Presentation Authors: Mahadevan Rajasekaran*, Hosong Yu, SeungMo Yuk, Raag Bhargava, Rucha Deshpande, Jessica Magana, Thomas Fuller, Jill Buckley, Valmik Bhargava, San Diego, CA
Introduction: Repeated transurethral interventions can exacerbate urethral strictures or cause stricture recurrence by increasing tissue damage. A clear understanding of molecular mechanisms involved in increased fibrogenesis after repeated transurethral interventions would enable development of optimal strategies to minimize progression and prevent stricture recurrence. We tested the hypothesis that repeated transurethral mechanical stretch accelerates fibrogenesis by GIV/Girdin pathway (considered a central hub for pro-fibrogenic signaling networks) leading to increased collagen deposits in scar tissues.
Methods: Electrocautery was used to induce strictures in middle aged rabbits (12 months; n=6; Fig A- top left). Rabbits (n=3) that showed evidence of stricture development at 14 days post-injury were further subjected to urethral wall stretch using a Foley catheter (balloon inflated to 14 mm diameter for 10 minutes; Fig A; top right). Repeat dilations were performed once a week for 4 weeks. Animals were then allowed to recover and subjected to retrograde urethrogram (RUG) to confirm stricture progression. All the animals were sacrificed at 45 days post-injury. Urethral tissues were harvested and subjected to immunostaining for markers of fibrosis.
Results: RUG showed a significant increase in stricture severity after repeated balloon dilations (Fig B; right panel). Immunostaining showed strong labelling for GIV and Collagen -1 (Fig C-D; blue arrowheads).
Conclusions: Our findings confirm that this approach is a viable in-vivo model to study transurethral intervention induced fibrogenesis. It further supports our hypothesis that urethral wall stretch worsens stricture severity due to GIV/Girdin-mediated fibrogenesis. Targeting GIV pathway may be a novel strategy to prevent stricture recurrence.
Source of Funding: UCSD Academic Senate