesis of bladder outlet obstruction. It has been postulated that inflammation induces prostatic fibrosis but this relationship has never been tested. Here, we characterized the fibrotic response to inflammation in a mouse model of chronic bacterial-induced prostatic inflammation. Transurethral instillation of the uropathogenic E. coli into C3H/HeOuJ male mice induced persistent prostatic inflammation followed by a significant increase in collagen deposition and hydroxyproline content. This fibrotic response to inflammation was accompanied with an increase in collagen synthesis determined by the incorporation of 3H-hydroxyproline and mRNA expression of several collagen remodeling-associated genes, including Col1a1, Col1a2, Col3a1, Mmp2, Mmp9, and Lox. Correlation analysis revealed a positive correlation of inflammation severity with collagen deposition and immunohistochemical staining revealed that CD45+VIM+ fibrocytes were abundant in inflamed prostates at the time point coinciding with increased collagen synthesis. Furthermore, flow cytometric analysis demonstrated an increased percentage of these CD45+VIM+ fibrocytes among collagen type I expressing cells. These data show-for the first time-that chronic prostatic inflammation induces collagen deposition and implicates fibrocytes in the fibrotic process.

SUBMITTER: Wong L

PROVIDER: S-EPMC4065064 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Prostatic inflammation induces fibrosis in a mouse model of chronic bacterial infection.

Wong Letitia L Hutson Paul R PR Bushman Wade W

PloS one 20140620 6

Inflammation of the prostate is strongly correlated with development of lower urinary tract symptoms and several studies have implicated prostatic fibrosis in the pathogenesis of bladder outlet obstruction. It has been postulated that inflammation induces prostatic fibrosis but this relationship has never been tested. Here, we characterized the fibrotic response to inflammation in a mouse model of chronic bacterial-induced prostatic inflammation. Transurethral instillation of the uropathogenic E ...[more]

PMID: 24950301

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Project description:There is increasing evidence showing that chronic non-bacterial prostatic inflammation is involved in the pathogenesis of benign prostatic hyperplasia (BPH) and male lower urinary tract symptoms (LUTS). It has also been reported that estrogen receptor ? (ER?) could have an immunoprotective role in prostatic tissue. Therefore, we investigated the effect of ER?-activation on not only prostatic inflammation, but also bladder overactive conditions in a rat model with nonbacterial prostatic inflammation.Male Sprague-Dawley rats (8 weeks, n?=?15) were divided into three groups: sham-saline group (n?=?5), formalin-vehicle group (n?=?5), and formalin-treatment group (n?=?5). The sham-saline group had sham operation and 50??l normal saline injected into each ventral lobe of the prostate. The formalin-vehicle group had 50??l 5% formalin injection into bilateral ventral lobes of the prostate. The formalin-treatment group was treated with 3?-Adiol (a selective ER? agonist precursor) at a dose of 3?mg/kg daily from 2 days before induction of prostatic inflammation, whereas formalin-vehicle rats received vehicle (olive oil). In each group, conscious cystometry was performed on day 28 after intraprostatic formalin injection or sham treatment. After cystometry, the bladder and prostate were harvested for evaluation of mRNA expression and histological analysis.In cystometric investigation, the mean number of non-voiding contractions was significantly greater and voiding intervals were significantly shorter in formalin-vehicle rats than those in sham-saline rats (P?<?0.05). In RT-qPCR analysis, mRNA expression of NGF, P2X2, and TRPA1 receptors was significantly increased in the bladder mucosa, and mRNA expression of TNF-?, iNOS and COX2 in the ventral lobes of prostate was significantly increased in formalin-vehicle rats compared with sham-saline rats (P?<?0.05). In addition, relative mRNA expression ratio of ER? to ER? (ER?/ER?) in the ventral lobes of prostate was significantly decreased in formalin-vehicle rats compared with sham-saline rats (P?<?0.05). These changes were ameliorated by 3?-Adiol administration in formalin-treatment rats.These results indicate that ER? activation by 3?-Adiol administration, which normalized the ER?/ER? expression ratio in the prostate, can improve not only prostatic inflammation, but also bladder overactivity. Therefore, ER? agonists might be useful for treating irritative bladder symptoms in patients with symptomatic BPH associated with prostatic inflammation. Prostate 77:803-811, 2017. © 2017 Wiley Periodicals, Inc.

