The current conception of interstitial cystitis/bladder pain syndrome (IC/BPS) is that it would be reasonable to distinguish IC/BPS with Hunner lesion usually diagnosed as IC from IC/BPS without Hunner lesion (BPS). Therefore, we investigated the differences of urine markers including vascular endothelial growth factor-A (VEGF-A), CXCL1, CXCL8 and CXCL10 previously reported as useful markers [Ref. 1] to detect IC/BPS patients separated from　overactive bladder (OAB) patients.

Urine was collected from 22 IC patients, 25 BPS patients, age and gender-matched 23 OAB patients and 12 controls with no history of IC, recurrent urinary tract infection or bladder cancer. In other groups of patients, bladder biopsied tissues were collected from 14 IC female patients, 12 BPS female patients and 14 age-matched female patients (controls) with stress urinary incontinence or pelvic organ prolapse. Representative four urine markers of IC/BPS such as VEGF-A, CXCL1, CXCL8 and CXCL10 were measured by a MILLIPLEX immunoassay kit. Immunohistochemical staining of VEGF-A and CD3 was examined in bladder tissues of each group, and the ratio of each staining per whole tissues (VEGF-A) or the number of T cells (CD3) was measured with Image J software. Statistical differences in these markers among the groups were determined by non-parametric ANOVA followed by multiple comparison test. The diagnostic efficiency of these markers was measured using receiver operating characteristic (ROC) analysis. In addition, all participants completed the O’Leary-Sant questionnaire including symptom indexes (OSSI) and problem indexes (OSPI), and visual analogue scale (VAS) pain scores, and the significant correlation between four urine markers and OSSI, OSPI and VAS pain scores was examined, respectively.

OSSI and OSPI were significantly increased in IC, BPS and OAB patients compared with controls whereas the significant increases in VAS pain scores were detected in IC and BPS patients compared with controls or OAB patients. VEGF-A and CXCL1 in urine were significantly increased in IC and BPS patients compared with controls or OAB patients although the significant increases in CXCL8 and CXCL10 were detected in IC patients compared with controls or OAB patients for CXCL8, and with controls, OAB or BPS patients for CXCL10 [Fig. 1]. According to the ROC analysis, VEGF-A (0.83), CXCL10 (0.79), CXCL1 (0.75) and CXCL8 (0.70) were significantly useful to detect IC/BPS patients among the study participants. On the other hand, CXCL10 (0.86), CXCL8 (0.78) and CXCL1 (0.70) were significantly useful to detect IC patients whereas VEGF-A (0.76) was significantly useful to detect BPS patients in the participants. VEGF-A and CXCL10 were significantly correlated with OSSI (r=0.22, 0.37), OSPI (r=0.22, 0.35) and VAS pain scores (r=0.33, 0.37). In addition, the expression of VEGF-A in bladder tissues was significantly increased in IC and BPS patients compared with controls whereas the significant increases in the number of T lymphocytes were observed in IC patients compared with controls or BPS patients [Fig. 2].

CXCL10 can induce pro-inflammatory response by activating T lymphocytes whereas CXCL1 and CXCL8 are mainly chemotactic for neutrophils. In the present study, the significant increases in urine CXCL10 levels and the number of T lymphocytes in bladder tissues were observed in IC patients, and CXCL10 was a useful urine marker to detect IC, indicating that Hunner lesion is associated with a true interstitial inflammation modulated by activating T lymphocytes. On the other hand, it has been reported that VEGF not only plays a key stimulatory role in angiogenesis, but also induces sensory and motor peripheral plasticity, alters bladder function, and promotes visceral sensitivity [Ref. 2], and that systemic blockade of VEGF signalling with anti-VEGF-neutralizing antibodies was effective in reducing pelvic/bladder pain in cyclophosphamide-induced cystitis model [Ref. 3]. In the present study, the significant increases in urine VEGF-A levels and the expression of VEGF-A in bladder tissues were observed in IC/BPS patients although VEGF-A was a useful urine marker to detect BPS. The possible mechanism of the increases in urine VEGF-A levels could be hypoxia in bladder tissues due to chronic inflammation in IC patients whereas the mechanism for the increases in VEGF-A levels in BPS patients remains unknown.

It would be useful to detect IC and BPS using CXCL10 and VEGF-A as urine markers, respectively, suggesting that Hunner-type IC and non-Hunner-type BPS could be classified as a separate entity of the disorder in the future.

Furuta A, et al. Int Urogynecol J 29: 961-6, 2018
Malykhina AP et al. BMC Physiol 12: 15, 2012
Lai HH, et al. BJU Int 120: 576-83, 2017