Hypothesis / aims of study
Due in large part to damaging changes caused by inflammation during bladder outlet obstruction, bladder dysfunction persists in many patients following de-obstruction surgery. This clinically presents as persistent lower urinary tract symptoms and post-operative urinary retention. Our lab has extensively studied the mechanisms that trigger the bladder’s inflammatory response to obstruction, but the role of endogenous anti-inflammatories in the bladder, notably Annexin A1, has never been explored. In this study, we aim to assess the ability of Annexin A1 to enhance the resolution of inflammation following de-obstruction and improve functional bladder recovery.
Study design, materials and methods
Sprague Dawley rats underwent bladder outlet obstruction via proximal urethral ligation around a 1 mm (o.d.) catheter. De-obstruction was performed after 12 days and rats were randomized to treatment with 1 mg/kg/day of AC2-26 (the active N-terminal peptide of Annexin A1) in PBS or vehicle for two days. For inflammation assays, 25 mg/kg of Evans blue dye was injected IV one hour prior to sacrifice. Bladders were then weighed and Evans blue concentrations were measured spectrophotometrically. For functional assays, suprapubic tubes were placed at the time of obstruction and awake cystometry was performed two days after de-obstruction. Functional assays included a sham surgery group while inflammation assays included a no-treatment group to establish controls. The sham cohort underwent loose urethral ligature placement and subsequent removal after 12 days.
Interpretation of results
We demonstrate that the resolution of inflammation following bladder outlet de-obstruction is augmented significantly when treated with AC2-26, the active N-terminal peptide of Annexin A1. This is seen as a reduction in Evans blue dye extravasation and as well as bladder weights. Furthermore, the addition of AC2-26 results in normalization of micturition cycles with less urinary retention even when controlled for the effects of surgery.