Project description:Lower urinary tract symptoms (LUTS) relate to storage and/or voiding disturbances which are common among aging men. Disease etiology is largely unknown, and diagnosis is currently based on subjective symptom scores. While mainstay treatments can be ineffective and bothersome, biomarker discovery efforts may facilitate objective diagnostic criteria for personalized medicine and new potential druggable pathways. Since inflammation is one of its plausible etiologies, the goal of this project is to explore urinary metabolite and protein biomarkers as a non-invasive method to diagnose of LUTS which is induced by inflammation. Herein, a bacterial-induced prostatic inflammation model was established with C57BL/6J mice infected with uropathogenic E. coli 1677. Mouse urine samples were collected from control and treatment mice. Mass Spectrometry-based multi-omics analysis was employed here to discover urinary protein and metabolite-based biomarkers specific to prostatic inflammation-induced LUTS. We investigated the use of isobaric dimethylated leucine (DiLeu) labeling for metabolite identification and quantification for the mouse urine samples, and because of the use of DiLeu labeling, we combined metabolomics and proteomics on the same LC-MS platform. Overall, a total of 143 amine-containing metabolites and 1058 urinary proteins were identified and quantified, among them, 14 metabolites and 168 proteins were significantly changed by the inflammation treatment. Five metabolic pathways and four inflammatory-related biological processes were potentially disrupted. After compare with LUTS patient and other previously report, metabolite creatine and protein Polymeric Ig receptor presents especially attractive combined biomarker for prostatic inflammation induced LUTS and could be further used as the LUTS patient stratification. Overall, this study found urine metabolomics and proteomics to be an informative and noninvasive method for candidate biomarkers determination and etiologies classification of LUTS induced by inflammation.

Project description:BackgroundEchinococcus multilocularis causes alveolar echinococcosis (AE), a rising zoonotic disease in the northern hemisphere. Treatment of this fatal disease is limited to chemotherapy using benzimidazoles and surgical intervention, with frequent disease recurrence in cases without radical surgery. Elucidating the molecular mechanisms underlying E. multilocularis infections and host-parasite interactions ultimately aids developing novel therapeutic options. This study explored an involvement of unfolded protein response (UPR) and endoplasmic reticulum-stress (ERS) during E. multilocularis infection in mice.MethodsE. multilocularis- and mock-infected C57BL/6 mice were subdivided into vehicle, albendazole (ABZ) and anti-programmed death ligand 1 (αPD-L1) treated groups. To mimic a chronic infection, treatments of mice started six weeks post i.p. infection and continued for another eight weeks. Liver tissue was then collected to examine inflammatory cytokines and the expression of UPR- and ERS-related genes.ResultsE. multilocularis infection led to an upregulation of UPR- and ERS-related proteins in the liver, including ATF6, CHOP, GRP78, ERp72, H6PD and calreticulin, whilst PERK and its target eIF2α were not affected, and IRE1α and ATF4 were downregulated. ABZ treatment in E. multilocularis infected mice reversed, or at least tended to reverse, these protein expression changes to levels seen in mock-infected mice. Furthermore, ABZ treatment reversed the elevated levels of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α and interferon (IFN)-γ in the liver of infected mice. Similar to ABZ, αPD-L1 immune-treatment tended to reverse the increased CHOP and decreased ATF4 and IRE1α expression levels.Conclusions and significanceAE caused chronic inflammation, UPR activation and ERS in mice. The E. multilocularis-induced inflammation and consecutive ERS was ameliorated by ABZ and αPD-L1 treatment, indicating their effectiveness to inhibit parasite proliferation and downregulate its activity status. Neither ABZ nor αPD-L1 themselves affected UPR in control mice. Further research is needed to elucidate the link between inflammation, UPR and ERS, and if these pathways offer potential for improved therapies of patients with AE.

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Prostatic inflammation induces fibrosis in a mouse model of chronic bacterial infection.

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Prostatic inflammation induces fibrosis in a mouse model of chronic bacterial infection.

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