Prostatic Inflammation Induces Fibrosis in a Mouse Model of Chronic Bacterial Infection

Wong, Letitia; Hutson, Paul R.; Bushman, Wade

doi:10.1371/journal.pone.0100770

Cited by 55 publications

(60 citation statements)

References 66 publications

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“…This led to the hypothesis that prostatic inflammation contributes to the pathogenesis of BPH/LUTS by inducing prostatic fibrosis and impairing opening of the bladder neck–prostate complex during voiding. Using a previously described mouse model of bacterial‐induced prostatic inflammation , we recently characterized the fibrotic response to inflammation in the prostate . Our findings demonstrated that chronic prostatic inflammation results in a significant increase in prostate collagen content, strongly supporting a role for inflammation in prostatic fibrosis.…”

Section: Introductionsupporting

confidence: 54%

“…Our previous work demonstrated that collagen deposition was significantly increased in bacterial‐induced prostatic inflammation and this increase was associated with enhanced collagen synthesis as determined by 3 H‐hydroxyproline incorporation and mRNA expression of collagen genes . Here, we measured the stability of the newly synthesized collagen in saline and E. coli instilled prostates using a direct in vivo radiolabeling method.…”

Section: Resultsmentioning

confidence: 94%

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Resolution of chronic bacterial-induced prostatic inflammation reverses established fibrosis

2014

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Background Prostatic inflammation has been suggested to contribute to the etiology of lower urinary tract symptoms by inducing fibrosis. We previously used a well-characterized mouse model of bacterial-induced prostate inflammation to demonstrate that chronic prostatic inflammation induces collagen deposition. Here, we examined stability of the newly synthesized collagen in bacterial-induced prostatic inflammation and the reversibility of fibrosis after resolution of infection and inflammation. Methods Uropathogenic E. coli 1677 was instilled transurethrally into adult C3H/HeOuJ male mice to induce chronic prostatic inflammation. Collagen was labeled by 3H-proline administration for 28 days post-inoculation and 3H-hydroxyproline incorporation measured to determine stability of the newly synthesized collagen. Inflammation score was graded using a previously established system and total collagen content was measured by picrosirius red staining quantitation and hydroxyproline content. Resolution of inflammation and reversal of collagen deposition was assessed after treatment with antibiotic enrofloxacin for two weeks on day 28 post-inoculation followed by an eight-week recovery period. Results Decay analysis of incorporated 3H-hydroxyproline revealed the half-life of newly synthesized collagen to be significantly shorter in infected/inflamed prostates than in controls. Treatment with antibiotic enrofloxacin completely eradicated bacterial infection and allowed resolution of inflammation. This was followed by marked attenuation of collagen content and correlation analysis verified a positive association between the resolution of inflammation and the reversal of collagen deposition. Conclusions These data demonstrate, for the first time, that inflammation-induced prostatic fibrosis is a reversible process.

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Section: Introductionsupporting

confidence: 54%

Section: Resultsmentioning

confidence: 94%

Resolution of chronic bacterial-induced prostatic inflammation reverses established fibrosis

2014

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“…Chronic inflammation leads to collagen deposition and fibrosis associated with increased LOX expression [52] and increased stromal collagen deposition has also long been recognised as a major contributing factor to the increased mammographic density that increases risk of breast cancer [23, 25, 53, 54]. This study suggests that expression of epithelial cell-specific CCL2 by mammary epithelium increases mammary cancer susceptibility in mice through inducing a low level of chronic inflammation in the mammary gland, characterised by increased macrophage infiltration and fibrosis associated with perturbed collagen deposition and remodelling.…”

