We previously reported that mice with experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), develop profound urinary bladder dysfunction. Because neurogenic bladder in MS patients causes marked bladder remodeling, we next examined morphometric and molecular alterations of the bladder in EAE mice. EAE was created in female SJL/J mice by immunization with the p139-151 encephalitogenic peptide of myelin proteolipid protein in complete Freund's adjuvant, along with intraperitoneal injections of Bordetella pertussis toxin. Seventy days after immunization, mice were scored for the level of neurological impairment and then killed. Spinal cord sections were assessed for demyelination, inflammation, and T cell infiltration; the composition of the bladder tissue was measured quantitatively; and gene expression of markers of tissue remodeling and fibrosis was assessed. A significant increase in the bladder weight-to-body weight ratio was observed with increasing neurological impairment, and morphometric analysis showed marked bladder remodeling with increased luminal area and tissue hypertrophy. Despite increased amounts of all tissue components (urothelium, smooth muscle, and connective tissue), the ratio of connective tissue to muscle increased significantly in EAE mice compared with control mice. Marked increases in mRNA expression of collagen type I α(2), tropoelastin, transforming growth factor-β3, and connective tissue growth factor (CTGF) were observed in EAE mice, as were decreased levels of mRNAs for smooth muscle myosin heavy chain, nerve growth factors, and muscarinic and purinergic receptors. Our results suggest that bladder remodeling corresponding to EAE severity may be due to enhanced expression of CTGF and increased growth of connective tissue.
The pathophysiology of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is poorly understood. Inflammatory and autoimmune mechanisms may play a role. We developed a murine model of experimental autoimmune prostatitis (EAP) that mimics the human phenotype of CP/CPPS. Eight-week-old mice were immunized subcutaneously with prostate-specific peptides in an emulsion of complete Freund's adjuvant. Mice were euthanized 10 days after immunization, and lymph node cells were isolated and assessed for recall proliferation to each peptide. P25 99-118 was the most immunogenic peptide. T-cell and B-cell immunity and serum levels of C-reactive protein and nitrate/nitrite levels were evaluated over a 9-wk period. Morphometric studies of prostate, 24-h micturition frequencies, and urine volume per void were evaluated. Tactile referred hyperalgesia was measured using von Frey filaments to the pelvic region. The unpaired Student's t-test was used to analyze differences between EAP and control groups. Prostates from p25 99-118-immunized mice demonstrated elevated gene expression levels of TNF-α, IL-17A, IFN-γ, and IL-1β, not observed in control mice. Compared with controls, p25 99-118-immunized mice had significantly higher micturition frequency and decreased urine output per void, and they demonstrated elevated pelvic pain response. p25 99-118 immunization of male SWXJ mice induced prostate-specific autoimmunity characterized by prostate-confined inflammation, increased micturition frequency, and pelvic pain. This autoimmune prostatitis model provides a useful tool for exploring the pathophysiology and new treatments.
Objectives Animal models of vaginal distention (VD) have demonstrated increased expression of chemokine (C-C motif) ligand 7 (CCL7). In this study, we investigated the expression of CCL7 in mice models of simulated birth trauma-induced urinary incontinence utilizing VD and pudendal nerve transection (PNT). Methods Forty-nine mice were divided into 6 groups: VD, sham VD, PNT, sham PNT anesthesia, and age-matched controls. The urethra, vagina, and rectum were harvested for the expression of CCL7 immediately or 24 hours after assigned procedure. Venous sampling for quantification of serum CCL7 was also performed. An ANOVA model was used to compare the relative expression of CCL7 in each group. Results Urethral CCL7 expression in the VD group was significantly higher than control group after 24 hours (p<0.01). There was no difference in the urethral CCL7 expression in PNT, sham PNT, sham VD or anesthesia groups compared with controls. No statistically significant difference was noted in the vaginal and rectal expression of CCL7 between any of the groups except for sham PNT. Statistically significant differences were noted in the serum CCL7 expression in VD, PNT and sham PNT (p<0.01 in all) groups after 24 hours compared with the control group. Conclusions This study demonstrates over-expression of urethral CCL7 after VD but not PNT. This suggests that nerve injury does not contribute to the CCL7 over-expression. The over-expression of CCL7 in the serum of mice after VD suggests a translational potential where CCL7 measurement could be used as a surrogate for injury after delivery.
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