It has been revealed that bladder fibrosis induced by chronic bladder ischemia, partial bladder outlet obstruction, or spinal cord injury (SCI) has a close relationship with bladder dysfunction in these disease conditions [1,2,3].
Nintedanib, which has been approved as a therapeutic agent for idiopathic pulmonary fibrosis, blocks the receptors of pro-fibrotic growth factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF). Therefore, we investigated whether antifibrotic treatment with nintedanib can restore lower urinary tract (LUT) dysfunction using mice with spinal cord injury (SCI).

Twenty three female C57BL/6 mice were divided into 3 groups. In goup A, spinal intact (SI) mice were performed sham operation. In group B, vehicle was administered for 2 weeks after 2-week SCI. In group C, 100 mg/kg of nintedanib was administered daily for 2 weeks after 2-week SCI.  SCI was produced by transecting the spinal cord at the level of T 8/9.
At 4 weeks after SCI, filling cystometrograms (CMGs) were recorded under an awake condition. First, under 1.5-2.0% isoflurane anesthesia, a PE-50 tube was inserted into the bladder through the dome as a cystostomy catheter. After complete recovery from anesthesia, CMGs were recorded by filling the bladder with saline (0.01 mL/min) to observe rhythmic bladder contractions for at least 120 min. After bladder activity stabilized, we collected the data.
Intercontraction intervals (ICI), non-voiding contractions (NVC), voided volume, and voiding efficiency were measured and compared. Then, mRNA expression of HIF-1, VEGF, FGF-1, TGF-β, Collagen 1a (Col 1a), and Col 3a in bladder tissues were measured by RT-PCR.

In CMGs, ICI, the number of NVC, voided volume, and voiding efficiency were significantly improved in Group C compared to Group B (Fig. 1). TGF-β was increased in group B, but decreased in group C (Fig.2). The levels of VEGF, FGF, and collagen (1a nd 3a) were not increased in group B compared to group A, but decreased in group C. HIF-1 was increased in group B, but not changed by nintedanib (Fig.2)

Bladder distention induces chronic bladder ischemia, which upregulates HIF-1, and TGF-β. TGF-β, which is known as an important factor that modulates the tissue fibrosis, is upregulated by HIF-1 or other pro-fibrotic growth factors such as FGF and PDGF.
Nintedanib induced functional improvements of both storage and voiding dysfunctions in SCI mice, which is associated with the reductions in growth factors such as TGF-β, VEGF and FGF as well as in fibrotic changes evident as decreased collagen transcripts.  However, nintedanib did not improve the HIF-1 level, indicating that nintedanib can have an antifibrotic effect without affecting bladder ischemia.  Additionally, there were no significant increases in Col 1a, Col 3a in SCI mice compared to SI mice. This is because 4-week SCI might be short to induce the enough fibrotic changes in the SCI bladder. Nevertheless, antifibrotic treatment with nintedanib can reduce collagen synthesis in SCI bladders and improve bladder dysfunction without improving bladder ischemia.

Nintedanib induced functional improvements of both storage and voiding dysfunctions in SCI mice. Thus, inhibition of fibrosis-related growth factors could be an effective modality for the treatment of neurogenic LUT dysfunction and bladder remodeling after SCI.

Oeractivity and structural changes in the chronically ischemic bladder. Azadzoi KM, Tarcan T, Kozlowski R, Krane RJ, Siroky MB. J Urol 1999 Nov;162(5):1768-78.
Preventive effects of a HIF inhibitor, 17-DMAG, on partial bladder outlet obstruction-induced bladder dysfunction. Iguchi N, Donmez MI, Malykhina AP, Carrasco A Jr, Wilcox DT. Am J Physiol Renal Physiol 2017 Nov 1;313(5):F1149-60.
Improvement in Spinal Cord Injury-Induced Bladder Fibrosis Using Mesenchymal Stem Cell Transplantation Into the Bladder Wall. Lee HJ, An J, Doo SW, Kim JH, Choi SS, Lee SR, Park SW, Song YS, Kim SU. Cell Transplant  2015 24(7):1253-63.