Several studies have been reported that the interruption of bladder fibrosis may be associated with improvement of interstitial cystitis (IC) [1, 2]. In our previous study, nintedanib, which has been clinically approved as a therapeutic agent in idiopathic pulmonary fibrosis, showed an antifibrotic effect on the bladder and an improvement of detrusor overactivity in spinal cord injured mice associated with improvement of C-fiber hyperexcitability [3]. Therefore, we investigated whether antifibrosis treatment using nintedanib can improve the IC-like pathologic conditions.

Female C57BL/6 mice were divided into 3 groups (each N=8): (A) Sham, (B) IC mice treated with vehicle, and (C) IC mice treated with nintedanib. For inducing an IC-like model, one-hour intravesical instillation of hyaluronidase (5 mg/ml) and lipopolysaccharide (5 mg/ml) mixed with 0.9% saline was conducted 3 times once a week. From the last instillation, vehicle or nintedanib (50mg/kg) was subcutaneously administered daily for 3 weeks. Then, the pain assessment using Von-Frey filaments and cystometry was conducted. Trichrome staining, RT-PCR of the bladder, and immunohistochemistry of L6-S1 dorsal root ganglia (DRG) and L6 spinal cord were performed to investigate the improvement of bladder fibrosis, inflammation, nociception, and central sensitization.

In pain assessment, 50% thresholds of target force were significantly reduced in group B vs. A (p=0.001), but recovered in group C vs. B (p=0.001). In cystometry, non-voiding contractions (NVCs, numbers/min; 0.39 ± 0.11 vs. 0.13 ± 0.07) and voiding efficiency (VE, %; 72.1 ± 8.6 vs. 87.1 ± 9.5) were worsened in group B vs. group A, but restored in group C (NVCs 0.15 ± 0.09/min, VE 84.0 ± 4.8%) (Fig 1-a). Bladder fibrosis increased in group B was improved in group C in trichrome staining (Fig.1-b). mRNA levels related to inflammation (IFN-r, CCR2), nociception (TACR2), P2X purinergic (P2X3, P2X4, P2X7), muscarinic (M2), and β-adrenergic receptors (β2, β3) in the bladder mucosa were increased in group B vs. group A, but decreased in group C vs. group B (Fig 1-c). In immunohistochemistry, TRPV1 in L6-S1 DRG and CX3CR1, GFAP, and CCR2 in L6 spinal cord were upregulated in group B vs. group A, but reduced in group C vs. group B (Fig 1-d).

The increased expressions of proinflammatory cytokines, M2-muscarinic, β2- and β3-adrenergic, P2X-purinergic, and TACR2 receptors in the bladder mucosa and upregulated TRPV1 in L6-S1 DRG indicate that bladder inflammation induced by repetitive damage is closely related to detrusor overactivity, afferent sensitization of bladder, and chronic bladder pain. In addition,  neural remodeling at the central nervous system (CNS) level, which is evidenced by the enhanced signals of CX3CR1 and GFAP in L6 spinal cord, seems to be implicated in this mechanism, too.
Antifibrosis treatment using nintedanib improved detrusor overactivity and afferent hyperexcitability evidenced by improved cystometric parameters and decreased M2-muscarinic, β3-adrenergic, and P2X-purinergic receptors. Moreover, antifibrosis treatment also improved chronic bladder pain, and this mechanism seems to be implicated in the anti-inflammatory effect of nintedanib and interruption of neural remodeling in CNS although it was not corroborated whether nintedanib directly affects CNS or not.

Antifibrosis treatment using nintedanib improved detrusor overactivity and chronic bladder pain in the IC mouse model. Therapeutic effects seem to be mediated by inhibitions of bladder afferent hyperexcitability as well as central sensitization.

Choi D, Han JY, Shin JH, et al. Downregulation of Wnt11 is associated with bladder tissue fibrosis in patients with interstitial cystitis/bladder pain syndrome without Hunner lesion. Sci Rep 2018;8:9782.
Ryu CM, Shin JH, Yu HY, et al. N-acetylcysteine prevents bladder tissue fibrosis in a lipopolysaccharide-induced cystitis rat model. Sci Rep 2019;9:8134.
Kwon J, Lee E, Cho H, et al. Antifibrosis treatment by inhibition of VEGF, FGF, and PDGF receptors improves bladder wall remodeling and detrusor overactivity in association with modulation of C-fiber afferent activity in mice with spinal cord injury. Neurourol Urodyn 2021;40:1460-9.

Continence 2S2 (2022) 100292
DOI: 10.1016/j.cont.2022.100292