Benign Prostatic Hyperplasia (BPH) is a complex condition leading to Lower Urinary Tract Symptoms in aging men, characterized by cellular proliferation, smooth muscle dysfunction, inflammation, and fibrosis. While BPH is known to involve heightened macrophage infiltration, the specific contribution of infiltrating monocytes/macrophages to the disease mechanism remains uncertain. This research explores the impact of reducing circulating monocytes and subsequently limiting their tissue infiltration by using Ccr2 knockout (Ccr2-KO) mice. Ccr2-KO and wild type mice were implanted with testosterone and estradiol (T + E2, 25 mg + 2.5 mg) pellets. Urinary function was assessed via weekly void spot assays over 12 weeks, and prostatic macrophage levels were visualized and quantified in tissue sections using an F4/80 antibody. Additionally, Ki-67 staining was used to evaluate cell proliferation, and picrosirius red staining to assess collagen accumulation. Increased voiding frequency which developed in T + E2 mice, was significantly ameliorated in Ccr2-KO mice, however, both Ccr2-KO and wild type (WT) mice showed increased bladder weights after three month, representing a hypertrophic response to bladder outlet obstruction. T + E2 substantially increased the density of macrophages in WT but not Ccr2-KO mouse prostate. Proliferation rate, as indicated by Ki-67 positivity, was elevated in the vental and anterior prostate lobes but was only marginally reduced in Ccr2-KO mice. Most importantly, a significant prostatic collagen accumulation was observed in WT mice that was markedly reduced by Ccr2 deficiency post T + E2 treatment. The absence of Ccr2 mitigates urinary dysfunction and alters prostatic macrophage levels and collagen accumulation in steroid hormone imbalance. These findings suggest a crucial role for monocyte infiltration, giving rise to macrophages or other cell derivatives, to drive fibrosis.

BACKGROUND: Prostatic fibrosis, characterized by the accumulation of myofibroblasts and collagen deposition, is closely associated with LUTS and may lead to mechanical obstruction of the urethra. Additionally, Metabolic Syndrome (MetS), characterized by central obesity, high blood sugar, lipid metabolism disorders, and hypertension, is increasingly recognized as a proinflammatory condition linked to prostate inflammation.
METHODS: Clinical data from 108 subjects who underwent transurethral resection of the prostate or bipolar plasmakinetic enucleation of the prostate were prospectively collected between June 2021 and August 2022. Patients were divided in two groups according to whether or not they had a diagnosis of MetS. Specimens were stained with Masson trichrome and the periurethral prostatic fibrosis extent was evaluated using quantitative morphometry.
RESULTS: Forty-three patients (39.8%) were diagnosed with MetS. Patients with MetS showed a significantly greater extent of prostatic fibrosis than the others (68.1 ± 17.1% vs. 42.5 ± 18.2%, P < 0.001), and there was a positive correlation between the number of positive MetS parameters and the extent of prostatic fibrosis (R2 = 0.4436, P < 0.001). Multivariate regression analysis revealed that central obesity (B = 2.941, 95% confidence interval, 1.700-3.283), elevated fasting glucose (B = 1.036, 95% confidence interval, 0.293-1.780), reduced HDL cholesterol (B = 0.910, 95% confidence interval, 0.183-1.636) and elevated triglycerides (B = 1.666, 95% confidence interval, 0.824-2.508) were positively correlated to prostatic fibrosis. Elevated blood pressure, however, was unrelated to prostatic fibrosis (B = 0.009, 95% confidence interval, -0.664-0.683).
CONCLUSIONS: The present findings suggest that prostatic fibrosis is positively correlated with MetS and its components including central obesity, elevated fasting glucose, reduced high density lipoprotein cholesterol and elevated triglycerides.

Fibrosis is the pathological basis for the clinical progression of benign prostatic hyperplasia (BPH). Prostatic fibrosis is an important risk factor in patients with BPH who experience lower urinary tract symptoms. Bisphenol A (BPA) is an environmental endocrine disruptor (EED) that causes prostate defects. The effects of BPA on the prostate were investigated in this study using mouse and human prostate cell models. BPA-induced mouse prostatic fibrosis is characterized by collagen deposition and an increase in hydroxyproline concentration. Furthermore, BPA-exposed prostatic stromal fibroblasts exosomes promote the epithelial-mesenchymal transition of epithelial cells. High-throughput RNA sequencing and functional enrichment analyses show that substantially altered mRNAs, lncRNAs and circRNAs play roles in cellular interactions and the hypoxia-inducible factor-1 signaling pathway. The results showed that exosomes participated in the pro-fibrogenic effects of BPA on the prostate by mediating communication between stromal and epithelial cells and triggering epithelial changes.

OBJECTIVE: This study aimed to investigate the effects of sex hormone imbalance on rat prostatic inflammation and fibrosis and identify the key molecules involved.
METHODS: Castrated Sprague-Dawley (SD) rats were treated with a constant dose of oestradiol (E2) and different doses of dihydrotestosterone (DHT) to achieve different oestrogen/androgen ratios. After 8 weeks, serum E2 and DHT concentrations, relative seminal vesicle weights, histopathological changes and inflammation were measured, collagen fiber content and oestrogen receptor (ER) and androgen receptor (AR) expression were detected, mRNA sequencing and bioinformatics analysis were performed to identify differentially expressed genes (DEGs).
RESULTS: The severity of inflammation in the rat dorsolateral prostate (DLP) was higher, collagen fibre content and ER expression in the rat DLP and prostatic urethra were increased and AR expression in the rat DLP was decreased in the 1:1 E2/DHT-treated group than that in the 1:10 E2/DHT-treated group. RNA-seq analysis identified 487 DEGs, and striking increases in the expression of mRNAs encoding collagen, collagen synthesis and degradation enzymes, growth factors and binding proteins, cytokines and chemokines, and cell-surface molecules were confirmed in the 1:1 E2/DHT-treated group compared to the 1:10 E2/DHT-treated group. mRNA expression of secreted phosphoprotein 1 (Spp1) and protein expression of osteopontin (OPN, encoded by Spp1) were increased in the 1:1 E2/DHT-treated group compared to the 1:10 E2/DHT-treated group, and Spp1 expression correlated positively with Mmp7, Cxcl6 and Igfn1 expression.
CONCLUSIONS: The imbalance in the oestrogen/androgen ratio may affect rat prostatic inflammation and fibrosis, and OPN might be involved in this process.

