Basic Research - Neurourology & LUTS/BPH & Others(구연) (E-033) ANTI-FIBROTIC 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 WI Urology, Daegu Fatima Hospital, Urology, Daegu Fatima Hospital, Urology, Daegu Fatima Hospital, Urology, Daegu Fatima Hospital, Research Institute, Daegu Fatima Hospital, Research Institute, Daegu Fatima Hospital, Urology, University of Pittsburgh School of Medicine Joonbeom Kwon, Yeon-Joo Kim, Yoon-Hyung Lee, Jaesoo Kim, Eun-Ju Lee, Min-Su Han, Naoki Yoshimura Background: Chronic spinal cord injury (SCI) rostral to the sacral level causes lower urinary tract dysfunction such as detrusor overactivity (DO) and bladder wall remodeling with fibrosis. Nintedanib, an triple inhibitor of VEGF, FGF, and PDGF receptors, has been approved for idiopathic pulmonary fibrosis. / Objectives: This study examined the effects of anti-fibrotic treatment using nintedanib on DO and bladder fibrotic changes, as well as the modulation mechanisms of C-fiber afferent pathways. / Materials and Methods: Thirty female C57BL/6 mice were divided into; group A: spinal intact (SI) mice, group B: spinal cord injury (SCI) mice treated with vehicle, and group C: SCI mice treated with nintedanib. SCI was produced by transecting the spinal cord at the level of T8/9 under isoflurane anesthesia. Sham surgery was conducted in SI mice. At two weeks after SCI, the vehicle or 50mg/kg nintedanib was subcutaneously administered daily for two weeks. At four weeks after SCI, intercontraction interval (ICI), maximum contraction pressure (MCP), baseline bladder pressure (BBP), non-voiding contractions (NVCs), voided volume, residual volume, and voiding efficiency were measured by awake cystometry (CMG). mRNA expressions of fibrosis-related molecules, vanilloid, muscarinic and β-adrenergic receptors, and purinergic were measured in bladder tissues and L6-S1 dorsal root ganglia (DRG) by RT-PCR. Trichrome staining and Western blot analysis of TGF-β and fibronectin were conducted in the bladder to evaluate bladder fibrosis. Expression levels of a C-fiber afferent marker, TRPV1, in DRG was also conducted by immunohistochemistry to examine whether the nintedanib treatment modulates C-fiber afferent marker expression. / Results and Conclusion: Results In CMG, NVCs were significantly increased, and ICI, voided volume and voiding efficiency were decreased in group B compared to group A whereas group C demonstrated an significant improvement in these parameters compared to group B.  RT-PCR analysis showed upregulation of mRNA levels of fibrosis-related molecules such as TGF-b1, TGFBR1, Col 3a, and fibronectin in group B vs. group A in bladder mucosa and detrusor layers. However, overexpression of these fibrosis-related molecules in bladder mucosa were decreased in group C.  mRNA levels of muscarinic (M2, M3) and β-adrenergic receptors (B2, and B3) were increased in bladder mucosa, but not in detrusor, of group B vs. group A whereas group C showed decreased expression of these receptors.  mRNA levels of TRPV1, TRPA1, TRPM8, P2X2, P2X3, P2X4, and P2X7 receptors were upregulated in DRG of group B vs. group A; however, TRPV1, TRPA1, P2X2, and P2X3 expressions were downregulated in group C. In Trichrome staining, fibrotic changes were generally found in lamina propria rather than detrusor layer in group B vs. group A.  Western blotting also showed that TGF-b1 and fibronectin were elevated in group B vs. group A and decreased in group C vs. group B.  In immunohistochemical staining of DRG sections, TRPV1 expression was enhanced in group B, but decreased in group C. Conclusions Anti-fibrotic treatment, which inhibits VEGF, FGF, and PDGF receptors, improved bladder dysfunction and bladder fibrosis in SCI mice. In addition, nintedanib-induced improvement of detrusor overactivity in SCI mice is likely to be mediated by modulation of bladder C-fiber afferent activity as evidenced by downregulation of C-fiber markers such as TRP and P2X receptors. keywords : Bladder fibrosis, Detrusor overactivity, Spinal cord injury