Section: Discussionmentioning

confidence: 99%

CCL2-driven inflammation increases mammary gland stromal density and cancer susceptibility in a transgenic mouse model

et al. 2017

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BackgroundMacrophages play diverse roles in mammary gland development and breast cancer. CC-chemokine ligand 2 (CCL2) is an inflammatory cytokine that recruits macrophages to sites of injury. Although CCL2 has been detected in human and mouse mammary epithelium, its role in regulating mammary gland development and cancer risk has not been explored.MethodsTransgenic mice were generated wherein CCL2 is driven by the mammary epithelial cell-specific mouse mammary tumour virus 206 (MMTV) promoter. Estrous cycles were tracked in adult transgenic and non-transgenic FVB mice, and mammary glands collected at the four different stages of the cycle. Dissected mammary glands were assessed for cyclical morphological changes, proliferation and apoptosis of epithelium, macrophage abundance and collagen deposition, and mRNA encoding matrix remodelling enzymes. Another cohort of control and transgenic mice received carcinogen 7,12-Dimethylbenz(a)anthracene (DMBA) and tumour development was monitored weekly. CCL2 protein was also quantified in paired samples of human breast tissue with high and low mammographic density.ResultsOverexpression of CCL2 in the mammary epithelium resulted in an increased number of macrophages, increased density of stroma and collagen and elevated mRNA encoding matrix remodelling enzymes lysyl oxidase (LOX) and tissue inhibitor of matrix metalloproteinases (TIMP)3 compared to non-transgenic controls. Transgenic mice also exhibited increased susceptibility to development of DMBA-induced mammary tumours. In a paired sample cohort of human breast tissue, abundance of epithelial-cell-associated CCL2 was higher in breast tissue of high mammographic density compared to tissue of low mammographic density.ConclusionsConstitutive expression of CCL2 by the mouse mammary epithelium induces a state of low level chronic inflammation that increases stromal density and elevates cancer risk. We propose that CCL2-driven inflammation contributes to the increased risk of breast cancer observed in women with high mammographic density.

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“…gonorrhoeae may cause the acute inflammation to become chronic. Research using rat models has shown that chronic prostate inflammation can cause fibrosis of the prostate and its surrounding tissues [12]. Additionally, controlling chronic prostate inflammation can, to some extent, reverse the progression of fibrosis [13].…”

Section: Discussionmentioning

confidence: 99%

Risk Factors associated with Paraurethral Duct Dilatation following Gonococcal Paraurethral Duct Infection in Men

et al. 2016

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No studies have explored the risk factors for paraurethral duct dilatation following paraurethral duct infection by Neisseria gonorrhoeae in men undergoing ceftriaxone therapy. The present study was performed to explore the risk factors for paraurethral duct dilatation following paraurethral duct infection by N. gonorrhoeae in men undergoing ceftriaxone therapy and thus guide clinical interventions. We compared the demographic, behavioral, and clinical data of men with paraurethral duct infection by N. gonorrhoeae with and without dilatation of the paraurethral duct. Univariate analysis showed significant differences in age, disease course of the infected paraurethral duct, Chlamydia trachomatis infection in the paraurethral duct, and a history of paraurethral duct infection by N. gonorrhoeae between the patient and control groups (P<0.05). Multivariate logistic regression analysis showed consistent results (P<0.05). This study that shows delayed treatment may be a major risk factor for paraurethral duct dilatation secondary to paraurethral duct infection by N. gonorrhoeae in men. Age, C. trachomatis infection in the paraurethral duct, and a history of paraurethral duct infection by N. gonorrhoeae are also risk factors. Thus, educating patients to undergo timely therapy and treating the C. trachomatis infection may be effective interventions.

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Prostatic Inflammation Induces Fibrosis in a Mouse Model of Chronic Bacterial Infection

Cited by 55 publications

References 66 publications

Resolution of chronic bacterial-induced prostatic inflammation reverses established fibrosis

Resolution of chronic bacterial-induced prostatic inflammation reverses established fibrosis

CCL2-driven inflammation increases mammary gland stromal density and cancer susceptibility in a transgenic mouse model

Risk Factors associated with Paraurethral Duct Dilatation following Gonococcal Paraurethral Duct Infection in Men

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