Fibrogenic and inflammatory processes in the prostate are linked to the development of lower urinary tract symptoms (LUTS) in men. Our previous studies identified that osteopontin (OPN), a pro-fibrotic cytokine, is abundant in the prostate of men with LUTS, and its secretion is stimulated by inflammatory cytokines potentially to drive fibrosis. This study investigates whether the lack of OPN ameliorates inflammation and fibrosis in the mouse prostate. We instilled uropathogenic E. coli (UTI89) or saline (control) transurethrally to C57BL/6J (WT) or Spp1tm1Blh/J (OPN-KO) mice and collected the prostates one or 8 weeks later. We found that OPN mRNA and protein expression were significantly induced by E. coli-instillation in the dorsal prostate (DP) after one week in WT mice. Deficiency in OPN expression led to decreased inflammation and fibrosis and the prevention of urinary dysfunction after 8 weeks. RNAseq analysis identified that E. coli-instilled WT mice expressed increased levels of inflammatory and fibrotic marker RNAs compared to OPN-KO mice including Col3a1, Dpt, Lum and Mmp3 which were confirmed by RNAscope. Our results indicate that OPN is induced by inflammation and prolongs the inflammatory state; genetic blockade of OPN accelerates recovery after inflammation, including a resolution of prostate fibrosis.

BACKGROUND: Chronic inflammation of the prostate leads to the formation of excess fibrous connective tissue, which hinders patients recovery and aggravates the symptoms.
OBJECTIVE: This study aimed to confirm the correlation between inflammation and prostatic fibrosis and the abnormalities of urodynamic and microcirculation in the prostate gland in humans, and the possibility of increasing the effectiveness of treatment of patients with chronic nonbacterial prostatitis using antisclerotic therapy.
METHODS: The study was carried out in two stages. At the first stage, pathomorphological findings, uroflowmetry data and degree of microcirculation disturbance were studied in 18 patients with chronic prostatitis who underwent prostate biopsy. At the second stage, an open prospective randomized comparative study was conducted. Two groups of patients with chronic nonbacterial prostatitis with signs of inflammation were formed. A control group (n=29) received standard treatment, rectal 0.5 methyluracil suppositories three times per week, 20 suppositories per course. In addition to the standard treatment, the patients of the study group (n=31) were administered Longidaza 3000 IU rectal suppositories also three times a week, 20 suppositories per course.
RESULTS: Prostatic fibrosis worsens microcirculation by one and half times and statistically significantly negatively affects urodynamic. Using Longidaza resulted in neutralizing the negative consequences of the formation of excess fibrous connective tissue. Overall, an excellent and good effect was achieved in 21 (67.7%) and 9 (29.1%) patients of the study group, respectively; only in one case (3.2%) there was no effect. In the control group, an excellent and good effect was achieved in 14 (48.3%) and 11 (37.9%) patients, respectively; in 4 patients (13.8%) the treatment was considered of low effectiveness.
CONCLUSIONS: Prevention of the fibrous connective tissue formation and regression of the fibrosis are pathogenetically valid. Anti-sclerotic enzyme therapy with Longidaza in the form of rectal suppositories results in a significant improvement in the symptoms of prostatitis, an increase in the maximum urinary flow rate and an improvement in the microcirculation of the prostate.

Treatments of chronic bacterial prostatitis (CP) remain difficult problem. Bacterial prostatitis is a disease entity diagnosed clinically and by evidence of inflammation and infection localized to the prostate. Risk factors for UTI in men include urological interventions, such as transrectal prostate biopsy. Ensuing infections after prostate biopsy, such as UTI and bacterial prostatitis, are increasing due to increasing rates of fluoroquinolone resistance. The increasing global antibiotic resistance also significantly affects management of UTI in men, and therefore calls for alternative strategies. Prostatic inflammation has been suggested to contribute to the etiology of lower urinary tract symptoms (LUTS) by inducing fibrosis. Several studies have shown that prostatic fibrosis is strongly associated with impaired urethral function and LUTS severity. Fibrosis resulting from excessive deposition of collagen is traditionally recognized as a progressive irreversible condition and an end stage of inflammatory diseases; however, there is compelling evidence in both animal and human studies to support that the development of fibrosis could potentially be a reversible process. Prostate inflammation may induce fibrotic changes in periurethral prostatic tissues, promote urethral stiffness and LUTS. Patients experiencing CP and prostate-related LUTS could benefit from anti-inflammatory therapies, especially used in combination with the currently prescribed enzyme treatment with Longidase. Treatment results showed that longidase is highly effective in bacterial and abacterial CP. Longidase addition to standard therapeutic methods significantly reduced the disease symptoms and regression of inflammatory-proliferative alterations in the prostate.